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10 clinical trial recruitment strategies that work.

Strong clinical trial recruitment strategies start from a place of patient centricity, incorporating a variety of outreach methods designed to educate and engage potential participants. Creating a structured clinical trial patient recruitment plan before outreach begins is a smart way to ensure that the process is organized, efficient, and keeps the patient experience as the top priority.

In addition to patient centricity, time is also of the essence for clinical research recruitment. It is estimated that a delay in drug development can cost sponsors around $37,000 per day in operational costs and $600,000 to $8M per day in opportunity costs, and for patients with serious conditions, getting access to a better treatment option quickly can be vital. The clinical trial recruitment strategies below are designed to help sponsors meet or surpass their recruitment timelines and connect patients with research opportunities that are a good fit for them.

1. Get to know your patient population

When designing a medical study , considering the patient’s point of view will ensure that the trial doesn’t put unnecessary burdens on participants. To better understand patient concerns, Antidote conducted a survey to assess patients’ preferences toward types of clinical trials: observational, interventional, trials for a treatment addressing side effects, and trials for entirely new medications. With 4,000 respondents, we were able to glean useful insights regarding best practices for marketing clinical trials and what to ask focus groups before a launch.

For example, we learned that patients living with chronic conditions are often uninterested in trials for a new drug or therapy — meaning when marketing these types of trials, it can be beneficial to highlight the potential benefits of an investigational treatment compared to the current options available. When choosing a company to conduct patient recruitment , ask about how they differentiate their outreach approaches for specific trial condition areas to make sure the approach is strategic.

2. Inform health care providers about your trial

If you are conducting a clinical trial for a condition that requires patients to have a close relationship with their doctors, informing relevant medical professionals about a trial can be a smart strategy. According to a CISCRP survey, 64% of patients would prefer hearing about a clinical trial opportunity directly from their healthcare provider. 

Outreach materials designed specifically for doctors can be a great way to convey any relevant information about the clinical trial that they can share with patients. If your site has relationships with local hospitals or providers in the area, leverage your network to increase awareness about the trial among the staff.

3. Connect with nonprofit partners and patient advocates

Getting connected with relevant nonprofit partners and others in the patient advocacy space can be a way to reach patients and have them receive information about your clinical trial from a source they already know and trust. Some organizations may promote a trial for a fee, while others may offer free or discounted promotions — but because this outreach is so targeted, the return on investment is typically high.

Antidote’s Partnerships Associate, Valerie Tufaro, said: “Patient Advocacy Groups are trusted resources to patients and care partners for information on current research, treatment options, and overall day-to-day support. They have a direct line to patient feedback and can speak to what the patient needs are at any given time, while also speaking to how their needs change as research advances. This information puts them in a unique position to be at the forefront of developing new patient engagement methods and increasing patient participation in research.”

4. Work with a patient-centric clinical trial recruitment company

Working with a company that focuses on patient centric recruitment can alleviate many of the struggles that often delay medical research. Finding eligible participants is one of the biggest challenges of conducting clinical trials, but a good clinical trial recruitment company will know how to think strategically about an outreach plan.

When assessing a clinical trial recruitment company, understanding how they get to know the patient population, how they communicate with patients, and what relationships they maintain with advocacy groups can help you ascertain whether their methods will connect you to engaged individuals who are likely to be interested in participating in research.

5. Utilize digital recruitment campaigns

Digital advertising provides an ideal opportunity to go beyond existing site databases in order to meet patients where they are . Making use of online outreach can publicize a trial to the 3.5 billion social media users in the world , and with interest- and keyword-based targeting, marketers can easily find patients who are actively searching for treatment options and condition information.

Furthermore, cookie tracking and retargeting can provide multiple touchpoints for a patient to learn about a trial, increasing the time they spend considering taking part. While a research site may only make contact once or twice, online advertisements can get in front of the same patient multiple times through retargeting campaigns.

6. Provide localized lab service options

Using technology to be innovative with clinical trial patient recruitment has been an important focus as of late, especially since the COVID-19 pandemic showed how useful virtual clinical trial recruitment tools could be. Virtual trials make it easier and safer for patients to participate in research, and stop an individual’s location from being an obstacle to participation.

If a trial is decentralized but still requires in-person aspects, it is important to ensure that any visits can be conducted locally so patients can truly participate from anywhere. Partnering with local lab services can also speed up recruitment for complex studies that require patients to have lab values tested in order to qualify for the trial.

7. Contact patients who are already interested in trials

Contacting patients who are not qualified for a trial wastes time and money, and can be disheartening for the individuals, too. Reaching out to patients that have already shown an interest in clinical trials and having information that indicates that they are likely to be eligible can create a more streamlined process for all involved.

Some services, such as lab test and Electronic Health Record (EHR) companies , have access to blood test information and other patient data so trial sponsors can screen for inclusion criteria in advance. Additionally, working with a clinical trial recruitment company that maintains a patient database can give sponsors access to a large population of patients who are interested and likely to be eligible to take part.

8. Screen for multiple trials at a time 

Sponsors often run multiple trials in the same condition area, so screening for all of them at once is a smart strategy to save time and cost. Patient recruitment companies often employ the use of online pre-screeners, which can simplify this process for patients and collect valuable information at the same time.

Based on a patient’s response to location and condition questions, the pre-screener can then route them to questions related to the inclusion and exclusion criteria of multiple trials. This can make the process more user friendly for patients and provide sponsors with helpful information in the process.

9. Use patient follow-up services 

Though a clinical trial is a major focus for a sponsor, for patients, signing up for a trial may be a task that is continually pushed to the bottom of a long to-do list. Automated follow-up services, such as texts and emails, can nudge patients to take the next step without being invasive.

Some trial recruitment companies will also provide site follow-up services so sponsors can easily stay on top of the progress patients have made and flag sites that are slow to respond. This can save money by reducing patient drop-off rate and recruitment timelines simultaneously.

10. Keep patient retention top of mind

Oftentimes, patient retention is considered a separate project by trial teams — but for a strategic approach, it is best to consider recruitment and retention in tandem. For example, engagement through electronic patient-reported outcome tools ( ePRO ) can help patients feel more committed to participating in a trial.

Allowing for in-home visits or remote doctor check-ins is a great way to improve retention and reduce the likelihood that a patient will drop out due to inconveniences. Additionally, ensuring that site personnel are well-trained in answering questions and providing excellent service can make sure every patient experience is a positive one, meaning they will be more engaged with the trial as a whole.

An Antidote, we use a diverse approach we call precision recruitment to quickly identify eligible patients and beat timelines. Learn more about our methods by downloading our case studies.

We save clients 6 months in outreach time – learn how:

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Participant Recruitment, Screening, and Enrollment

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Participant recruitment and retention are key success factors in a clinical trial. Failure to enroll the required number of participants in a timely manner can have significant impact on trial budget and timelines, and data gaps due to under-recruitment or early dropout of participants may lead to misinterpretation or unreliability of trial results.

Prior to the start of a trial, a thorough recruitment plan should be set up, considering the screen failure rate, the potential need to replace early dropouts, and the geographical distribution of participants, timelines, and budgetary constraints. Understanding how to calculate the recruitment rate based on the number of enrolled participants per site per month will help in assessing the probability of successful recruitment. In addition, recruitment planning tools and services such as comparison with benchmarking data from analogous historical or ongoing trials, simulation tools, and specialist service agencies may support the setup of a robust recruitment plan. Risk factors with the potential of leading to under-recruitment, over-recruitment, or recruitment of unsuitable participants should be identified upfront to allow risk mitigation as far as possible, e.g., through protocol amendments or increasing the number of participating centers. Evaluation of the most appropriate channels to identify and contact trial candidates will ensure optimal turnout in relation to the financial and resource investments. Strategies for participant screening, enrollment, and retention are reviewed in this chapter.

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Wermuth, P. (2022). Participant Recruitment, Screening, and Enrollment. In: Piantadosi, S., Meinert, C.L. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52636-2_38

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Clinical Trial Recruitment

Recruiting patients to enroll in clinical trials requires a methodical approach. Whether it be a new drug, therapy or device entering the market, the pharma companies launching these treatments have to effectively recruit the right patients. (Clinical trials are essentially research studies conducted to collect the necessary data that quantifies the safety and efficacy of a proposed treatment.)

Research shows that as much as 86% of clinical trials do not reach patient recruitment deadlines. This can lead to increased costs, drained resources and inefficient use of resources, unmet needs of stakeholders, and unmet drug launch deadlines. 

Meeting patient recruitment deadlines is difficult for a number of reasons. Pharma companies must be able to reach prospective patients to educate them about the clinical trial and encourage them to participate. To become eligible for the clinical trial recruitment process, prospective patients have to meet specific eligibility criteria, including a number of inclusion criteria and exclusion criteria.

Any initiative that involves multiple stakeholders (HCPs, sponsors, and clinical research teams) can be challenging. Pharma companies must meet the needs of each stakeholder without sacrificing anyone’s needs. Deadlines are tight during clinical trial recruitment, and individual goals need to be met throughout the timeline to stay on track for a drug or treatment launch. 

Communications must be streamlined, effective and personalized for individual target audiences. Pharma companies also need to ensure physician awareness of the available clinical trials and ensure that eligibility criteria are practical.  

For pharma companies to maximize patient enrollment, they require an expert recruitment strategy that educates key stakeholders through effective digital and traditional marketing.

Evolving Nature of Clinical Trials

Over the years, methods for engaging and educating patients about clinical trials have transformed. 

The devices and platforms patients use to research available clinical trials have ultimately shifted from traditional to digital. Previously, information about clinical trials was often spread through direct mail and through patients’ appointments with their healthcare providers. Face-to-face, traditional methods of patient recruitment have been supplemented and many have been replaced with digital media methods, such as e-mail marketing and search engine marketing.

With the rise of digital marketing and increased access to clinical trial availability, patients are also now more involved in the recruitment process than ever before. Recruitment efforts have taken a patient-centric focus to align with recent changes in patient engagement. Instead of seeking information face-to-face from their healthcare providers, friends or family members, patients are informing themselves through the internet. Patients are searching for up-and-coming treatments or therapies, and sharing experiences with their peers on various websites and social media platforms. 

Pharma advertising agencies and marketers have shifted their approach to accommodate this change in behavior—which means taking to the internet to reach eligible patients where they’re present.

Constructing an Effective Clinical Trial Recruitment Process

To increase recruitment rates, pharma companies must know where to reach eligible patients and how to reach eligible patients. Once potential patients are identified, they must undergo a pre-screening process to confirm that they meet the inclusion criteria and exclusion criteria. Patients then need to be connected with a clinical research site and supported through a strategic follow-up process that promotes appointment scheduling while the patient, or lead, is still “warm”.

1. Identify patient population media habits.

First of all, who is the patient population for the clinical study? In this phase, market research is performed to understand the specific media consumption behaviors of the patient population. What channels are they currently using? What platforms are they using to search information or connect with other patients in their community?

Identifying the patient population is critical for choosing the appropriate channels to market clinical trial recruitment needs, as well as tailoring the message and personalizing it to resonate with the intended audience. What pieces of information are most important to that specific patient population? 

Because many patients are still learning about clinical trial patient recruitments through their healthcare providers, it’s beneficial to identify the HCPs currently diagnosing and treating the condition of the clinical trial. What type of HCPs are involved with the condition—physicians, nurses, behavioral therapists? This can help you spread information about recruitment needs and provide valuable insight into the media behaviors of other patients in the community. 

Where are these patients searching for information—social media, online advocacy groups, support groups, print materials? Develop a marketing strategy to advertise on these frequented channels. Market research will tell you whether paid advertising, search engine advertising, or traditional print advertising is best suited for your audience. 

2. Develop a pre-screening and screening strategy.

Once the potential participants have been identified and reached, trial sponsors and recruitment leaders need an effective strategy to screen these patients. 

What eligibility criteria need to be assessed to ensure patients are qualified for the clinical trial? Which qualities or features must they have (inclusion criteria) and which qualities or features must they not have (exclusion criteria) to be eligible for the clinical trial? Patients are often pre-screened by research organizations, over the phone or through the internet, before the face-to-face screening process. There are call centers and research sites dedicated to this step of the process. 

If patients meet the necessary criteria during the pre-screening process, they’ll move forward to an in-person screening process. The screening process often includes a physical exam and a review of the study participants’ medical history. Mental health assessments and lab testing are also common during the screening process. 

3. Connect patients to their study sites. 

Pharma companies must aid the process of eligible patients reaching their study locations to ensure successful recruitment. This process should be as simple and user friendly as possible, to avoid eligible patients dropping out of the process before reaching the research location.  

To streamline the process and encourage a seamless transition from screening to site selection, companies need to develop a system to be expeditious in connecting patients to their sites. One common technique used in this stage is called  a “warm transfer.” At the end of the screening process, when a patient is still on the phone with the call center representatives or trial sponsors, they may three-way call the research site to connect the patient with the research team. 

Call center operators and trial sponsors should also be prepared to share information about the soonest available appointments for patients to attend. To successfully recruit patients, the research team must do everything they can to facilitate the appointment scheduling process and support patients from the pre-screening stage up until they attend the site appointment.

Any helpful materials that include information about the appointment (listing the date, time, and location of the research site) should be given to the study participants too. 

4. Follow-up with patients and monitor the turn out. 

The time between patient referral to patient enrollment is precious. Sponsors and research teams need to minimize this time in order to maximize the number of patients successfully recruited. Monitoring patients throughout the recruitment process and offering the support and information they need is essential to retaining as many patients as possible. 

The follow-up process is often done through an online portal or software that enables the sponsors and research team to monitor participants as they progress through the clinical trial. These specialized systems can also show data on the number of patients successfully recruited per research site. Data from these systems can drive insights into whether the inclusion and exclusion criteria are practical, and which specific locations are in need of more participants. 

Part of the follow-up process is providing continued support for patients, whenever necessary. This includes after-hours support, support with appointment rescheduling, as well as streamlining resources and information to ensure a seamless process. 

On average, clinical trial patient recruitment rates are considerably low. Once eligible patients are identified, the pressure is on to retain these patients and ensure that they meet all milestones throughout the clinical trial process. 

Call center operators must be easily accessible to patients throughout the process. They should be available to answer questions, provide information, reschedule appointments and follow-up with patients every step of the way. 

How Good Apple Can Help

Securing study participants and retaining them from patient referral to appointment follow-up is a challenging undertaking that requires a strategic approach. 

Overcoming the common challenges of clinical trial recruitment (meeting strict recruitment timelines, meeting the needs of key stakeholders, reaching prospective clients where they’re receptive, ensuring physicians are aware of available clinical trials, and streamlining communications between HCPs , trial sponsors and patients) requires expert solutions. We have fine-tuned our approach from years of experience enhancing patient retention in clinical trials through comprehensive, custom marketing strategies that work to mitigate the common challenges of the patient recruitment process. 

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Recruiting for clinical trials: patient-centric clinical trial recruitment strategies that work, introduction.

The current model of clinical trial recruitment is inefficient. This is reflected clearly in statistics such as 80% of clinical trials in the US being delayed due to issues with recruitment and 85% of all clinical trials failing to recruit enough patients [ 1 , 2 ]. Delays in clinical trials attributed to recruitment challenges result in substantial financial, temporal, and resource costs for sponsors. Cancellation of clinical trials due to failure to recruit sufficient patients represents even larger losses.

Over 75% of the general public report a willingness to participate in clinical trials [ 3 , 4 ], yet insufficient patient recruitment is the leading cause of early termination in randomized controlled trials (RCTs) [ 5 ]. So, what are the reasons for this disconnect? In an actively recruiting clinical trial, the recruiter is carrying out the following tasks: identifying potentially eligible participants and reaching out to them; informing them of the trial, the protocol, and other trial aspects; pre-screening; verifying patients’ understanding and confirming voluntary participation; conducting screening procedures; and enrolling participants [ 6 ]. Thus, clinical trial recruitment is much more than simply gaining participant interest; it’s also about understanding participants, connecting them with opportunities that are most suitable to their individual needs, educating and engaging them, and building positive rapport.

Clinical trials that prioritize patient-centric practices may see better patient recruitment and retention rates, potentially leading to faster achievement of recruitment targets compared to trials that do not prioritize patient-centered approaches. In this article, we will discuss how patient recruitment for clinical trials can be improved through a lens of patient centricity. The patient-centric perspective can be applied to the entirety of the patient funnel, from engaging initial interest to randomizing and informing patients, as well as to building a trusted community of research participants. This article will provide recruiters with a comprehensive set of actionable strategies that go beyond the basics and which can be directly implemented into the recruitment process. The strategies are organized into 3 main stages: preparing the trial for recruitment success, recruiting patients for the trial, and optimizing the recruitment strategy after recruitment begins.

Pre-recruitment: Preparing the trial for recruitment success

Protocol design

Effective methods for increased patient recruitment in clinical trials should be implemented as early as the protocol design stage. In patient-centric strategies, patients are viewed as key stakeholders rather than simply participants. It follows that patients should be engaged, consulted with, and considered at every stage of decision making, including the design of the trial protocol. Reach out to patient advocacy groups and give them a seat at the table. If patients are given a voice, recruiters and sponsors can better understand their needs and their concerns going into a clinical trial, and can take those considerations into account during protocol design. A patient-informed protocol and trial design can help patients feel safe and more confident in their decision to participate.

Another area for opportunity lies in the eligibility criteria. Lasagna’s Law posits that investigators tend to overestimate the number of eligible participants. Unfortunately, in reality, eligibility criteria are often too specific and end up limiting the pool of potential participants [ 7 ]. If the trial has been delayed for too long due to insufficient recruitment, investigators might amend the protocol to increase participant inclusivity, but this can lead to variation in participant populations pre- and post-amendment. One study of 3,400 clinical trials found that 40% of them amended trial protocols after the first subject visit, causing, on average, 4 month delays [ 7 ]. In one third of these cases, the amendments were found to be avoidable [ 8 ]. More thorough consideration of design elements in the trial protocol can prevent the need for amendments and minimize trial delays.

Eligibility criteria for clinical trials are also sometimes unnecessarily exclusionary; a need for efficient REB (research ethics board) approval tends to create a pattern of reusing old protocols and trial designs that have been previously approved by the REB [ 9 ]. However, this creates a reliance on predetermined eligibility criteria that might not be relevant to each study. Eligibility criteria may also unintentionally screen out marginalized communities, disregarding their disease incidence relative to that of the overall population ( Power , 2022). Identifying and challenging unintentionally exclusionary criteria could increase the number of eligible participants as well as decrease recruitment time.

Accessibility

Trial accessibility is a major barrier to recruitment and participation that can take many forms. Structural barriers seem to be one of the main reasons for why patients don’t participate in clinical trials [ 10 ]. Trial site locations are a primary consideration; in the US, 70% of people live over 2 hours away from a major research site [ 11 ]. This silos the pool of eligible participants - it excludes patients who live in rural communities, as they either aren’t being contacted for participation or can’t physically come to the research site. Likewise, clinical trials tend to be conducted at the same large hospitals and sites frequently selected by CROs and sponsors, thereby attracting repeat patients and limiting exposure to potential new pools of eligible participants. Expanding trial site locations, as well as replacing sites with only moderate performance records can be a potential solution [ 10 ]. Including trial sites that are reachable by foot or public transit for a wide demographic (for example, those located in large cities) can greatly increase accessibility. Consideration should also be given to how the trial design can be improved to increase geographical accessibility. Questions such as “how often will the patient need to access the site?” and “can these travel requirements be minimized?” should be considered. In the following section, we discuss how components of decentralized trials can address some of these questions.

Remuneration for participants can also help ease accessibility issues. It is often difficult for people to take time off work to travel to the site for participation, especially on a regular basis. If patients need to travel long distances to reach the site, will travel-related costs be reimbursed? Will they also receive compensation for lost work hours? Ideally, participants can be assessed for reimbursement on an individual basis; someone who is unemployed and could walk to the travel site within a few minutes would naturally incur fewer costs related to travel and time off work as compared to someone who has to leave their job early and take a cab to the site. Another way to increase accessibility is by accommodating childcare; if parents are reimbursed for the costs of childcare or if trial sites have on-site childcare services, it would make participation easier for those with dependent children.

The issue of accessibility also takes non-physical forms such as information accessibility. Up-to-date information on current clinical trials, their location(s), eligibility criteria, and other important factors for participation may be difficult for participants to find and understand. Power is aiming to address this through a patient-friendly platform that increases accessibility by centralizing clinical trial information in a way that’s easy for patients to find and understand.

Finally, when expanding trial locations, consideration should be given to where new sites will be situated in relation to the expected patient population. If a site is located in an area that has a high percentage of particular racial or ethnic minorities, the informed consent form can be translated into the language(s) that the local population speaks. As an example, for a trial site located in a neighborhood with a predominantly Hispanic population, then the site might have better success with patient recruitment if it has Spanish-speaking staff on the team and has ICFs available in Spanish as well. This can further help enhance participant understanding of the trial, thereby increasing the rate of consent. This strategy can be extended to different touchpoints throughout the trial, not just the consent form. For example, in terms of overall staff diversity, participants are more likely to engage in clinical trials if they see their diversity reflected in the trial staff, including investigators, physicians, trial coordinators, and personnel at the site ( Power , 2022). Power has authored a whitepaper that has actionable recommendations for how recruiters and investigators can ensure that they’re recruiting a sample that appropriately reflects the diversity of the target population. Thoughtful consideration for ensuring diversity lends itself to a strong investigator-participant rapport, which can improve participant retention as well as recruitment in future trials.

Leveraging decentralized trial components

Clinical trial decentralization involves bringing the trial to the patient, rather than demanding the patient go to the trial [ 12 ]. The adoption of decentralized clinical trials (DCTs) has been accelerated by the Covid-19 pandemic, as physical access to trial sites was reduced and virtual practices became increasingly normalized. In fully decentralized trials, all of the following take place without direct contact between participants and the research team: participant recruitment, administration and delivery of the study intervention, and monitoring and reporting of health outcomes and measurements. Trials can exist anywhere along the gradient between fully centralized and fully decentralized, by selectively incorporating components of DCTs such as telehealthcare, partnering with local service providers, wearable medical devices, virtual interfaces for data recording, and home-care and home-delivery services.

When trial sites partner with local clinics, lab services, and pharmacies, participants can utilize local service providers in their community to get prescriptions filled, complete screenings, and have bloodwork, tests, and check-ups performed, the results of which can be shared digitally with the trial team. Healthcare apps allow patients to monitor and input their own data on a daily basis, and also serve to record adherence to treatment plans. Similarly, wearable devices allow for real-time and continuous data collection, omitting delays from patient reporting. Digital screening services allow patients to check in remotely while at home or at work, increasing the ease of participation. Finally, at-home care and at-home delivery services are easy ways to equip patients with the care, medicine, and resources they need to receive the treatment intervention without having to travel to the trial site.

Any new tools should be easy to use, familiar, and accessible to the patients, so they do not unintentionally replace the old barriers with new barriers in the form of access to technology. In one survey, 98% of patients revealed satisfaction with telemedicine services; the key is to use these tools appropriately and effectively [ 12 ]. Aiming to make the patients’ trial participation experience easier is very likely to increase the success of both recruitment and retention. Further, by engaging the broader community such as local pharmacies, the workload is decreased for site investigators who would normally be responsible for such activities.

Recruiting for clinical trials: Six patient-centric recruiting strategies

In this section, we outline six strategies for effective, patient-centric recruitment that sponsors and investigators can incorporate.

1. Understanding the patient population for a given clinical trial

One important aspect of a successful recruiting effort is concise identification of the target audience so that messaging can be tailored. It’s essential to understand certain things about the trial’s target patient population, such as how patients speak about their condition, where patients go to look for information or help, and what might motivate patients to search for or participate in a trial. Consider asking some of the following questions:

• What demographic of the population is most affected by the condition being investigated?
• What patient health status is required (i.e. healthy, or moderately or severely affected by a given condition)?
• How does the nature of the condition being studied impact the daily lives of the patients?
• At what stage of their healthcare journeys are the patients?

Patient in relation to others

• What’s the disease incidence? Is it a rare disease? Is it a common disease?
• Is it hereditary?
• Do the patients tend to rely on caregivers?

Patient in relation to trial

• How much previous experience do the patients have in clinical trial participation?
• What is the nature of the clinical trial? Is it observational or interventional? Is it an acute intervention (i.e. surgery or treating a flare-up?) or a long term intervention (i.e. prolonged use of pharmaceuticals)? Does it investigate a new treatment or aim to confirm the efficacy of existing interventions?
• What are the main concerns patients might have about participating in clinical trials?
• How could participating in this study affect the personal lives of the participants?

The next step is to utilize this information to adapt outreach efforts. For example, if the study population is elderly, are there more suitable means of outreach that are more accessible to those patients? If patients are usually filling prescriptions online, digital marketing campaigns might be more suitable for catching their attention. If they’re going in person to the pharmacy, physical posters might be a better option.

At this stage, it’s also important to consider the main deterrents expressed by patients as to why they choose not to participate in clinical trials. For example, one concern may be fear of being randomly assigned into a treatment condition that the patient perceives as harmful or inferior to the alternative treatment [ 13 ]. If the trial has a placebo arm but will offer the intervention to the placebo group once data collection is completed, that would be an important message to communicate.

Overall, outreach strategies should remain personable; patients want to feel heard and valued as an integral part of the clinical research process.

2. Choosing the right mix of recruitment strategies for the clinical trial’s needs

Once the target population is well characterized and understood, it is easier to choose the recruitment platforms that are best suited for reaching the desired audience. Below is a list of strategies that could be used:

Physician referral networks

• One study revealed that 64% of patients would prefer to hear about clinical trial opportunities from their primary medical practitioners [ 14 ].
• Recruiters can build a network of healthcare practitioners by reaching out directly to clinics, offices, and professionals in the relevant geographic area(s), as well as specialists in certain fields.
• A set of trial messaging can be prepared for healthcare practitioners to share with their patients if interested.
• Recruiters can act as a research liaison, making themselves available to patients who express interest via their healthcare practitioner.

Patient advocacy groups and non-profit partners

• Trial sponsors and sites can establish themselves as a positive and consistent presence in the patient community, and share educational resources. Being a consistent source of information and opportunity and allowing patients to reach out can help in establishing this presence as well as trust.

Analytics platforms

• A large share of information on clinical trial reports is buried in unstructured text, rather than being searchable or structured [15]. Analytic platforms can uncover and synthesize high volumes of information that can provide insight into patient demographics, how to reach them, and how to optimize a given recruitment strategy.

Digital recruitment campaigns

• Online platforms can be highly effective tools for recruiting potential participants.
• Social media campaigns allow recruiters to cast a wide net and tailor their messaging to be as broad or as specific as needed.
• Digital advertising may involve diverse platforms such as: Facebook, Instagram, Twitter, Reddit, and Google amongst others.

Physical, traditional media outlets

• Newspapers, magazines, billboards, posters, radio spots, and fliers.

Patient-centric recruitment platforms

• Patient-centric recruitment platforms like Power provide a platform for patients and researchers to connect seamlessly; patients can search for clinical trials for their specific condition and in their location and researchers can connect with them directly through the platform

3. Providing clear information so patients can make an informed decision

The link between clear communication and successful recruitment and retention can’t be underestimated. One reason why patients may withdraw from clinical trials is not understanding the trial design or protocol, along with confusion around what’s expected of them [4]. There are many strategies to ensure patients are educated enough to make an informed decision. These include:

1. Avoid jargon: Use plain language when possible, avoid complex medical and scientific terms, and ensure that potentially confusing terminology is explained.

2. Focus on active consent, not passive consent: Simply presenting documents such as consent forms to patients transfers the burden of understanding to them. Explain what’s contained in the document, emphasize the importance of reading it in its entirety, and indicate who they can speak to if they don’t understand it or if they require a verbal explanation.

3. Be transparent and specific: Provide patients with step-by-step directions regarding what is expected of them pre-, mid-, and post-trial. Offer this information willingly, not just upon request.

4. Verify understanding: Once patients have been provided with information, questions can be asked to ensure they’ve understood the messages. Consider asking them to explain the most important aspects back, and be present for the learning process. Establish a point of contact (an individual or group of individuals) on the trial team that is accessible to patients to answer questions, address comments, and clarify concerns. Provide this contact information to the patient so they don’t feel that their opportunity to learn about and understand the trial is limited to one meeting.

5. Share extra resources: Give patients the tools to explore topics further if they are interested or don’t feel they have enough information to make an informed decision. Power is an example of an accessible and comprehensive resource that connects patients to information on medical conditions, treatment interventions, completed and ongoing clinical trials, and more, so patients can better understand their role as a participant in clinical research.

4. Making eligibility criteria for the clinical trial easy to understand

A 2021 study revealed that up to 7% of eligibility criteria for studies on clinicaltrial.gov were completely incomprehensible [16]. Some general rules for improving the clarity of eligibility criteria are to ensure that they:

• Are binary (i.e. they all have a ‘yes’ or ‘no’ response)
• Include a type of assessment (which can be checked by referring to previous medical notes)
• Are anchored to a timeline with the trial (i.e. within x amount of days from the trial start date)

Likewise, it’s recommended to remove redundancies to enhance clarity. For example, an exclusion criteria of ‘not meeting all the inclusion criteria’ is not necessarily the most straightforward to convey this point. Replace medical jargon with common/layman’s terms where possible, and if not possible, make sure to explain the terminology. Here are some examples of improving clarity and comprehension:

• Rather than ‘women ≥ 50 years of age’, try ‘patients of female sex age 50 and older’.
• Rather than ‘unifocal breast cancer’, try ‘unifocal breast cancer, meaning there is a single tumor in the breast’.
• Rather than ‘Eastern Cooperative Oncology Group (ECOG) 0, 1’, try ‘Eastern Cooperative Oncology Group (ECOG) is a standardized performance scale that measures a cancer patient’s level of functioning and independence. This is a 6-point scale (from 0-5). Participants must score either 0 or 1 to be eligible for participating, indicating high levels of functionality and independence’.

5. Creating a positive experience for the patient

Participation in a clinical trial is a journey for the patient, and recruiters can focus on key touch points throughout that journey. This includes ensuring that the lead investigator and the site staff are approachable, available, and carry positive demeanours. This might be especially important when working with a group of participants for whom clinical trials are a novel experience. If participants feel that staff are not available or interested, they are more likely to withdraw and less likely to return as a participant for future clinical trials. It’s equally important that the medical practitioners administering the intervention are enthusiastic, as investigator enthusiasm has been cited as one of the most important factors for successful recruitment at the trial site [ 7 ].

From the first call or point-of-contact to educating the participant, screening and onboarding, administering interventions, and follow-up visits and check-ins, the patient should feel valued. Patients deserve to be informed at every point in their journey, presented with easily digestible information, and should feel comfortable to ask questions, which requires staff that are approachable. As mentioned previously, one key consideration here is to hire diverse site staff. Historic mistrust of the healthcare system within marginalized communities can be a barrier to participation; one way to mitigate this is to ensure the diversity sought for amongst patients is reflected in staff.

6. Keeping patients engaged in the clinical trial process

Patient retention is as important as initial patient recruitment. Roughly 30% of patients drop out of clinical trials [ 17 ]. Patient dropouts in clinical trials can result in significant financial losses, as well as losses of valuable time and data, and may affect the reputation of the trial. By keeping patients engaged throughout the clinical trial process, retention can be maximized, which translates into improving the completion and success rate of clinical trials. Some things that can help include:

Clear and frequent communication: Clinical trial staff should establish clear lines of communication with trial participants from the outset, ensuring that they understand the requirements of the trial and have access to support if needed. Regular check-ins and updates can help build trust and foster a positive relationship between participants and staff.

Personalized support: Depending on the trial's resources and available personnel, staff may consider providing dedicated support to each participant, such as a patient support liaison. This may help participants feel more connected to the trial and ensure that their individual needs and preferences are addressed.

Flexibility: Trial staff should be flexible and accommodating when scheduling appointments, tests, and follow-ups, taking into account the needs and preferences of each participant.

It’s key to remain in contact with participants throughout the entire duration of the clinical trial (and often even after), so that they feel valued and welcome to express any concerns they may have. Establish consistent touch points (times) for members of the research team to check in with participants. This could be done through phone calls, emails, regular mail, apps, or video calls.

Sponsors should also strongly consider utilizing patient follow-up services. Follow-up is essential both for monitoring patient health and for receiving feedback about the trial experience. Ask patients what worked for them and in which areas there was room for improvement. Understand the positives and negatives of their experience and integrate that feedback into future trials.

Optimizing the clinical trial recruitment strategy in real-time

Recruitment strategies should be monitored and optimized as recruitment is in progress. Continuously evaluate progress to stay on track - What is the clinical trial accrual target, and is the current progress on track toward meeting it? If not, why? There are different ways to calculate clinical trial recruitment rate, with the best method being dependent on the metric(s) selected for monitoring. One way is to assess the number of patients recruited at each site over a given period of time, indicating the success of individual trial sites. At the trial level, the general method is to divide the total number of patients recruited thus far by the number of trial sites recruiting, then divide that by the period of time elapsed since recruitment began. This will give an accrual rate in the form of the number of patients per site per month/week/etc. Assessing recruitment progress in an ongoing fashion, according to the metric(s) that are identified as being most relevant to the specific trial and its recruitment goals, may allow investigators and recruiters to identify areas for improvement early enough that acute changes can be made to speed-up recruitment and reach the original recruitment target on time [ 18 ].

Key takeaways

Research findings indicate that current approaches for recruiting and retaining patients for clinical trials are not optimal. Optimization of recruitment strategies begins as early as protocol design; engage patients in this process and ensure they are valued as key stakeholders. Increase the physical accessibility of trial sites; shift from clustering all trials at large research institutions to creating community connections so that patients can rely on their local services as a liaison to the research team. Integrate components of decentralized clinical trials, like delivery services, at-home care, and healthcare apps, so patients are less burdened by the time and cost of traveling to and from the trial site. Increase communication by appointing a designated patient liaison on the trial team, hiring diverse, multilingual site staff, avoiding medical jargon, and being specific and upfront about expectations and resources for patients.

Once it's time to engage in active recruitment, ensure patients are made aware of trial opportunities by understanding the specific needs and characteristics of the key population and providing them with information based on those needs. Leverage communication and media platforms that the target population for the trial normally engages with.

Once participants’ attention is captured, efforts should be made to ensure they feel welcomed as well as informed and educated about the trial itself. Eligibility criteria should be written in plain language, and medical terminology should be explained clearly so patients can better understand why they’ve been recruited and what the study involves. Likewise, the informed consent process can be used to be specific and clear regarding the expectations of the patient and to double check to make sure they’ve understood. Creating a positive experience for the patient, where they feel heard and valued, is paramount to reducing dropout rates. Finally, establish open lines of communication between trial staff and patients; check in with patients, send reminders, ask for feedback, and accommodate their needs. Keeping patients engaged for the duration of the trail will aid in participant retention.

Finally, once the initial recruitment process has begun, the recruitment strategy can be actively monitored in order to make adjustments on the fly. Identify successes and weak points. What strategies are successfully engaging the most patients? Can more resources be allocated to those strategies to enhance recruitment? Are any of the strategies failing to provide tangible results, and if so, can they be dropped altogether to refocus resources on strategies offering better returns? Ask for ongoing feedback from the research and site staff, as well as the patients, and aim to implement it in a timely manner. Utilizing a combination of the tactics outlined in this article can help increase patient recruitment.

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A 4 Step Clinical Trial Recruitment Plan to Attain Your Sample Size

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Nick has over 15 years experience in clinical and health research participant recruitment.

Step 1- Determine and communicate the benefits of participating in the study

Step 2 – analyze the study design’s impact on recruitment, step 3 – create a detailed forecast, step 4 – create a marketing strategy.

Recruiting patients for clinical trials can be tedious and difficult, often requiring a lot of time and money.

And last-minute patient recruitment can be a nightmare as well as a poor approach to meet your trial recruitment goal.

Therefore, recruiting successfully for a clinical trial requires a well-managed and thorough clinical trial recruitment plan template.

The more time you reserve to map out the enrollment process, the better equipped you will be to handle unexpected things. With careful research and advanced planning, you’ll get a better outcome.

Pro Tip: Planning is critical if your study is to be completed on time and within budget. If you’d rather have this step completed for you–you can request a recruitment plan from us that’s tailor-made for your study.

In this post, we’ll outline the steps to create an effective clinical trial recruitment plan.

It’s important to take time to research and understand your potential participants. This is a basic rule, yet it is sometimes ignored. Understanding your participants can provide a great deal of insight for how to effectively reach out to your potential patients.

Learn the real reasons that motivate people to join your study. Is it because they are looking for a new treatment? Or is it because they don’t have health insurance and are looking for medical care at no cost?

Next, decide how you’re going to compensate participants. Develop a budget to promote the study, as well as to reimburse the patients for travel and inconvenience. What are the potential fees for advertising? Will you compensate your patients through travel allowances, gift cards, or stipends for their absence at work?

Be transparent and have a well-thought-out plan. This can present your study in a legitimate way and avoid any serious misconceptions. It’s imperative that everything is clear and concise.

Determining eligibility criteria and study design are major parts of your trial. These steps are a major undertaking and serve as the core of the study. That being said, there are important things to contemplate as you set out the roadmap for your clinical trial.

Having a clear design and straightforward guidelines for your study will give you a clear understanding of where you may need to make adjustments. And adding the step of appraising the study design’s effect on patient recruitment is an important addition to your patient recruitment plan. If there are parts of your design that will make clinical trial recruitment difficult, consider mending your plan and process.

For research, everything is about data. Yet when it comes to patient recruitment, planning, or marketing, research staff tend to forget to apply their knowledge of simple math. It’s critical to create metrics during the design phase. This helps you measure your clinical trial recruitment plan against your executed campaign and the associated results.

An Illustration

Your goal is to conduct a clinical trial about type 2 Diabetes and the study requires 100 patients.

It’s been estimated that about 20% of people drop out of a given clinical study. This means you would need: 100 x 120% = 120 people should be screened to achieve enrolment requirements.

Moreover, there are various criteria to fulfill, not just whether the patient is diabetic. For example, viable patients must not have any other pre-existing conditions, must meet maximum or minimum bodyweight requirements, and so on. Once you’ve considered all the stipulations, you should expect a small fraction of screened patients to be eligible for your study.

Projecting for Success

Let’s consider a hypothetical scenario. Assume that in order to gain the 100 participants you need from above, you will pre-screen candidates – either by phone or through online surveys. Those that qualify are then physically screened in a first appointment to determine final eligibility. Of those patients, let’s assume that only 30% of the candidate pool truly fit the requirements to participate in your clinical trial.

Based on the initial figures above, this is:

120 ÷ 30% = 400 people

From a written perspective, this equation reflects the number initially screened to allow for patient dropout, divided by the percentage of patients that will be truly eligible. This equals the number of people that responded to an ad and who are interested and therefore should be initially screened via phone or an online survey in order to glean enough participants.

You should attempt to predict multiple varying scenarios.

If the benefits of enrolling in the study are significant, assume that many patients would be interested in participating. Assume you will need to screen at least 50% more candidates (150% of your initial goal of 400 patients) to achieve enrolment goals: 400 x 1.5 = 600 people that should be screened to achieve participant requirements.

If the benefits are somewhat appealing, double the number: 400 x 2 = 800 people that should be screened.

If the reasons to join are not very appealing, triple the number: 800 x 3 = 2,400 people that should be screened.

As you can see, for every 100 patients needed to complete your type 2 Diabetes study, you’ll need to screen a total number of 626-1,251 potential participants.

Try to work backward and think about the numbers. Anticipate different scenarios and back them up with various solutions. You might not have the answer for everything, but well-prepared metrics will help you arrive at more solid answers and provide invaluable experience on future studies that involve similar patient pools.

A detailed recruitment and enrollment forecast for your study will help you meet your target sample size. If you’d like the number of potential participants forecasted for your study our Due Diligence analysis is backed by empirical data from similar studies we’ve recruited for in the past. You can request one here at no cost.

How can you get 626 or 1,251 patients? Marketing plays an important role in finding and retaining patients. However, many researchers fail to realize how difficult it is to get people’s attention and thus neglect this step in their patient recruitment plan.

Some Just Don’t Want to Know You

A common mistake in the enrollment process is the failure to factor in the number of non-responses during clinical study recruitment. For instance, let’s say you need 800 patients for your trial. You have access to a mailing list of 1,000 patients through a partner who’s able to send an email about the study. Can you brush it off and move on to the next task?

No; the work is not done yet.

Studies show the average email open rate is about 20% . This means you’ll be missing out on informing 800 people from that mailing list because they never read the email and therefore, are completely unaware of your trial.

What about the 20% who open the email? Assuming the benefits of participating in the study are very appealing, what is the major factor that will fail to convert them?

The Major Factor to Gain Conversions

The answer to the question above is simple: the email’s content. The information sent in the email body can make a huge difference.

Stick to this rule: write really good content.

Put a lot of effort into writing the ads. Think about the positives of participating. (Remember, it needs to adhere to the principles of GCP and be approved by an ethics committee.) Your content should be easy to read, easy to understand, answer the right questions, and address any potential concerns.

New Opportunities

Technology advancement has allowed us to reach out to more people than ever before. Make sure you leverage all media outlets when planning your clinical trial recruitment. Traditional methods – such as newspaper, TV, and radio advertising have declined in reach and cost-effectiveness over the last decade.

Social media advertising, search advertising, email campaigns, and niche-connected websites are great places to find participants for your trial. You can also reach out to certain patient advocacy groups, university student organizations, or work with relevant health professionals.

Estimate the Numbers

Whichever medium you choose to promote your study, it’s essential to estimate the numbers based on prior experiences. Instead of making guesses, speak to another researcher who has used a similar method before and utilize information from their results. Remember that all strategies take time to get off and running, so plan to start early.

Advanced research, setting clear goals, and a little extra effort can help the recruitment plan phase go a long way. Paying close attention to the trial design is vital to the success of any study.

Ready to take the next step in planning your clinical trial recruitment? These guides will help:

• Does Social Media Recruitment Make Sense for My Clinical Trial?
• The Volunteer-Researcher Relationship
• Beginner’s Guide to Using Facebook Advertising for Patient Recruitment

If you’re looking for more insight on how to better recruit patients for your clinical trial contact Trialfacts today to find out how we can help you fulfill your recruitment goals.

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Recruitment Strategies for Clinical Trials That Work

Clinical trial recruitment can be a significant barrier to trial success. 

Some researchers estimate upwards of 90 percent of clinical trials fail to recruit the required number of study participants causing nearly the same proportion of trials to become delayed, costing study sponsors enormous amounts of time and money. 

High patient dropout and poor retention rates combined with these dreary statistics make optimizing a trial’s recruitment strategy a high priority.

Set Up Your Trial for Success 

Proactive study decision-making can affect the success of a clinical trial immensely. Certain decisions, such as picking the proper sites or the number of expected participants from each site, can affect downstream efforts from the study sponsor and the sites themselves. 

Additionally, successful studies have a realistic enrollment time estimate by allowing for inevitable enrollment problems in the proposed timeline. 

Improper protocol design is another disastrous facet of clinical trial failure and can derail a study before it even begins. Additionally, attempting to perform a study in an area with direct competition with other studies’ recruitment efforts can contribute to study failure. 

After we set up our trial for success, what strategies can we take to overcome recruitment challenges? What considerations can we make beforehand to lessen the recruitment burden? Here are a few ways to set your trial up for success before recruitment:

What Are the Top Five Ways To Optimize Trial Recruitment?

There are several methods commonly used to recruit patients. The most successful recruitment tactics involve clear communication and convenience. Let’s look at the best ways to optimize trial recruitment below.

#1: Understand the Needs of the Patient

The best way to optimize your recruitment efforts is to develop a patient-centric protocol to ensure the patient is prioritized throughout the study. 

Not only will this help with initial recruitment, but patients who feel their needs are being appropriately acknowledged and addressed are more likely to remain in a study. 

Developing a patient-centric protocol can be a multifaceted approach. From the beginning, creating recruitment materials directed toward the patient can grab their attention immediately. 

Attractive emails or directly mailing study information can grab a potential study participant’s attention immediately.

Provide Accessible Information

Providing easy-to-read study information at a health literacy level appropriate for the target study population (usually a fourth to sixth-grade reading level) can go a long way toward promoting study comprehension. 

Some successfully recruited studies employ an additional educational session, such as a brief telephone conversation, to educate the participant about the trial’s purpose.

Other commonly implemented recruitment strategies such as producing flyers, brochures, newspaper ads, and billboards can also be effective. Once again, knowing the target audience for these strategies is essential. 

For example, young adults between 18 to 24 are unlikely to interact with a physical newspaper, similar to elderly adults over 70 coming across a social media advertisement. 

Recruitment materials should also be geographically and culturally appropriate . If the study aims to recruit in another non-English speaking country, the materials must be translated appropriately into the local language.

Encourage Family and Community Support

Family members are often patients’ core support members. Without the moral, and sometimes literal, support from family, patients become much less likely to make appointments and adhere to prescribed medications, let alone participate in a clinical trial. 

Another way to involve a different kind of family is through community outreach. Studies have shown that support from the community can be just as beneficial to patient satisfaction in a study as their biological family.

Consistent Feedback Is Key

Finally, constant feedback during the trial can tremendously improve participant retention and overall satisfaction. Consistent check-in and evaluation without being invasive can help study participants once again feel their inclusion in the study is appreciated. 

#2: Utilize Referrals

A referral system is one of the best ways to improve clinical trial recruitment while saving money. Patients often prefer to hear about a trial from their healthcare provider instead of a third party. 

The most effective approach to connect with prospective participants is through their primary caregivers. 

When a patient’s healthcare provider offers the opportunity to participate in a study, the offer comes off less as an advertisement and more as a chance to participate in research that can benefit not only themselves but other patients with similar medical problems. 

Research suggests the majority of the general public prefers to hear about a study from their primary care provider, but very few studies recruit this way. Establishing a network of providers is a low-cost, effective way to reach patients in a way they trust. 

#3: Implement Technology

In today’s society, it would be a missed opportunity not to implement digital advertising to support clinical trial recruitment. 

Physical media, such as flyers, brochures, and newspaper ads, have now become an expensive advertising option compared to digital advertising online. Even other audiovisual media formats such as television and radio cost more per advertisement and reach fewer potential study participants. 

Social media, in particular, reaches billions of people at any given time. No other media format even comes close to how widespread and accessible social media has become. 

Implementing keyword targeting and advertising on sites most likely to reach the target study audience are two great ways to utilize social media to your advantage. 

#4: Provide Incentives

Incentives are a commonly used, effective tactic to recruit participants for clinical trials. Study participants often wonder what is in it for them when volunteering for a study. 

Outside of furthering our clinical knowledge through responsible research, it can be challenging to incentivize participants properly. While some studies have shown that altruism is the most effective motivator to participate in research, study participants enjoy incentives that make them feel like their time in a study is appreciated. 

Incentives do not have to be monetary, either. Other options include transportation to and from study appointments, hotel accommodations, and food and drink. 

Ultimately, making a participant’s involvement in a study as easy as possible will benefit recruitment and retention. 

#5: Don’t Forget About Patient Retention

Even with the most successful recruitment tactic, no study can succeed without adequate patient retention. Despite this, many studies fail to factor in just how vital retention can be. 

While many of the previously mentioned recruitment strategies, such as family involvement and incentives at follow-up visits, can also be applied to support retention, there are additional schemes sponsors can employ.

Patient engagement can dramatically increase retention. Besides essential follow-up visits and phone calls, a more comprehensive and patient-centric approach to follow-up can be beneficial. 

Knowing the patient population and the intervention or disease state being investigated can point study sponsors in the right direction. 

For example, in a study of young adults 18 to 24, implementing an online chat service to discuss study concerns can effectively engage the target population. In addition to consistent participant check-in during the study, it can also be helpful to self-evaluate how the study is going. 

Regular check-in and self-assessment during the recruitment phase can prove just as valuable as planning. Tracking site study participation closely can give study sponsors more insight into enrollment and retention. 

Sometimes the decision has to be made to close or terminate study recruitment at a site early if the site is not on track. Doing so can limit valuable resource loss at locations that may not perform as well as others. 

BONUS: Partner With a Clinical Research Organization (CRO)

Clinical Research Organizations (CRO) can be immensely helpful in orchestrating a clinical trial. CROs can considerably improve a clinical trial’s efficiency, scalability, and overall success. 

While utilizing a CRO is an investment, some CROs can provide global clinical trial support and expertise in pharmaceuticals, biotechnology, and medical devices that can prove invaluable.

CROs can help navigate some of the problems and considerations previously discussed, such as regulatory concerns and protocol optimization. 

At iProcess Global Research , you can expect exceptional teams and operations to provide cutting-edge research to help organizations with clinical trials. 

With a constant demand for clinical trials, iProcess continues to meet the demand for specialists who can provide the high quality and competence required to facilitate clinical trial recruitment for success.

Sources: 

Effectiveness of Participant Recruitment Strategies for Critical Care Trials: A Systematic Review and Narrative Synthesis | SagePub

How to Optimize Patient Recruitment | PMC

Optimizing Clinical Trials Recruitment via Deep Learning | NIH

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10 Jan 2024

Patient Recruitment in Clinical Trials: A Blueprint for Success

Patient recruitment in clinical trials within the planned time is a big challenge in drug development. It could lead to missed deadlines and higher costs and can consume much of the development timeline. To address this, careful recruitment strategies are crucial from the start and throughout the study.

In this article:

• 1.The Significance of Patient Recruitment in Clinical Trials
• 2.Patient Demographics and Diversity - Why Does it Matter?
• 3.Factors Influencing Patient Participation in Clinical Trials
• 4.Leveraging Technology for Clinical Trial Recruitment

The Significance of Patient Recruitment in Clinical Trials

Recruitment of patients is vital for the success of clinical trials. It ensures that studies stay on schedule, preventing delays affecting the overall duration. Having enough diverse participants is crucial for reliable results. Timely recruitment respects participants' time and minimizes the burden on them and researchers. It also contributes to cost-effective trials and increases the chances of regulatory approval. Patient recruitment is not just a logistical necessity; it's a fundamental part of ethical and successful clinical research.

Patient recruitment in Clinical Trials includes identifying, sourcing, and educating individuals for pre-screening and initial discussions regarding potential trial participation. This process consists of all patient-related activities leading up to the moment when the individual signs an informed consent form. The patient is deemed officially "recruited" and becomes eligible for the subsequent screening phase.

Patient Demographics and Diversity - Why Does It Matter?

Ensuring diversity in clinical trials is crucial because a drug's effectiveness in one population may not guarantee similar outcomes in others. Also, currently, there are no guidelines mandating diversity in clinical trials. This leads to a lack of representation in research.

Genetics significantly impact diseases and health outcomes, revealing variations among ethnic and racial groups. Failure to test drugs on diverse populations can overlook potential differences in efficacy. For example, albuterol, a widely used asthma inhaler , was found to be less effective in African descent individuals as compared to those of European descent after years of widespread use.

The persistent lack of diversity in trials stems from various challenges. Limited access is a primary barrier, as awareness and trial information are essential for participation. Many trials occur in academic hospitals requiring insurance coverage, making it less likely for individuals from ethnic minorities, often with less access to insurance, to be informed about or participate in these trials. Efforts to address these issues are ongoing; however, there is no straightforward solution to this complex problem.

Factors Influencing Patient Participation in Clinical Trials

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• Clinical Research Explained

Patient Recruitment

• 6. May 2024

Understanding Clinical Research

Phases of clinical trials, patient recruitment process, recruitment strategies, challenges in patient recruitment, overcoming recruitment challenges, ethical considerations in patient recruitment, regulations and guidelines.

Patient recruitment in clinical research is a crucial aspect of the drug development process. It involves identifying and enrolling suitable participants for clinical trials, which are a necessary step in the evaluation of new treatments, therapies, and medical devices. This process requires a thorough understanding of the study’s objectives, the target population, and ethical considerations. It also involves a range of strategies and techniques to attract and retain participants.

Despite its importance, patient recruitment is often a challenging task for researchers. It is estimated that up to 80% of clinical trials fail to meet their recruitment targets within the planned timeframe. This can lead to delays, increased costs, and even the failure of the trial. Therefore, effective patient recruitment strategies are essential to the success of clinical research.

Clinical research is a branch of healthcare science that determines the safety and effectiveness of medications , devices, diagnostic products, and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis, or for relieving symptoms of a disease. The results of clinical trials can lead to changes in health policies, clinical practice, and further scientific investigation.

Before a clinical trial can begin, extensive laboratory testing is done to identify potential treatments. Once laboratory testing indicates that a treatment could be effective and safe, a plan or protocol is developed for the clinical trial. This protocol outlines what will be done in the study, how it will be conducted, and why each part of the study is necessary.

Clinical trials are conducted in several phases, each with a different purpose and set of participants. Phase I trials involve a small group of people (20-80) to evaluate safety, determine a safe dosage range, and identify side effects. Phase II trials involve a larger group of people (100-300) to further evaluate its effectiveness and safety. Phase III trials involve large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.

Phase IV trials are conducted after the intervention has been marketed. These studies continue testing the study drug or treatment to collect information about their effect in various populations and any side effects associated with long-term use. Each phase is considered a separate trial and, after completion of a phase, investigators are required to submit their data for approval from the FDA before continuing to the next phase.

The patient recruitment process begins with the identification of eligible participants. This involves a detailed review of the study’s inclusion and exclusion criteria, which are guidelines that determine who can participate in the study. These criteria can include factors such as age, gender, type and stage of disease, previous treatment history, and other medical conditions.

Once potential participants are identified, they are typically pre-screened through phone calls or online questionnaires to further assess their eligibility. If they meet the pre-screening criteria, they are then invited for an in-person screening visit. During this visit, they undergo a detailed medical examination and their medical history is reviewed to confirm their eligibility.

There are various strategies that researchers use to recruit participants for clinical trials. These include traditional methods such as newspaper advertisements, flyers, and direct mail, as well as digital methods such as online advertising, social media, and email campaigns. Some studies also use patient registries and databases to identify potential participants.

Another common strategy is to collaborate with physicians and healthcare providers who can refer their patients to the study. In some cases, researchers also engage with patient advocacy groups and community organizations to help reach potential participants. Regardless of the method used, all recruitment materials must be approved by an ethics committee or institutional review board to ensure they are appropriate and ethical.

There are several challenges that researchers face when recruiting participants for clinical trials. One of the main challenges is finding eligible participants. Many clinical trials have strict inclusion and exclusion criteria , which can make it difficult to find suitable participants. In addition, some people may be reluctant to participate in clinical trials due to fears about side effects, inconvenience, or lack of understanding about the trial process.

Another challenge is retaining participants for the duration of the study. Participants may drop out of the study for various reasons, such as experiencing side effects, finding the study procedures burdensome, or feeling that the study is not benefiting them. This can lead to incomplete data and can affect the validity of the study results.

There are several strategies that researchers can use to overcome these challenges. One strategy is to design the study in a way that minimizes the burden on participants. This could involve simplifying the study procedures, providing flexible visit schedules, or offering compensation for participation. In addition, providing clear and comprehensive information about the study can help alleviate fears and misconceptions about clinical trials.

Another strategy is to use targeted recruitment methods. This involves identifying specific groups that are likely to be eligible for the study and focusing recruitment efforts on these groups. For example, if the study is investigating a treatment for a specific type of cancer, the researchers could collaborate with oncologists and cancer support groups to reach potential participants. Using a combination of different recruitment methods can also increase the chances of reaching the target number of participants.

There are several ethical considerations that researchers must take into account when recruiting participants for clinical trials. One of the main considerations is informed consent. This means that potential participants must be given comprehensive information about the study, including its purpose, duration, procedures, risks and benefits, and their rights as participants. They must also have the opportunity to ask questions and must freely agree to participate without any coercion or undue influence.

Another ethical consideration is the principle of justice, which involves ensuring that the benefits and burdens of research are fairly distributed. This means that researchers should strive to include a diverse range of participants in their study, and should not exclude certain groups without a valid scientific reason. They should also ensure that participants are not exploited, and that they are adequately compensated for their time and inconvenience.

There are several regulations and guidelines that govern the conduct of clinical trials, including patient recruitment. In the United States, these include the Federal Policy for the Protection of Human Subjects (also known as the Common Rule), the Food and Drug Administration (FDA) regulations, and the Good Clinical Practice (GCP) guidelines. These regulations and guidelines provide a framework for the ethical conduct of research and protect the rights and welfare of research participants.

These regulations require that all clinical trials must be reviewed and approved by an institutional review board (IRB) before they can begin. The IRB reviews the study protocol, including the recruitment plan, to ensure that it is ethical and that participants’ rights and welfare are protected. They also monitor the study while it is ongoing to ensure that it continues to meet ethical standards.

Patient recruitment is a critical aspect of clinical research, but it is also one of the most challenging. It requires a thorough understanding of the study population, effective recruitment strategies, and a commitment to ethical principles. Despite the challenges, successful patient recruitment is essential for the advancement of medical science and the development of new treatments and therapies.

As clinical research continues to evolve, new strategies and technologies are being developed to improve patient recruitment. These include the use of electronic health records to identify potential participants, online platforms for participant engagement, and mobile technologies for remote data collection. With these advancements, the future of patient recruitment in clinical research looks promising.

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Using Workflow Mapping to Improve the Recruitment Process in Clinical Trials

(Originally presented abstract at 2019 Annual Conference San Antonio) Sara Sampaio MD, CCRP , *, Sepideh Saroukhani MD, MS, PhD candidate, Aryn Knight BS, CCRP, Jennifer L. Chambers RN, BSN, CCRC, Emerson C. Perin MD, PhD, FA

Introduction

In this article, we describe the strategies and approaches developed at the Center for Clinical Research at Texas Heart Institute (THI) in Houston, Texas, to facilitate efficient participant recruitment for heart failure–related randomized controlled trials (RCTs). Randomized trials are typically complex in terms of the target population, protocol design, and intervention strategies — factors that can hinder the recruitment of a sufficient number of eligible participants. Thus, detailed upstream planning is crucial to guide recruitment efforts — especially in trials that focus on serious medical conditions such as heart failure — and a trained recruitment team is needed to execute protocol-specified tasks. Despite extensive literature on strategies for enhancing participant recruitment in research, little has been reported about the actual activities and experiences associated with recruitment and about the impact of organizational strategies on this work.

To improve RCT recruitment at our clinical research center, we developed a systematic approach to identifying, qualifying, and consenting clinical trial participants, and we established a division dedicated to participant recruitment. Our workflow is based on the best practices used by study staff who were recruiting participants for heart failure RCTs. Nonetheless, we believe that this structure could be used to manage and organize the recruitment processes for various types of RCT, given that the recruitment challenges inherent in heart failure RCTs are also commonly encountered in most other RCTs targeting serious medical conditions.

Randomized controlled trials are the gold standard for evaluating the efficacy and safety of medical and health care interventions, as they produce the highest level of supporting data for evidence-based medicine. 1  The RCT is one of the most complex and costly study designs in which every step is prespecified in the protocol and is to be precisely executed as planned. The recruitment process, which aims to identify and enroll representatives of the target population in sufficient numbers to fulfill the sample-size and power demands of the study, requires ongoing communication and integration between the research team and potential participants. 2,3

Recruitment Barriers in the Randomized Clinical Trial

Recruiting sufficient participants is key to any RCT’s success. 4,5  Although several studies (including systematic reviews and meta-analyses) have investigated recruitment barriers and have aimed to identify potential strategies for improving enrollment in RCTs, slow or insufficient recruitment persists as a major problem. 6-8  An analysis of registered RCTs showed that 19% of the studies were closed or terminated early because of failure to recruit enough participants. 9 Findings from other studies indicate that 86% of RCTs in the United States did not meet their recruitment targets within prespecified timelines, 7,10  and Lamberti et al. 11  found that study timelines in a group of biopharmaceutical clinical trials doubled beyond planned enrollment periods due to low recruitment rates. Furthermore, the recruitment process for trials with chronically or severely ill participants (such as those with heart failure) tends to be more laborious and requires more effort and time from the recruiting team, compared with trials targeting healthy populations or those with less-serious medical conditions. 12

Heart failure is the leading cause of hospitalization among elderly populations in the United States. 13,14  Its incidence is expected to increase 46% between 2012 and 2030, by which time more than 8 million US adults will have heart failure. 15  Numerous RCTs are investigating ways to improve the care of patients with heart failure, 14,16  although because of the high prevalence and incidence of this condition, the pool of available patients who meet eligibility criteria for heart failure RCTs and are willing to participate in them tends to be overestimated. 8  Because of their high complexity, heart failure RCTs may require multiple pre-screenings and follow-ups to confirm or reconfirm eligibility depending on the number of protocol inclusion and exclusion criteria and study-specific concerns for participant safety. Such complexities could result in large numbers of screening failures and low enrollment rates. Evidence from several heart failure trials indicates that for every participant enrolled, approximately 100-150 potential participants were screened. 12,17

Multiple factors may contribute to this paucity of eligible or willing participants: (1) the clinical scenario for heart failure is broad and ranges from classic symptoms (e.g., dyspnea, edema) to less common clinical presentations (e.g., severe fatigue, gastrointestinal distress, depression), any of which can be severe and debilitating 14 ; (2) patients with heart failure tend to be older 18  and sicker, with various associated comorbidities that can lead to multiple emergency department visits and hospitalizations 16 ; (3) the severity of symptoms and complexity of the disease, especially when accompanied with loss of autonomy and inability to engage in self-care, can render patients unable or disinterested in participating 19,20 ; (4) heart failure trials are usually complex and can have more than 50 inclusion and exclusion criteria to capture specific heart failure types and stages. 12,14

Changing Recruitment Paradigms

Recruitment is the most time-consuming task of an RCT and can take up to 30% of the study timeline. 21  Therefore, a well-planned recruitment process is required to avoid exceeding the study budget and planned timeline. Beyond upstream planning at the trial design level, which is crucial to guide recruitment efforts, establishing an efficient structure to execute the process will greatly facilitate prescreening and recruitment efforts. 22

Recruitment is usually done by trained clinical research coordinators (CRCs). In addition, CRCs typically perform several other trial-related activities, including data collection and documentation, management and scheduling of study visits and procedures for all participants, and submission of regulatory documentation; these duties may vary, depending on the infrastructure at the study site. CRCs also work closely with study investigators, study sponsors, clinical research organizations, and monitors to administratively and clinically maintain the conduct of the trial. As only one part of these responsibilities, the recruitment process itself includes multiple specific tasks: reviewing medical records and prescreening potential participants for eligibility, providing detailed information about the study to potential participants and taking time to address their concerns and questions about the trial, obtaining authorizations for release of information (ROI) and collecting required medical records, discussing and clarifying inclusion and exclusion criteria with investigators, keeping potential participants well informed as the recruitment process moves forward, and finally, scheduling the first study visit.

Not surprisingly, CRC workload has been reported as one of the key factors that interrupts participant recruitment. 22  The negative impact of CRC workload on recruitment success might be minor at the beginning of a study; however, as the study moves forward, tasks related to enrolled participants in the trial are likely to take priority over tasks related to new participant recruitment, disrupting ongoing enrollment.

Methods and Results

The principal goals of an RCT recruitment process are to identify potential participants, to prescreen their medical records to determine eligibility, and to enroll the requisite number of eligible participants within planned study timelines. Maintaining an efficient process for achieving recruitment goals throughout an RCT requires optimal allocation of time and staffing to efficiently manage the pool of potential participants and to ensure that all possible candidates receive the attention and information that they need to become an enrolled participant. Our objective was to create a preplanned, standardized process to follow whenever we reach out to a potential participant.

We took a two-pronged approach. First, we listed all recruitment tasks, mapping every step from the initial contact with the potential participant to his or her enrollment. On the basis of whether specified tasks were administrative or clinical in nature, we designed a dedicated recruitment team that would be equipped and able to carry out these tasks. Second, we created a recruitment division within our clinical research center to centralize the entire recruitment and prescreening process for all of our clinical research trials and to facilitate staff training and oversight.

Standardizing Recruitment Activities

The first step toward systematizing our recruitment process was to gain knowledge about the factors that were affecting recruitment at Texas Heart Institute, from both site and participant perspectives. We interviewed stakeholders (e.g., clinical staff, patients, trial participants) and observed our process to understand its strengths, weaknesses, and gaps; we supplemented this knowledge with an extensive literature search of known barriers to successful recruitment. For example, lack of understanding about the randomization process is one reason that potential participants may be reluctant to enroll in an RCT; they are more likely to feel comfortable about participating if they are well informed about the study. Thus, study staff must be able to take time to explain and clarify various study-related concepts, such as the principle of clinical equipoise, the rationale behind randomization, and the need for having a placebo group. Additionally, potential participants should be given sufficient time to think about the study and the required procedures, consult with their health care providers, and ask questions before consenting to participate. This process requires staff who are available to respond to potential participant questions and concerns in a timely manner.

Once we better understood our own recruitment processes, we listed all of the tasks involved in the process and noted their sequences, integrations, and interdependencies. For example, medical records cannot be accessed before a potential participant returns the signed ROI authorization form, and prescreening is not possible until relevant medical records can be obtained; in addition, many tasks require multiple follow-ups to move the process forward. We then used cross-functional process mapping (CFPM) to arrange these tasks into an organized workflow with clear division of responsibilities. This provided a standardized, evidence-based foundation for establishing and staffing the new recruitment division within our clinical research center.

Cross-Functional Process Mapping

Process mapping techniques are management tools used to design and reengineer processes and to improve workflows or outputs. Recently, they have gained popularity in health care settings and have been widely used, especially in health care quality-improvement projects. 23  The key advantage of process maps is that they provide a concise visual demonstration of task interdependencies and integrations, such that the average adult should be able to clearly understand the process, regardless of his or her position or educational background.

In particular, CFPM technique encompasses an especially broad level of detail; it is useful for identifying flaws and bottlenecks (such as duplication of effort) that could make a process inefficient. A CFPM workflow can be easily communicated to all team members: Within a single diagram, CFPM delineates all activities involved in the process, the functional unit that performs each activity, the sequences of tasks, their interdependencies, and key decision points, quickly providing a profound understanding of the entire process. Accordingly, CFPM workflows are useful for training purposes as well. Considering these advantages, we decided to use CFPM to model the proposed workflow in the recruitment division.

The CFPM workflow starts with a triggering event, which in our case is when a potential participant reaches out to our recruitment division or we receive a new referral from a physician or other medical staff. Vertical bands (so-called “swim lanes”) represent the functional units within the division. Personnel assigned to each functional unit are responsible for the tasks that are shown within its swim lane. 24  Tasks are presented using basic flowchart shapes (Fig. 1), each of which has an underlying functional meaning as to the type of task within the process. Detailed task-specific instructions or documents may accompany the map as needed to clearly articulate a given task.

To create our workflow process map, we determined which recruitment activities required clinical knowledge so that we could classify each task as either clinical or administrative. We then used these classifications to map the structure for our recruitment division, for which we established three distinct functional units: the  recruitment assistant , a non–clinically trained individual who handles strictly administrative tasks; the  recruitment coordinator,  a clinically trained individual who handles the initial clinical recruitment tasks, thus relieving some of the CRC’s extensive workload; and the  CRC,  who handles the remaining clinical recruitment tasks (Fig. 2).

Recruitment Assistant

The recruitment assistant handles nonclinical administrative tasks in the recruitment process. Overall, the recruitment assistant is responsible for ensuring that potential participants receive requisite information and other resources about the trial(s) of interest and that their concerns and questions are adequately addressed throughout the prescreening process. To equip the recruitment assistant with needed skills and knowledge, we provide training specific to the aims and processes of the clinical trials for which we are actively enrolling participants.

The recruitment assistant’s key responsibilities include making the first contact with potential participants who reach out or are referred to the center and staying in touch with them throughout the prescreening process. These activities do not require a clinical background; thus, we find it more beneficial to have an assistant experienced in customer relations. Indeed, the quality of the first encounter and the manner in which the research study is communicated could substantially influence a potential participant’s decision to take part in the research.

After receiving an inquiry from a potential participant or a referral from one of our recruitment sources, the recruitment assistant responds to the potential participant within 48 hours. Following Good Clinical Practice guidelines, the recruitment assistant uses institutional review board–approved scripts to guide his or her communications with potential participants throughout the process. The initial discussion includes general information about clinical research, how investigational therapies differ from current FDA-approved treatments, and available clinical trials at our institution. If the potential participant is interested in enrolling in one of our RCTs, the recruitment assistant asks for permission to administer a questionnaire that has broad questions about the potential participant’s medical history in order to determine if initial inclusion criteria will be met. All of the information obtained is entered into our clinical trial management system.

If no reason for exclusion is identified, access to the potential participant’s medical records is necessary for the prescreening process to continue. We have developed a standardized information package to be sent to the potential participant by the recruitment assistant; this package includes an ROI authorization form to be signed by the potential participant, study brochures, a copy of the informed consent document, and contact information for the study team. Once the ROI form is signed and returned, the recruitment assistant requests all necessary medical records within 48 hours. Follow-up calls to health care providers and to the potential participant also take place within specific timeframes (Fig. 2). After all medical records are retrieved, the recruitment assistant creates and organizes the potential participant’s file in accordance with our standard operating procedures and transfers it to the recruitment coordinator for review.

To address complex or clinical questions, the recruitment assistant connects potential participants with staff who have relevant expertise, such as the study CRC, research nurses, managers, or investigators. In addition, the recruitment assistant updates the clinical trial management system throughout the prescreening process to document all interactions with potential participants and to revise their status as needed. Finally, if a non–self-referred potential participant becomes unwilling to participate or is found to be ineligible during prescreening, the recruitment assistant provides feedback to the potential participant and to the referral source.

If a non–self-referred individual does enroll in a trial, the recruitment assistant follows up with the referring physician to keep him or her abreast of the patient’s status in regard to study participation.

Recruitment Coordinator

The recruitment coordinator is a person with a clinical background who is experienced in clinical research—for example, a research nurse, registered nurse, nurse practitioner, physician’s assistant, medical graduate, or foreign medical graduate. The recruitment coordinator handles the prescreening tasks that are clinical in nature; he or she oversees the prescreening and recruitment activities for all trials being conducted at Texas Heart Institute, supervises the work done by the recruitment assistant, and supports the recruitment assistant when needed.

The recruitment coordinator reviews medical records, maintains a prescreening log, and fills out a chart summary and a study-specific inclusion and exclusion criteria checklist. If additional medical records are needed to complete the prescreening, the recruitment coordinator asks the recruitment assistant to request the required records. After completing the prescreening process, the recruitment coordinator contacts the potential participant to review the medical history, resolve any outstanding issues, and answer any questions about the study and the previously sent informed consent document. Throughout this process, the recruitment coordinator and recruitment assistant update the potential participant’s status in the clinical trial management system.

If the prescreening review of the medical records indicates that the potential participant is not eligible for the current clinical trial(s), this information is entered into the study’s prescreening log and shared with the CRC. The prescreening log must be kept updated by the recruitment coordinator, as it is an important tool in evaluating the trial’s recruitment outcome.

Clinical Research Coordinator

When a potential participant meets all prescreening inclusion criteria and no exclusion criteria are identified, his or her file is sent to the CRC (Fig. 2), who contacts the potential participant to discuss enrollment. If the potential participant is willing and able to proceed, the CRC schedules the initial study visit, during which the participant will sign the informed consent document and complete any baseline tests required by the study protocol.

The recruitment process is complete once the participant signs the informed consent document. The CRC will continue to monitor and communicate with the participant throughout the trial.

The RCT recruitment process includes attracting, shortlisting, selecting, and enrolling suitable study participants. The success of this process depends on having access to a pool of potential participants and efficiently performing all tasks until the potential participant becomes an enrollee by signing the RCT informed consent document. Rapidly evolving electronic health record systems, patient portals, and many other resources and advertising campaigns have increased public awareness about RCTs and have facilitated access to potential participants. Findings from a recent national public survey show that approximately 90% of the US population agree that RCTs are important for improving health, 25  and more than 70% of Americans are at least somewhat willing to participate in clinical trials . 25-27  Even so, lack of resources to handle all received inquiries (e.g., calls, emails, letters) and referrals in a timely manner remains problematic for many sites recruiting RCT participants. 27

We found that visualizing our recruitment procedures and staffing gave us a better understanding of the entire process. First, we noticed that the administrative workload during recruitment can be extremely heavy and may interfere with the many other responsibilities that CRCs take on in conducting RCTs. By adding administrative assistance to the recruitment team, we modified the process and directed the administrative workload away from the CRC. Having another team member available to speak, respond, and answer questions facilitates constant contact with participants, maintains active communications with referral sources, and promotes potential participant education while alleviating the CRC’s workload. Notwithstanding, the CRC is responsible for the overall conduct of the trial, and his or her involvement in the recruitment process is essential. In other words, in the new setting, the recruitment team and the CRC work in harmony to make sure that the recruitment process follows institutional review board requirements, Good Clinical Practice guidelines, and the study protocol.

Second, visualizing the workflow enabled us to identify delays, redundant work, unnecessary complexities, and critical failure points in our recruitment process. By modifying the process and clearly delineating the roles and responsibilities of the various recruitment team members (along with their interdependencies), we were able to create a recruitment workflow that contains as few tasks and staff as necessary, thereby promoting efficiency.

Third, developing this workflow has facilitated staff training and process consistency during the conduct of our institution’s RCTs.

Conclusions

Careful planning and the development of strategies to manage administrative and prescreening workload has enabled constant and consistent RCT recruitment efforts and activities at our center. In addition, maintaining active communications with potential participants and referral sources has increased their engagement with the center and has motivated referral sources to refer more potential participants.

This model contributes to a common understanding of the recruitment process. Although this workflow is based on the best practices by CRCs working on heart failure RCTs at Texas Heart Institute’s Center for Clinical Research, we believe that the process we undertook is highly adaptable and will be useful for systematizing and managing the recruitment process in many other types of RCT. The goals, steps, functional units, and personnel required to meet any given institution’s needs can easily be determined, organized, and mapped by using these techniques.

This work was supported by general funding from the Texas Heart Institute.

Disclosures

The authors report no known conflicts of interest associated with this publication and no significant financial support for this work that could have influenced its outcome.

Acknowledgment

Jeanie F. Woodruff, BS, ELS, contributed to the editing of the manuscript.

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Fig. 1.  Basic flowchart shapes and their functional meanings.

Fig. 2.  Recruitment workflow diagram. CTMS: clinical trial management system; ROI: release of information authorization form; SOP: standard operating procedure. Reprinted with permission from Texas Heart Institute.

5 thoughts on “Using Workflow Mapping to Improve the Recruitment Process in Clinical Trials”

The blog specifically described the strategies and approaches developed at the Institute. Keep posting. Thank you.

Agree…. Thank you for such an informative blog.

Appreciated the detailed description of task assignments which improved recruitment workflow. Interested to learn how such a center prioritizes studies with similar inclusion criteria. For example, prescreening determines a patient may be eligible for three studies at the center; which is offered first and according to what criteria? Do early investigators or pilot studies get “first dibs” at approaching this patient or studies falling behind in recruitment goals? Very interesting things to consider and would love to hear how other research centers handle this.

Hi Nina, Thank you for your question. This happens quite often at our center. Our approach has been to discuss all options with the physician that referred the patient, in case the patient was referred by a physician, When the patient reached out to the center ( self-referred patients), we do discuss all options available at our site and let the patient decide in which trial he would like to participate. After consent, if a patient screen-fail, we may offer him other options as well.

Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy and safety of medical and health-care interventions, since they provide the most robust evidence for evidence-based medicine. The recruiting procedure in life science which strives to locate and enrol sufficient numbers of members of the target community to meet the study’s sample size and power requirements, necessitates continual contact and integration between the research team and potential participants.

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7 Clinical Trial Recruitment Strategies For 2024

Finding the best clinical trial recruitment strategies is critical to attracting patients against the clock.

• Are you struggling to recruit patients for your clinical trials?
• Do you find it challenging to reach the right participants for your research?
• Are you tired of traditional recruitment methods yielding low enrollment rates?

Clinical trial patient recruitment remains a tremendous hurdle that needs to be addressed.

Factors affecting recruitment include overestimating eligible patients, a lack of concern for patients’ needs and preferences, and poorly-targeted outreach. 

Patient recruitment is an expensive and lengthy process – sometimes more than any other clinical trial stage. Thus, effective clinical trial patient recruitment strategies are critical to the time and financial economy of the process.

This article is for:

• Pharmaceutical companies seeking to optimize patient recruitment.
• Clinical research organizations aiming to enhance enrollment rates.
• Researchers and investigators looking for novel approaches to attract diverse participants.
• Healthcare professionals involved in trial coordination and patient engagement.

We understand the frustrations and complexities of patient recruitment, and through our shared experiences, we aim to empower you with actionable insights and proven strategies to power through this process with confidence.

Patient Recruitment in Clinical Trials

The role of patient recruitment is to effectively reach the required sample size for a clinical trial. Recruitment is the highest cost in a clinical trial and takes more time than any other stage, yet up to 75% of clinical trials fail to meet recruitment targets . 

There’s a well-documented phenomenon of researchers hugely overestimating the pool of available patients for clinical trials. Lasagna’s Law and Muench’s Third Law both reference this, the latter of which suggests dividing the estimated number of eligible patients by ten to get a more realistic idea. 

For one study , authors looking for 289 IBS patients screened 2149 patients from an estimated pool of 180,000 to reach their target. The process was estimated to take four months and had a budget of $5000. In actuality, it lasted 24 months and cost just over $75,000. 

Sufficient enrollment in clinical trials is necessary to compensate and cover for anticipated patient retention rates, resulting in a large enough pool from which to gather useful clinical data. Therefore, a successful trial depends on a large enough pool of enrolled volunteers , and recruitment strategies need to maximize this pool. 

Why is Patient Recruitment So Important?

Patient recruitment can take longer than any other stage of the study and often the majority of its budget. With low retention rates, recruitment becomes a critical compensatory tactic to ensure the study can run with an effective sample size. 

Clinical trials can improve recruitments using specialized recruitment plans to optimize each stage of the recruitment process for increased attendance. 

Surgical trials are the most unpredictable in terms of recruitment. It’s thought that this is due to the wide range of conditions present for patient populations regarding the complexity of the issues eligible to receive surgical treatment. For example, carpal tunnel is a lot more common and will have a much higher pool of potential patients than something like hip fractures, which occur far more seldom and among a population likely to have a high rate of comorbidities, affecting their eligibility. 

What are Clinical Trial Recruitment Strategies?

Recruitment strategies in research are the framework, design, and specific approach developed to maximize patient participation for each specific research question. The specific approach will depend on the study population, the budget, and the question being asked. 

Recruitment strategies can take the shape of four main templates : 

• All patients are recruited together, and the trial starts with everyone involved at once;
• Recruitment happens in batches as the trial progresses;
• Continuous recruitment is employed until the number of desired recruits is reached;
• Recruitment is ongoing until a fixed point in time.

Recruitment methods can include referrals, media, text messages, and cold calls, among others. The method of choice will depend on the target population and how expensive it is to conduct and is unlikely to be the only method used. 

Patient Recruitment Plans

A patient recruitment plan aims to maximize enrolment by a series of steps. It typically employs a basic template of:

• Research – Identify the target audience and any obstacles they may face when joining the trial.
• Outreach – Establish a budget, and decide on your methods of interacting with your pool of patients.
• A/B test design – The recruitment process should have different approaches, focusing mainly on recruitment and a backup plan. For example, this A/B method will apply to targeting, media, and messaging. 
• Advertising – Designing media that will appeal to the target audience while following FDA guidelines .

The key targets are the simplification of the study protocols, knowing the patient population, and achieving the desired sample size. 

Deciding on screening processes, batch, continuous, or time-limited recruitment strategies; as well as sample sizes that are powered to detect the minimum clinically important difference in a comparative study; will all be important steps in the achievement of these targets.

So, it follows that by improving these key stages, patient recruitment can be increased. With this in mind, here are seven popular and effective patient recruitment strategies for clinical trials.

7 Clinical Patient Recruitment Tactics & Strategies

1 – direct outreach and follow-up .

While researchers are heavily focused on outreach, it can be easily overlooked that the patients themselves have plenty to manage in their own lives. Direct contact and follow-up can mean the difference between a distracted glance and focused attention from potential patients, and this can be as simple as sending text messages to gauge interest and to follow-up. 

With thousands of potential patients in the pool, this personal touch can be achieved with automated services such as Mosio . 

2 – Referrals

Referrals are by far the cheapest method of recruiting patients. According to the Center for Information and Study on Clinical Research Participation ( CISCRP ), 64% of the public believes they should learn about clinical research from primary care providers. Yet, only 0.2% of people are recruited this way.

It stands to reason, then, that a strong network of primary physicians would be a low-cost, preferential approach to recruitment and should be prioritized. Effective networking and the regular sharing of eligibility criteria between researchers and healthcare professionals is the key to increasing referrals. 

3 – Social media

While audio-visual and print media have been the traditional approaches to outreach, they’re the most expensive and outdated formats. Digital recruitment campaigns follow patients to wherever they are on social media across any platform. 

This approach is significantly cheaper than most other media approaches in cost-per-recruit. It can involve personal or generalized ads, depending on the necessary precision of the targeting. 

4 – Flexibility

Where possible, it’s important to reduce the impact of the trial on eligible recruits. Removing as many barriers to participation in trials is the most effective way of improving recruitment numbers. One way to do this is to bring the trial to the patient. 

Siteless trials are on the rise, and they work by partnering with local labs to provide a convenient port of entry for the eligibility checks. This cuts down on travel. Decentralized or virtual trial set-ups, where applicable, speed up enrolment times and increase participation. 

5 – Cast a wide net

Patients who have been turned down at the eligibility stage for previous trials are much less likely to apply for a second study. When screening, it can be useful to either screen for multiple studies at once or collect eligibility data compiled for future use. Should patients meet the criteria of future trials, they can be contacted directly to participate. This cuts down on the cost of contacting ineligible patients. 

6 – Factor in patient retention

While retention might be considered a separate challenge, limiting the factors that lead to patients dropping out of trials achieves the same goal. Strategies for this can also be implemented in the selection process. 

Recruitment teams should be employing patient engagement practices and making sure they are available for patients throughout the process. Offering feedback services or educational tools to patients helps them feel engaged and invested in the process. 

 7 – Understand your patients

Little of what has been discussed would be possible without understanding what is important to the patients as stakeholders in the trial process. 

Listening to the Patient’s Voice and incorporating it into the study design at the beginning of the selection process will help tailor the test design, practical applications, and follow-up procedures accordingly. 

Understanding patient preferences will go a long way to increasing recruitment and retention. 

Patients can often feel like guinea pigs in clinical trials, and the process can take too long, or testing can be too invasive. There are many elements to recruitment that need to be considered when looking to improve sample sizes, but the patient’s voice is one of the most often overlooked and can be the most valuable. 

High outreach costs and poor recruitment strategies often lead to failed trials, so identifying and improving weak methods is crucial to improving the function of clinical trials.

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Factors influencing recruitment to research: qualitative study of the experiences and perceptions of research teams

Lisa newington.

1 NIHR Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Guy’s Hospital, SE1 9RT, London, UK

Alison Metcalfe

2 Florence Nightingale School of Nursing and Midwifery, King’s College London, James Clark Maxwell Building, SE1 8WA London, UK

Recruiting the required number of participants is vital to the success of clinical research and yet many studies fail to achieve their expected recruitment rate. Increasing research participation is a key agenda within the NHS and elsewhere, but the optimal methods of improving recruitment to clinical research remain elusive. The aim of this study was to identify the factors that researchers perceive as influential in the recruitment of participants to clinically focused research.

Semi-structured interviews were conducted with 11 individuals from three clinical research teams based in London. Sampling was a combination of convenience and purposive. The interviews were audio recorded, transcribed verbatim and analysed using the framework method to identify key themes.

Four themes were identified as influential to recruitment: infrastructure, nature of the research, recruiter characteristics and participant characteristics. The main reason individuals participate in clinical research was believed to be altruism, while logistical issues were considered important for those who declined. Suggestions to improve recruitment included reducing participant burden, providing support for individuals who do not speak English, and forming collaborations with primary care to improve the identification of, and access to, potentially eligible participants.

Conclusions

Recruiting the target number of research participants was perceived as difficult, especially for clinical trials. New and diverse strategies to ensure that all potentially eligible patients are invited to participate may be beneficial and require further exploration in different settings. Establishing integrated clinical and academic teams with shared responsibilities for recruitment may also facilitate this process. Language barriers and long journey times were considered negative influences to recruitment; although more prominent, these issues are not unique to London and are likely to be important influences in other locations.

Participant recruitment is vital to the success of a research study, and yet many research projects fail to recruit a sufficient number of participants [ 1 ]. Increasing participation in clinical research has become a key area of focus within the NHS, with the aim of facilitating evidence-based policy, improving health outcomes and reducing health inequality [ 2 ]. The identification of optimal recruitment methods is gaining interest and a recent systematic review of strategies aimed at improving recruitment to randomised controlled trials (RCTs) identified 45 relevant studies and categorised six types of intervention: trial design, obtaining consent, approach to participants, financial incentives, training for recruiters and trial coordination [ 3 ]. Overall, the general strategies found to be effective in improving recruitment included: making telephone reminders to non-responders, having opt-out procedures where potential participants are required to contact the trial team if they do not want to be contacted about a trial, and having open rather than blinded trial designs [ 3 ]. It is not known whether more trialists are now adopting these strategies, or if they are proving successful in other settings or for other research methodologies.

Attempts to optimise recruitment and retention for non-interventional research studies include a range of techniques, such as using large sampling frames, sending reminders, running wide-scale publicity campaigns, providing free helplines and providing material in the respondents’ own languages [ 4 ]. While there may be universal elements to improving clinical research recruitment, reports of successful recruitment strategies for non-intervention studies are often directed at the particular target demographic group, for example: African American Elders [ 5 ], palliative care patients and their carers [ 6 ], adolescent mothers [ 7 ] and individuals from minority groups [ 8 ]. It is clear that recruitment and retention strategies need to be relevant to the target population and the research methodology used, and therefore the optimum strategy is likely to vary. However, further investigation of research recruitment according to different study designs is required to enable an evidence-based approach to recruitment.

The views of the researchers and clinicians involved in participant recruitment are beginning to be explored. We recently conducted a systematic review and thematic meta-synthesis to investigate this subject and found that the recruitment process could be defined by five key themes: building a research community, securing resources, the nature of the research, professional identities, and recruitment strategies [ 9 ]. Across all five themes there were reports of competition and compromise. Competition arose over funding, staffing and participants, and between clinical and research responsibilities; whilst compromise was needed to create study designs that were acceptable to patients, clinicians and researchers. Overall the views of researchers and clinicians were similar, which was partly explained by the overlapping elements of their roles.

The factors and situations that prompt some individuals to agree to participate in clinical research when others decline have also received attention, with the hope of informing new recruitment practices. However, to date, this work has been predominantly directed at a single medical condition and there have been varied findings [ 10 - 14 ].

Geographical location has been shown to influence recruitment rates to RCTs, with large cities such as London associated with poorer recruitment [ 15 , 16 ]. Possible suggestions for lower recruitment rates in London are the more varied ethnic population (individuals who are traditionally more difficult to engage in medical research), higher population mobility (individuals potentially missing invitations or reminders to participate), and more university hospitals (creating research fatigue as individuals are repeatedly approached to participate in research) [ 15 ]. Research teams in London therefore not only have to contend with the recruitment issues faced elsewhere, but may face an additional set of issues associated with their location.

The aim of the current study was to identify and understand the factors affecting recruitment to clinically focused research in London, UK, with the aim of mapping the existing strategies and informing new approaches. This study adds to existing work by exploring pertinent themes that arose across different clinical areas, study designs and researcher roles, providing a broad view of the factors that researchers consider important for the recruitment of clinical research participants. The following questions were explored:

1) What do researchers perceive to be the influential factors in recruiting participants to their clinically focused research?

2) What steps do research teams take to optimise recruitment to their studies?

3) What are researchers’ perceptions of why potential participants consent or decline to participate in their research?

4) Does being located in London create any additional issues with recruitment?

A convenience sample of three research leads involved in clinically focused research and based in teaching hospitals in South London were identified and invited to participate in a one-off interview to discuss their experiences and perceptions of recruiting participants for their studies. The phrase clinically focused research was defined as any medical research requiring an individual’s consent to participate, including donation of tissue samples, observational studies and RCTs, and the discussion was limited to recruiting adult patients able to give informed consent. The interviews were semi-structured and used non-directive, open-ended questions based on topics identified from preliminary discussions with clinical researchers and from the existing literature; the topic guide is listed in Table  1 . Each participant was asked to identify other members of their team with differing roles and responsibilities, and a purposive sample of these individuals was also invited to participate in the study. The same topic guide was used throughout and additional individuals were identified as necessary to ensure a broad mix of research professions were included, and to enable interviewing to continue until saturation was reached. All interviews were conducted face-to-face by the primary author in early 2013 at locations chosen by the participants. The interviews were audio recorded and transcribed verbatim.

Interview topic guide

The interview data was analysed using the framework method established by Ritchie and Spencer [ 17 ]. The framework matrix was developed using NVivo 10 software (QSR) and incorporated the interview topic guide, ideas from the existing literature and prominent themes identified from a preliminary review of the transcripts. The transcripts were coded line by line and additional themes were entered into the matrix where necessary. The matrix was populated with summarised data according to participant and theme, and used to identify common and divergent issues in answer to the study research questions.

Ethical approval

This study was approved by the King’s College London, College Research Ethics Committee (Reference PNM/12/13-106). All participants gave informed consent to be interviewed. All but one participant also consented to anonymous quotes from their interviews being used in the resulting reports and publications.

A total of 15 individuals were invited to participate in the study, of which 11 agreed to be interviewed. Participant demographics are shown in Table  2 . One speciality registrar declined to be interviewed, citing that his role was predominantly clinical not research-based, and three speciality registrars did not reply to their invitations. The mean interview duration was 28 minutes, ranging from 19 to 48 minutes.

Participant demographics

*Medical doctor receiving advanced training in a specialist area.

The information provided has been limited to preserve the anonymity of the interviewees and their teams.

Interviewees were involved in a range of studies, all outpatient-based and run as part of three research teams (A, B and C) in three tertiary care hospital sites in South London. Study designs included a first-in-man drug trial, longitudinal observational studies, laboratory studies requiring one-off anonymous tissue samples, genetics studies, trials of therapy interventions, and physiological studies. All research teams carried out research with patients and healthy volunteers, and most interviewees had volunteered themselves as study participants at some stage. With the exception of the two clinical research scientists and the clinical research associate, all participants were also involved in clinical activities as part of their role. When asked why they became involved in clinical research, all participants reported having an interest in research at an earlier point in their career and acting upon this for a variety of reasons including: an extension of a previous role, the desire for more control over their work, part of their current training, to learn more about evidence-based medicine, to do something worthwhile, to improve job satisfaction and to ensure more sociable working hours. All interviewees were educated to degree level, four had gained a PhD and two were working towards a PhD or MD. All participants acknowledged difficultly in recruiting research participants and mentioned particular strategies or modifications that were made to improve recruitment within their teams. The general perception of recruitment was that it is hard to recruit the desired numbers in the allocated time and that more often than not, extensions to the recruitment period are required.

Influential factors in the recruitment of participants

Numerous factors were identified by the interviewees as influential in the recruitment of research participants and these were categorised into four main themes: infrastructure, nature of the research, recruiter characteristics and participant characteristics.

Infrastructure

The need for access to potentially eligible participants was emphasised throughout. Collaboration between hospital clinicians, GPs and researchers were viewed as essential for the identification of eligible patients and to avoid clinician gatekeeping. All research teams had established systems to facilitate the identification of patients, but there was awareness that potentially eligible patients seen in other departments or hospitals were frequently inaccessible.

“There will be a lot of patients going to [smaller hospitals], who could be enrolled in studies, but they’re not available there. They are available here. If they knew that we were doing it, and there was a mechanism for moving those patients for the duration of the trial here, I would think everyone would be happy. But there isn’t” . (Consultant, team A)

One team had developed a strategy where local hospitals were encouraged to identify eligible patients and refer them to the participating site for the duration of the trial. Whilst this was seen as a positive step, it was also acknowledged that greater recognition for the referring sites, in terms of funding and co-authorship, would be required to improve uptake.

The preparatory work carried out by research teams was considered highly influential in the success of recruitment. Screening patient records, identifying eligible patients, preparing appropriate recruitment material and ensuring that the relevant clinicians and researchers were fully informed about the study, were all recommended. These tasks were primarily the responsibility of the research nurses and research associates.

“Here, we do look through the clinic list and, myself on the busiest days, will look at the past three clinic letters and see if they’re going to be suitable, or if they’re already on the study. We do recommend that’s the best way to find patients. And then we’d print the relevant paperwork and put that in the notes, so the doctors can see. So then they don’t even have to think about it, it’s just there. I think that works best. I would say that maybe about half of places do that, because they haven’t got time. They haven’t got time to do the prep” . (Clinical research associate, team A)

One suggestion to improve access to patients was the use of opt-out systems. This was mentioned with reference to patients being required to opt out of research teams contacting them about relevant research projects, but was also discussed with regard to opting in to the routine donation of anonymous tissue samples (surplus to requirements for clinical tests) for clinically focused research. Neither system was currently in place.

Issue with the regulations surrounding ethical approval and the content of participant information sheets were commonly discussed. The interviewees thought that the approval process was too slow, which created delays in starting recruitment and raised concerns that their departments would get overlooked for involvement in multi-centre studies in favour of sites with faster turnaround times.

“We certainly need to improve the speed with which we’re able to take a study from application through to actually being run. We are unbelievable slow. Unbelievable top heavy with regulation… It often means, locally, that we get bypassed in these programmes” . (Consultant, team A)

The interviewees were also concerned that the information required by ethics committees led to the participant information sheets becoming excessively long and detailed, and off-putting to patients. The researchers were aware of the conflict between ensuring patients had sufficient information about a study to make an informed decision about participation, and providing accessible study literature, however many interviewees believed that with the current format, patients did not actually read the information sheets provided, instead relying on verbal discussions to make a decision about participation.

“I get a few who will [read the patient information sheets], but nobody does. I would say 98% of people don’t read it. I do a summary of what is important to them” . (Specialty registrar, team C)

Several researchers suggested inviting patients and members of the public to sit on ethics committees to provide feedback on this issue and one research team had implemented a strategy to use more images and pictures in their participant information sheets to improve readability.

Increasing public awareness of clinically focused research was widely thought to have the potential to improve research recruitment, with the exception of one interviewee who felt that people would only be interested in research when their health was affected. Whilst there were many comments on the need to increase awareness of research within hospitals and other healthcare facilities, interviewees had few suggestions of how this could be improved. There was frustration at the lack of media coverage or celebrity endorsement within their clinical areas, compared to the numerous high-profile campaigns for areas such as cancer research. However, the media was viewed as having both positive and negative effects on recruitment, depending on the nature of the coverage.

Nature of the research

The influence of the type of research on participant recruitment was discussed by all interviewees. It was noted that clinical trials were harder to recruit for than observational studies because they require greater commitment from the participants in terms of time and risk. The interviewees also acknowledged the difficulty between designing studies that were appealing to potential participants and ensuring they were scientifically robust.

“We wanted it to be a good trial from the beginning. So it wasn’t just ‘everybody gets [the intervention] and let’s see what happens’. Although that would have been much easier and might have given us the answer quicker. So it’s placebo controlled, randomised, double blind. Not only are we asking these people to possibly risk their lives, but they might not get it anyway” . (Clinical research scientist, team B)

Some studies incorporated open label or crossover phases after the initial RCT, which was believed to make the study more acceptable to patients. Other recommendations, such as allowing patients to have their study blood tests carried out in the community and offering evening and weekend research appointments, were suggested to reduce the time burden of research participation, but these strategies had not been adopted.

“I guess the big thing would be to try and reduce the burden of commitment to patients, as much as possible. If there was any chance that they could have research bloods taken with GPs, or in their local community, or research nurses could go and take the blood in their home, to avoid this” . (Research nurse, team A)

Payment for research participation was also discussed. Research leads highlighted the ethical issues associated with paying patients for research participation, whilst others acknowledged the role of payment as a driver in recruiting people to participate in their work. The semantics of this issue were important, with one interviewee stating that while it was unethical to pay patients to participate in research, there was the need to explore “being able to financially help volunteers better” . (Consultant, team A).

Recruiter characteristics

It was widely reported that patients were more likely to agree to participate research if they were asked by a medical doctor, specifically their usual doctor. Even for observational studies, which do not require a doctor to take consent, it was noted that recruitment was more successful if the doctor mentioned the study to the patient before the research nurse provided a more detailed explanation. In this respect, successful recruitment was seen as a team effort.

“Our clinicians are so pro-research they are very good at introducing it into the clinical consultation, which really helps, because if it’s first mentioned, I think, by a clinician it’s considered just a normal part of the clinical care, then I think people are sometimes a bit more accepting of it” . (Research nurse, team A)

In addition to the recruiters’ professional roles, their personality and knowledge of the research project were also considered influential. Although all interviewees had undergone the relevant research and ethics training, none had received specific training in recruitment. There was debate on whether it was possible to teach the art of recruitment and if so whether this would be useful. The more experienced researchers felt that specific training was unnecessary as recruitment style and strategy vary depending on the clinical speciality and the particular study involved, and on-the-job experience was believed to be more important that generic recruitment training. It was also suggested that an individual’s personality was central to their recruitment success, an aspect that is difficult to teach.

“ The art of getting people in; it’s not clear. If I couldn’t recruit to trials, I wouldn’t be doing trials… some of my colleagues are good at recruiting, some aren’t quite so good. Trying to tell someone what to do is just not helpful, is it? ” (Consultant, team B)

“Then it’s also your personality. I think patients, they need to trust you. If you are a little bit unsure about something – not about the protocol itself, because that changes and you can’t expect to know a thousand pages of protocol – but that you are confident. Holding their hands all they way during the study” . (Research nurse, team B)

The less experienced researchers believed they would have benefited from additional support during the early stages to learn how to optimise their recruitment success, but acknowledged that a general training programme was unlikely to be appropriate for all recruitment situations.

Interviewer: “Did anyone talk to you about recruiting?”

Respondent: “No, but it would have been helpful… No-one spoke to me and gave me any advice… Although studies are so different and patient groups are so different, that it’s probably slightly different for everyone” . (Specialty registrar, team A)

The clinical research scientists expressed frustration at being reliant on clinicians to recruit patients for their research, especially as they had completed the prerequisite training and had recruited patients previously; however current regulations prohibit non-clinicians from recruiting patients.

“I don’t know why they don’t think [scientists] can consent people here. We used to be able to. It’s only the last few years that we’ve not been able to. We’ve done all the consent courses and everything” . (Clinical research scientist, team B)

Participant characteristics

All interviewees thought that certain patients were more likely to agree to participate in clinically focused research than others. The reported reasons for this are explored in more detail in the section “Why do some individuals consent to participate and others decline?”, however it is important to highlight that for a potential participant to either consent or decline to participate in research, they must first be invited. This links to the previous issues of identifying and accessing eligible patients, but also relates to situations where potentially eligible patients may be denied the opportunity to take part. For example, several interviewees mentioned that individuals who do not speak or understand English are unable to participate in the majority of studies due to the absence of funding for interpreter and translation services.

“…that’s actually something we really need to think of as a team going forward with recruitment, because at the moment we’ve said, for example, if patients come with interpreters or they have no English, then we haven’t included them” . (Research nurse, team A)

One interviewee recalled using interpretation services in the past, but only as a last resort due to the additional workload created.

“It did happen in the past, that for some protocol it had been waived that you can have an interpreter, which can’t be a relative. Because it needs to be an independent interpreter. It needs to be really last chance, because it’s a lot of work, extra, on top of what you have to do” . (Research nurse, team B)

Where potential participants did speak sufficient English to be eligible for participation, but it was not their first language, some interviewees reported lower recruitment rates compared with native English speakers. Suggested reasons for this included communication issues or a general increased reluctance to participate in clinical research.

“Potentially there have been times in the past where I’ve felt that this person’s not really taking in what I’m saying, for various reasons, whether that’s to do with language differences, English not as a first language” . (Research nurse, team A)

Steps taken to optimise recruitment

Table  3 shows the recruitment strategies and specific techniques employed by the research teams and the interviewees’ suggestions of techniques to further improve recruitment. The recruitment strategies were divided into three main themes: preparation and planning, engendering patient support, and collaboration with clinicians. The majority of suggestions to improve recruitment were targeted at making research participation more appealing and less time consuming for patients.

Steps taken by research teams to optimise recruitment and interviewees’ suggestions for improvement

Why do some individuals consent to participate and others decline?

The interviewees believed that the main reason why patients agreed to participate in their research was altruism, including the desire to help future patients and the wish to give something back to the hospital and team that cared for them. For the latter, researchers were clear to point out their duty to ensure that research participation was truly voluntary, rather than an obligation.

“A common thing tends to be ‘you’ve done so much for me, I’m quite happy to do anything for you’. Which is a sort of double edged sword actually, because that’s very generous of them, but actually you want them to participate because they want to, and you have to say ‘well you don’t have to’, and you’ve got to think that they’ve actually understood” . (Research nurse, team A)

There was also a general consensus that many individuals who took part in clinically focused research valued the potential benefits of participation, namely the opportunity to access additional health checks, novel treatments, increased contact with clinicians and the clearly defined plan of care. For researchers who provided payment for participation in their studies, financial gain was also viewed as an important motivator.

“Some of the studies that we run here, we pay £50 a visit. So it’s also to do with people need a bit of extra cash at the moment” . (Research nurse, team C)

Furthermore, patients who were interested in the research question and believed that clinical research was worthwhile were considered more likely to accept the invitation to participate. As discussed previously, the nature of the research was also viewed as highly influential, with patients preferring to participate in non-interventional studies.

“I think it’s much easier to recruit for an observational study. Because we’re not doing anything that could harm them” . (Specialty registrar, team A)

No particular strategies were employed to recruit patients of different ethnicities or socio-demographic backgrounds, with the common belief that recruiters attempt to invite all eligible patients to participate, regardless of their background. Despite the fact that recruitment was limited to English language speakers, most researchers felt that they recruited a good spread of the local population, although this did depend on the clinical area under investigation and the time commitment involved.

“I suppose retired patients have probably said ‘yes’ more willingly. For our study, we are requiring them to have extra tests. Some of the patients have said they are worried about time. Or getting here from work earlier” . (Specialty registrar, team A)

For patients who declined to participate in clinical research, the predominant reasons were thought to be practical. Patients who were working were unable to take extra time off work for research appointments and the additional travel required to attend the hospital was also believed to be off-putting, especially for patients who did not live locally.

“I think for some, mainly it’s time I’d say. Because often they’ve been sat in the waiting room for up to an hour already. So when it gets to the point where they’ve had their appointment, they’ve been seen by a nurse… they’re just like ‘I’ve just not got time’. I think that’s the main issue” . (Clinical research associate, team A)

Fear was also considered important, mainly with respect to clinical trials. Fear of taking new drugs, fear of additional diagnoses being discovered from extra screening, fear of needles, fear of symptoms worsening and fear of the storage of tissue or genetic information were all suggested. Language was also thought to play a role. As discussed in the section “Participant characteristics”, some interviewees observed that individuals who spoke English as an additional language were more reluctant to participate compared with native English speakers.

“I have noticed sometimes, I’ve not quantified this yet, because we haven’t analysed out results, but people who maybe don’t have English as a first language are probably a bit more reluctant” . (Speciality registrar, team A)

Specific issues for London

When asked specifically about recruitment issues associated with their location in London, the researchers’ responses fell into two main themes: local research community and patient population.

Local research community

The interviewees described successful research communities within their own teams, although there was a lack of collaboration with local primary care services. It was suggested that establishing shared research databases and other systems to identify and access potentially eligible patients across different service providers would be beneficial for study recruitment, but that specific initiatives would be needed to facilitate this.

“It’s hard because, in my view, if you really want to do it, it will cost money. It will involve someone, a GP with a research interest in the catchment area. For example, they call it GPSI, which is a GP with a specialist interest in something, rheumatology or haematology et cetera, but one would have research, just purely doing research” . (Specialty registrar, team C)

In addition, researchers reported delays in the process of gaining ethical approval for their studies and a lack of financial support for in-house academic research, suggesting that local improvements could be made to these systems.

Despite these recommendations for improvement, the interviewees were generally positive about working in London and the level of research support provided.

“I think in terms of being in a big London teaching hospital, we are more geared up to research, just from personal experience having worked in district generals in [UK county], there was no set up for research and it was very much a minor thing, and if anyone was doing something, they didn’t have research nurses, it was very much clinician led. It was set up in their own interests really, their own studies. So the fact that we have a forum for research nurses here, and we are trying to actively put out the research message” . (Research nurse, team A)

Patient population

It was noted by the researchers that patients attending hospital appointments in London frequently report long travel times and this was believed to be detrimental to recruitment. This was attributed to the broad catchment area for tertiary healthcare, plus the large number of people who commute into London for work. Interviewees reported difficultly recruiting patients with long journey times, especially if research participation involved additional visits.

“There’s quite a large population of people that travel in. I guess that will affect people taking part in research. Because if they’re having to travel from Hertfordshire, that’s going to put people off, because yes, you can give them their travel expenses, but you can’t give them their three hours back” . (Research nurse, team C)

Being a tertiary care centre was also thought to have a positive effect on recruitment, with researchers commenting that patients may be more likely to trust an invitation for research participation from a specialist centre.

“So people do come in from other hospitals. Again, you have a wider group. Also, they tend to be, in a way, more sick. More likely to listen to the medic who’s telling them, ‘this isn’t a bad thing’” . (Clinical research scientist, team C)

The interviewees also discussed the diversity of the local population, and as mentioned previously, the lack of interpretation and translation services for research resulting in potentially eligible patients being excluded. However, in general it was felt that the researchers were able to recruit representative samples of their local populations.

Although all these issues were important to researchers, it was also acknowledged that most locations have problems with recruitment and that having sufficient resources and research staff should perhaps be considered more important than the location.

“I wouldn’t say there are any huge differences that I can think of. I think it really does depend on the staff and the resources that they’ve got, rather than the actual hospital and the patients coming in” . (Clinical research associate, team A)

The primary aim of this study was to identify the factors that researchers perceive as influential in the recruitment of participants to their clinically focused research. Infrastructure, the nature of the research, recruiter characteristics and participant characteristics were all deemed important. The first three themes are, in theory, more amenable to modification than the last, for example through the development of systems to improve identification and access to eligible participants [ 18 ], designing studies with reduced participant burden [ 10 ] and ensuring that recruiters have the appropriate knowledge and skills [ 19 ]. The discussion of participant characteristics focused on the concept that certain patients were thought more likely to agree to research participation than others. The danger with such an observation is the potential for recruiters to stereotype potential participants based on previous experiences, and therefore choose not to approach individuals who are otherwise eligible. As the NHS constitution pledges to inform all patients of research studies that are relevant to them and in which they may be eligible to participate [ 20 ], recruiters must be aware of the potential to deviate from this duty. In reality, the decision to participate in clinically focused research is frequently multifaceted and requires potential participants to consider the personal pros and cons of taking part at any given time [ 13 ]. The research nurses interviewed for the current study raised this point and explained their attempts to approach all eligible patients, regardless of any preconceptions about whether or not they would agree to participate.

The general perception that doctors are more successful at recruiting research participants than nurses has been explored previously. Donovan et al. [ 21 ] found no significant difference in recruitment rates between urology consultants and nurses for a prostate cancer RCT and calculated that nurses were more cost-effective recruiters, despite spending longer on average with each patient. In the current study, recruitment was viewed more as a team effort. Having the doctor mention research participation as part of the routine consultation was thought to be beneficial, as was having integrated clinical and academic teams on site. However, these strategies require sufficient staffing and resources and rely on specific funding for research posts [ 9 ]. The possible recruitment benefits of having an established therapeutic relationship with potential study participants [ 22 ], sharing similar cultural backgrounds or languages [ 23 ], and employing peer recruiters [ 24 , 25 ] have all been explored in the literature. However, the influence of the recruiter-participant relationship was not widely discussed by the interviewees, nor were the subjects of culture and ethnicity. There was a general consensus that recruiters adopted the same recruitment strategies for all demographic groups, but observational investigations of recruitment practices would be beneficial to further explore these issues. The use of eligibility criteria that include only those who speak sufficient English was attributed to a lack of resources available for interpreter services. Resource limitations would also restrict the use of peer recruitment programmes or other strategies aimed at including minority groups. As recruiting a representative sample is essential for the generalisability of research findings [ 26 ], additional investigation of this issue is required.

The research scientists interviewed were disappointed that they were no longer permitted to discuss their study directly with potential participants. This finding echoes the views of biomedical research scientists involved in placental perfusion studies [ 27 ]. The scientists raised legitimate concerns that the individuals involved in recruitment did not have sufficient knowledge of the intricacies of the study to be able to fully explain the background and rationale to potential participants, or to answer questions about particular methodologies [ 19 ]. It in current study, it was local, rather than national, policy that dictated the exclusion of research scientists from recruitment activities. The potential benefits of allowing research scientists to recruit participants to their research include reducing the workload for clinicians, providing expert knowledge of the study processes and rationale, and separating research recruitment from routine clinical care. The potential drawbacks include the research scientist having a vested interest in the research without the balance of coexisting clinical duties, and the absence of a previous therapeutic relationship with the patient. Further exploration of this issue is required, however it may be advantageous to consider including clinical research scientists as part of the recruitment team, with safeguards to guarantee that patients are not exploited.

The recommendation to use an opt-out system, where patients are required to contact the research team if they do not wish to be invited to participate in clinical research, was made in a recent systematic review [ 3 ]. Several interviewees suggested that this might be a beneficial system, however this strategy is not currently employed, and further work is required to pilot the use of opt-out within these settings. A variation of this strategy, where patients are invited to opt-in to the anonymous donation of surplus tissue after clinical tests, was also discussed. This type of tissue biobanking is available at the interviewees’ hospital sites for patients with a diagnosis of cancer, but is not routinely adopted in other clinical areas. Further research into the extension of biobanks to include other clinical specialties appears warranted [ 28 ].

The use of open, rather than blinded trial designs, and telephone reminders were also recommended by Treweek et al. [ 3 ]. There is debate over the utility of open study designs due to the potential for increased bias [ 29 ], but this methodology is gaining support [ 30 ]. The interviewees used modified versions of this strategy, such as having an open or crossover phase after the main trial, and believed this was beneficial for recruitment. None of the interviewees specifically discussed the use of telephone reminders.

The recruitment strategies employed by the interviewees were similar to those identified in our recent meta-synthesis, although there was less focus on emphasising the benefits of research participation in the current study [ 9 ]. In addition to the possible coercive aspect of emphasising the benefits , the interviewees believed that altruism was the key reason for patients accepting the invitation to participate, and therefore strategies based on highlighting potential personal benefits would not sit with this premise. The dominance of practical issues as proposed reasons for patients declining the invitation to participate in research have been documented elsewhere [ 9 , 10 ].

The key factors associated with conducting clinically focused research in London were language and travel time. Interviewees were unable to offer interpretation services to facilitate discussions about research with patients who did not speak sufficient English. The most recent government data shows that within the associated South London boroughs between 19.6-20.3 % of residents do not speak English as their primary language, compared with 15.3 % and 7.1 % in the next biggest UK cities Birmingham and Leeds, respectively [ 31 ]. The range of primary languages spoken is also greater in the interviewees’ regions, with more than 54 different languages, compared to 36 in Birmingham and 29 in Leeds [ 31 ]. Traditionally, individuals from ethnic minorities have been considered less likely to participate in clinically focused research, however studies from the USA suggest that this is not the case and recommend that more needs to be done to ensure access to research for minority groups, rather than interventions aimed at increasing willingness [ 32 - 34 ]. Strategies to aid the removal of language barriers identified in the current study would improve access to research and could potentially increase recruitment, however further investigation is required.

The interviewees also observed that patients with long travel times to the hospital were less willing to take part in research. When designing clinically focused studies, it may therefore be useful to explore the interviewees’ suggestions of increasing the use of information technology for data collection and forming collaborations with local healthcare services to minimise participant travel. As the average commuting time is 48 % longer in London than elsewhere in the country [ 35 ] this factor may be less problematic in other locations, however most tertiary and quaternary healthcare services conducting research are likely to experience similar travel issues.

Strengths and limitations

The current study adds to previous work by providing experiential reports and perceptions from research teams in three different non-cancer outpatient settings, within a specified geographical location. However, as the research teams involved were based in South London, further work is required to ascertain whether these findings translate to other regions, nationally and internationally.

Although interviewing was continued until saturation, the small sample size in the current study means it is not possible to infer any differences between the experiences and opinions of the different professions within the research teams. Furthermore, the current study relied on information collected from semi-structured interviews, and may have been subject to reporter bias. Attempts were made to minimise the degree of bias by selecting independent research teams and interviewing participants individually. Additional explorations of the researchers’ practices that include observation of the recruitment situation would be beneficial, but were beyond the scope of the current study.

Infrastructure, nature of the research, recruiter characteristics and participant characteristics were all believed to influence the success of recruitment to clinically focused research. Suggestions to improve recruitment included reducing participant burden, providing support for individuals who do not speak English and forming collaborations with primary care to improve identification of, and access to, potentially eligible patients. Despite the focus on London in the current study, the factors identified are not unique to this location and are therefore likely to be representative of other diverse cities within the UK.

Competing interests

There were no competing interests in the conduct of this study.

Authors’ contributions

LN and AM made substantial contributions to the design of the study. LN carried out the interviews, conducted the analysis and wrote the final manuscript. AM advised on research conduct from inception to completion, appraised the analysis process and revised the manuscript. Both authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2288/14/10/prepub

Acknowledgements

The authors would like to thank and acknowledge the contribution of the researchers who gave their time to be interviewed for this study.

This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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• Clinical trials and evidence

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Effectively Managing Clinical Trials, Recruitment, and Adaptive Trials

Learning how to effectively manage clinical trials, from recruitment to trial design and adaptability, is critical for the economic well-being of clinical research organizations..

• Veronica Salib, Assistant Editor

Clinical trial significance and success throughout the COVID-19 pandemic have inspired the launch of clinical trial branches for existing companies, such as Walgreens, and multiple startups. However, it is critical to note that while some clinical trials have public and widely recognized success, most are unsuccessful. Successful clinical research organizations have learned how to effectively manage clinical studies from all fronts, developing clear recruitment strategies and adapting trials as needed.

Clinical Trial Success Rates

As science advances, the clinical trial industry continues to grow and develop. The global market was valued at roughly $47 billion in 2021. A report by Grand View Research estimates an annual growth rate of 5.8% from 2022 to 2030.

Despite significant economic growth, the FDA notes that only 70% of drug trials move from Phase 1 to Phase 2. Roughly one-third of trials move from phase 2 to phase 3, while approximately 25–30% move from phase 3 to phase 4. This data suggests that roughly 90% of clinical trials fail.

From a scientific standpoint, failure is a necessary step toward success. A failed clinical trial can help clinicians and healthcare professionals gather the information that may provide background for later clinical trials. However, from a business perspective, clinical trials require funders and organizations to take considerable financial risk. Investors must understand the clinical business model and best practices to ensure the most significant financial success when deciding whether to back or start a clinical trial.

Factors to Consider in Clinical Trial Management

Based on a presentation from the University of Alabama Birmingham , three main areas of management are required in the business of clinical trials: program management, clinical trial management, and financial management. Understanding these management areas can better equip companies for a successful clinical trial.

Program Management

Managing the program involves hiring the teams in charge of the clinical trial and training them. This process is relatively easy for many established clinical research organizations (CROs) and pharmaceutical companies. Pharmaceutical companies already have their own pharmacists, healthcare professionals, engineers, and technicians on staff with some pre-established knowledge of the company’s practice.

Other factors to consider when managing the program include equipment, maintenance, supplies, and the development of a performance portfolio to assess the program’s efficacy.

Clinical Trial Management

In addition to managing the program as a whole, another critical aspect is actually managing the clinical trial. This often requires an in-depth feasibility assessment of all parts of the study. It provides leaders with information on the project's scope, how likely the company is to complete the project successfully, and how likely it is to meet the end goal. Below is a graphic from Applied Clinical Trials that details the varying components of the feasibility process.

In addition to conducting feasibility assessments, the CRO should also consider conducting an analysis of interest, answering the following question: are there enough potential participants interested in this trial? Assuming the answer is yes, the CRO can begin the patient recruitment process in collaboration with the clinical trial site .

The final portion of managing the actual clinical trial is understanding and planning for lack of success. As previously mentioned, most clinical trials are unsuccessful, meaning that the time, money, and work put into many clinical trials go wasted. Part of effectively managing a clinical trial from a business perspective is knowing when unsuccessful clinical trials should be discontinued and when they can be adjusted or repurposed. To mitigate wasted money, many companies are turning toward adjustable clinical trials to redirect efforts when early studies prove to be futile.

Money Management

The final business aspect of managing clinical trials is learning how to manage the finances associated with them. There are multiple costs related to clinical trials, including indirect fees paid to the clinical trial site or institutions conducting the study, patient care costs, personnel time, document storage, FDA audits, and more.

Best Recruiting Practices

As previously mentioned, part of a clinical trial’s success relies on recruiting the appropriate patient population. Recruitment strategies can vary dramatically depending on the intended therapeutic area, the age of patients, and the type of study — interventional or observational.

More often, recruiters are looking toward digital media recruitment strategies. While recruitment depends on the clinical trial site, an Antidote article lists some best practices for patient recruitment.

Chief of this recommendation is a patient-centric approach to recruitment. As with any part of clinical trials, a focus on the patient or types of patients in this trial is critical. When advertising for clinical trial recruitment, it is essential to answer any questions a patient may have clearly and easily. Leaving questions unanswered can hold patients back from pursuing the trial. In the same vein, another best practice is to plan for advertisements that reach the target audience, excluding or including recruitment strategies based on participant criteria. 

Another vital practice during recruitment is ensuring that all advertisements follow the platform's protocols, policies, and regulations. Advertisements typically require a financial contribution, which typically pays off by recruiting several patients. However, they can be taken down if the ads do not follow policies.

Analyzing the recruitment campaign is also crucial for ensuring that clinical trials stay on track business-wise. Funneling money into specific recruitment methods without analyzing their success is foolish. Companies who have previously done clinical trials may choose to assess the success of previous recruitment tools. In contrast, new companies may consider analyzing the campaign results halfway through recruitment.

Finally, researching and understanding new digital recruitment platforms and tools is critical for clinical trial leaders focused on the recruitment process.

Understanding Adaptive Clinical Trials

With a failure rate of nearly 90%, clinical trials lead to enormous research and development spending. Standard practice in the clinical trial landscape is to have a study protocol developed before its start and remain on the pre-determined pathway throughout the study, barring any safety concerns. Should the study produce unfavorable results, it would be discontinued. However, this rigid structure prevents clinical trials from being adaptive and able to accommodate unanticipated changes.

One proposed solution for reduced clinical trial spending is transitioning to an adaptive clinical trial model. According to Amgen , one of the best ways to improve clinical trial profitability is transitioning from a fixed to a flexible clinical trial design. "With adaptive designs, you can monitor the incoming data and modify the protocol based on what you're learning as the study unfolds," noted Rob Lenz, senior vice president of Global Development of Amgen, in the article. 

This doesn’t mean allowing any changes to be made at any point during a clinical trial. Instead, it identifies predetermined conditions that could indicate an adaption. Some examples provided by Amgen include dosage changes depending on efficacy data, trial size or duration changes to understand the impact better, or adding more patient types.

Another critical goal for clinical trial development and improvement is to improve the success rate of trials while reducing costs. In an article published by Amgen, the organization notes, “In conventional clinical development programs, tradeoffs are required if you want to prioritize speed, cost, or likelihood of success. To optimize for success, you often accrue more data at each stage of the program, but that makes the program go slower. Optimizing for cost by staging your investment also slows you down, while optimizing for speed tends to drive up the cost. With adaptive designs, it's possible to simultaneously increase the odds of success, reduce spending, and get to an answer more quickly.”

Instead of sticking to an incorrect assumption made before the start of a clinical trial or discontinuing a trial altogether due to false beliefs, adaptive clinical trials allow clinicians and researchers to correct some inaccurate assumptions and continue with the study.

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• NATURE INDEX
• 13 March 2024

How AI is being used to accelerate clinical trials

• Matthew Hutson 0

Matthew Hutson is a science writer based in New York City.

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For decades, computing power followed Moore’s law, advancing at a predictable pace. The number of components on an integrated circuit doubled roughly every two years. In 2012, researchers coined the term Eroom’s law (Moore spelled backwards) to describe the contrasting path of drug development 1 . Over the previous 60 years, the number of drugs approved in the United States per billion dollars in R&D spending had halved every nine years. It can now take more than a billion dollars in funding and a decade of work to bring one new medication to market. Half of that time and money is spent on clinical trials, which are growing larger and more complex. And only one in seven drugs that enters phase I trials is eventually approved.

Nature Index 2024 Health sciences

Some researchers are hoping that the fruits of Moore’s law can help to curtail Eroom’s law. Artificial intelligence (AI) has already been used to make strong inroads into the early stages of drug discovery , assisting in the search for suitable disease targets and new molecule designs. Now scientists are starting to use AI to manage clinical trials, including the tasks of writing protocols, recruiting patients and analysing data.

Reforming clinical research is “a big topic of interest in the industry”, says Lisa Moneymaker, the chief technology officer and chief product officer at Saama, a software company in Campbell, California, that uses AI to help organizations automate parts of clinical trials. “In terms of applications,” she says, “it’s like a kid in a candy store.”

Trial by design

The first step of the clinical-trials process is trial design. What dosages of drugs should be given? To how many patients? What data should be collected on them? The lab of Jimeng Sun, a computer scientist at the University of Illinois Urbana-Champaign, developed an algorithm called HINT (hierarchical interaction network) that can predict whether a trial will succeed, based on the drug molecule, target disease and patient eligibility criteria. They followed up with a system called SPOT (sequential predictive modelling of clinical trial outcome) that additionally takes into account when the trials in its training data took place and weighs more recent trials more heavily. Based on the predicted outcome, pharmaceutical companies might decide to alter a trial design, or try a different drug completely.

A company called Intelligent Medical Objects in Rosemont, Illinois, has developed SEETrials, a method for prompting OpenAI’s large language model GPT-4 to extract safety and efficacy information from the abstracts of clinical trials. This enables trial designers to quickly see how other researchers have designed trials and what the outcomes have been. The lab of Michael Snyder, a geneticist at Stanford University in California, developed a tool last year called CliniDigest that simultaneously summarizes dozens of records from ClinicalTrials.gov, the main US registry for medical trials, adding references to the unified summary. They’ve used it to summarize how clinical researchers are using wearables such as smartwatches, sleep trackers and glucose monitors to gather patient data. “I’ve had conversations with plenty of practitioners who see wearables’ potential in trials, but do not know how to use them for highest impact,” says Alexander Rosenberg Johansen, a computer-science student in Snyder’s lab. “Best practice does not exist yet, as the field is moving so fast.”

Most eligible

The most time-consuming part of a clinical trial is recruiting patients, taking up to one-third of the study length. One in five trials don’t even recruit the required number of people, and nearly all trials exceed the expected recruitment timelines. Some researchers would like to accelerate the process by relaxing some of the eligibility criteria while maintaining safety. A group at Stanford led by James Zou, a biomedical data scientist, developed a system called Trial Pathfinder that analyses a set of completed clinical trials and assesses how adjusting the criteria for participation — such as thresholds for blood pressure and lymphocyte counts — affects hazard ratios, or rates of negative incidents such as serious illness or death among patients. In one study 2 , they applied it to drug trials for a type of lung cancer. They found that adjusting the criteria as suggested by Trial Pathfinder would have doubled the number of eligible patients without increasing the hazard ratio. The study showed that the system also worked for other types of cancer and actually reduced harmful outcomes because it made sicker people — who had more to gain from the drugs — eligible for treatment.

Sources: IQVIA Pipeline Intelligence (Dec. 2022)/IQVIA Institute (Jan. 2023)

AI can eliminate some of the guesswork and manual labour from optimizing eligibility criteria. Zou says that sometimes even teams working at the same company and studying the same disease can come up with different criteria for a trial. But now several firms, including Roche, Genentech and AstraZeneca, are using Trial Pathfinder. More recent work from Sun’s lab in Illinois has produced AutoTrial, a method for training a large language model so that a user can provide a trial description and ask it to generate an appropriate criterion range for, say, body mass index.

Once researchers have settled on eligibility criteria, they must find eligible patients. The lab of Chunhua Weng, a biomedical informatician at Columbia University in New York City (who has also worked on optimizing eligibility criteria), has developed Criteria2Query. Through a web-based interface, users can type inclusion and exclusion criteria in natural language, or enter a trial’s identification number, and the program turns the eligibility criteria into a formal database query to find matching candidates in patient databases.

Weng has also developed methods to help patients look for trials. One system, called DQueST, has two parts. The first uses Criteria2Query to extract criteria from trial descriptions. The second part generates relevant questions for patients to help narrow down their search. Another system, TrialGPT, from Sun’s lab in collaboration with the US National Institutes of Health, is a method for prompting a large language model to find appropriate trials for a patient. Given a description of a patient and clinical trial, it first decides whether the patient fits each criterion in a trial and offers an explanation. It then aggregates these assessments into a trial-level score. It does this for many trials and ranks them for the patient.

Helping researchers and patients find each other doesn’t just speed up clinical research. It also makes it more robust. Often trials unnecessarily exclude populations such as children, the elderly or people who are pregnant, but AI can find ways to include them. People with terminal cancer and those with rare diseases have an especially hard time finding trials to join. “These patients sometimes do more work than clinicians in diligently searching for trial opportunities,” Weng says. AI can help match them with relevant projects.

AI can also reduce the number of patients needed for a trial. A start-up called Unlearn in San Francisco, California, creates digital twins of patients in clinical trials. Based on an experimental patient’s data at the start of a trial, researchers can use the twin to predict how the same patient would have progressed in the control group and compare outcomes. This method typically reduces the number of control patients needed by between 20% and 50%, says Charles Fisher, Unlearn’s founder and chief executive. The company works with a number of small and large pharmaceutical companies. Fisher says digital twins benefit not only researchers, but also patients who enrol in trials, because they have a lower chance of receiving the placebo.

Source: Citeline Trialtrove/IQVIA Institute (Jan. 2023)

Patient maintenance

The hurdles in clinical trials don’t end once patients enrol. Drop-out rates are high. In one analysis of 95 clinical trials, nearly 40% of patients stopped taking the prescribed medication in the first year. In a recent review article 3 , researchers at Novartis mentioned ways that AI can help. These include using past data to predict who is most likely to drop out so that clinicians can intervene, or using AI to analyse videos of patients taking their medication to ensure that doses are not missed.

Chatbots can answer patients’ questions, whether during a study or in normal clinical practice. One study 4 took questions and answers from Reddit’s AskDocs forum and gave the questions to ChatGPT. Health-care professionals preferred ChatGPT’s answers to the doctors’ answers nearly 80% of the time. In another study 5 , researchers created a tool called ChatDoctor by fine-tuning a large language model (Meta’s LLaMA-7B) on patient-doctor dialogues and giving it real-time access to online sources. ChatDoctor could answer questions about medical information that was more recent than ChatGPT’s training data.

Putting it together

AI can help researchers manage incoming clinical-trial data. The Novartis researchers reported that it can extract data from unstructured reports, as well as annotate images or lab results, add missing data points (by predicting values in results) and identify subgroups among a population that responds uniquely to a treatment. Zou’s group at Stanford has developed PLIP, an AI-powered search engine that lets users find relevant text or images within large medical documents. Zou says they’ve been talking with pharmaceutical companies that want to use it to organize all of the data that comes in from clinical trials, including notes and pathology photos. A patient’s data might exist in different formats, scattered across different databases. Zou says they’ve also done work with insurance companies, developing a language model to extract billing codes from medical records, and that such techniques could also extract important clinical trial data from reports such as recovery outcomes, symptoms, side effects and adverse incidents.

To collect data for a trial, researchers sometimes have to produce more than 50 case report forms. A company in China called Taimei Technology is using AI to generate these automatically based on a trial’s protocol.

Increased trial complexity

The cost of drug development continues to rise, and the size and complexity of clinical trials is a major factor. In the past two decades, the number of countries in which a clinical trial is conducted has more than doubled, and the average number of data points collected has grown dramatically. There are more endpoints — outcomes of a clinical trial that help to determine the efficacy and safety of an experimental therapy — and procedures to measure these outcomes, such as blood tests and heart-activity assessments. By comparison, eligibility criteria for participants, which include demographics such as age and sex and whether a participant is a healthy or a patient volunteer, have remained relatively consistent.

Source: Tufts Center for the Study of Drug Development. *Mean of total numbers

A few companies are developing platforms that integrate many of these AI approaches into one system. Xiaoyan Wang, who heads the life-science department at Intelligent Medical Objects, co-developed AutoCriteria, a method for prompting a large language model to extract eligibility requirements from clinical trial descriptions and format them into a table. This informs other AI modules in their software suite, such as those that find ideal trial sites, optimize eligibility criteria and predict trial outcomes. Soon, Wang says, the company will offer ChatTrial, a chatbot that lets researchers ask about trials in the system’s database, or what would happen if a hypothetical trial were adjusted in a certain way.

The company also helps pharmaceutical firms to prepare clinical-trial reports for submission to the US Food and Drug Administration (FDA), the organization that gives final approval for a drug’s use in the United States. What the company calls its Intelligent Systematic Literature Review extracts data from comparison trials. Another tool searches social media for what people are saying about diseases and drugs in order to demonstrate unmet needs in communities, especially those that feel underserved. Researchers can add this information to reports.

Zifeng Wang, a student in Sun’s lab, in Illinois, says he’s raising money with Sun and another co-founder, Benjamin Danek, for a start-up called Keiji AI. A product called TrialMind will offer a chatbot to answer questions about trial design, similar to Xiaoyan Wang’s. It will do things that might normally require a team of data scientists, such as write code to analyse data or produce visualizations. “There are a lot of opportunities” for AI in clinical trials, he says, “especially with the recent rise of larger language models.”

At the start of the pandemic, Saama worked with Pfizer on its COVID-19 vaccine trial. Using Saama’s AI-enabled technology, SDQ, they ‘cleaned’ data from more than 30,000 patients in a short time span. “It was the perfect use case to really push forward what AI could bring to the space,” Moneymaker says. The tool flags anomalous or duplicate data, using several kinds of machine-learning approaches. Whereas experts might need two months to manually discover any issues with a data set, such software can do it in less than two days.

Other tools developed by Saama can predict when trials will hit certain milestones or lower drop-out rates by predicting which patients will need a nudge. Its tools can also combine all the data from a patient — such as lab tests, stats from wearable devices and notes — to assess outcomes. “The complexity of the picture of an individual patient has become so huge that it’s really not possible to analyse by hand anymore,” Moneymaker says.

Xiaoyan Wang notes that there are several ethical and practical challenges to AI’s deployment in clinical trials. AI models can be biased . Their results can be hard to reproduce . They require large amounts of training data, which could violate patient privacy or create security risks. Researchers might become too dependent on AI. Algorithms can be too complex to understand. “This lack of transparency can be problematic in clinical trials, where understanding how decisions are made is crucial for trust and validation,” she says. A recent review article 6 in the International Journal of Surgery states that using AI systems in clinical trials “can’t take into account human faculties like common sense, intuition and medical training”.

Moneymaker says the processes for designing and running clinical trials have often been slow to change, but adds that the FDA has relaxed some of its regulations in the past few years, leading to “a spike of innovation”: decentralized trials and remote monitoring have increased as a result of the pandemic, opening the door for new types of data. That has coincided with an explosion of generative-AI capabilities . “I think we have not even scratched the surface of where generative-AI applicability is going to take us,” she says. “There are problems we couldn’t solve three months ago that we can solve now.”

Nature 627 , S2-S5 (2024)

doi: https://doi.org/10.1038/d41586-024-00753-x

This article is part of Nature Index 2024 Health sciences , an editorially independent supplement. Advertisers have no influence over the content.

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Clinical Trial Recruitment Practices: The Evolution of Ethical Considerations

Over the last few decades, the process of clinical trial conduct has evolved significantly. Clinical trial recruitment is one of these key areas. In addition to the advances in recruitment advertising through social media and other technologies, there are a number of practices that used to be considered acceptable, and even standard, which are no longer considered acceptable. In many cases, this is related to an increasing awareness and effort to avoid potential conflicts of interest for investigators, study teams, and referring physicians. At the same time, other practices, such as study sponsors providing direct staffing support for busy clinical sites, have become more popular.

This paper reviews practices related to clinical trial recruitment, with consideration of which are considered acceptable under current best practice, ethical and regulatory standards.

Practices Generally Considered Acceptable

1: payments to referral sources based on time and effort.

While the payment of “finder’s fees” to referral sources is considered unacceptable, it is usually considered appropriate to compensate a referral source for the time and effort that they spend on the referral process.

For example, if the nurse at a primary care center spends 6 hours looking at medical records to identify patients who may be eligible for the study, and calling those patients to tell them about the study and how to get more information if they are interested, it would be appropriate to compensate the nurse’s time at fair market value. It is important to remember that the compensation would be paid, regardless of whether any of the referred patients end up enrolled in the study, or even whether they screen for the study. Although this is generally considered acceptable by most oversight bodies (such as Institutional Review Boards (IRBs)), there are some ethicists who disapprove of this practice.

2: Assistance with trial-related site travel expenses

For many years, study sites have reimbursed trial participants for expenses related to study visits including such things as parking fees at the clinical site, cab fare to the clinical site, meals during long study visits, and sometimes even expenses like child care. For some studies, this may even be extended to include reimbursements for air travel and hotel stays when study participation requires long distance travel.

Generally, researchers, IRBs and sponsors agree that participation in clinical research should not incur additional expenses for the trial participant that they would not have encountered had they not been in the study. Therefore reimbursement of these expenses, or providing services to avoid the expenses (like giving meal or taxi vouchers), is both respectful and appropriate.

More recently, sponsors and sites have tried to facilitate the participation in research by providing transportation to clinical sites for study visits through third-party ride-service vendors like Uber™ or Lyft™, where the cost of the transportation can be directly billed to the site or sponsor. Although this is essentially the same concept as providing reimbursement for parking, or a taxi voucher, some IRBs and sites have been hesitant to use these services for reasons that are not clear. Although these on-demand services are novel for many people, there is no unique ethical or regulatory concern introduced that should prevent the use of these services to reduce the burden of participation.

3: Support for site study activities including recruitment

In studies with biopharma or other sponsors who provide funding, indirect costs in the contract often go toward the salary support for study staff who are tasked with multiple study-related activities, including subject recruitment/enrollment. In some cases, the study site contract may provide salary support as a direct cost, with team members assigned to the project for a certain percentage of time proportional to that support.

It is also fairly common for sponsors or CROs to provide extra temporary staffing support to a study site when activity is high; for example, to send a Clinical Research Associate to the site to help enter data into case report forms or answer data queries in advance of a data base lock deadline when the site finds itself understaffed. FDA has considered and accepted this practice of having study staff that is not in the direct employ of the investigator. 1

The appropriate participation of these supplementary team members requires that they work under the direction of the investigator, who remains responsible for all site activities related to the study, that they are trained for the tasks they are conducting, and that their responsibilities are documented as necessary in the delegation of authority log at the site.

An emerging type of support for study activities is the use of enrollment assistants at clinical sites. These are study team members who have salary support from the sponsor, but are assigned to, and work under, the direction of the site staff or investigator to support activities related to identifying potential study participants. Depending on the site needs and the study, their activities may include contacting referral sites to make them aware of the study, reviewing medical records to identify potential participants, outreach to potential participants, and pre-screening or screening activities. As with support for other study site functions, there are no regulatory or ethical prohibitions on staffing of this kind, assuming that the financial support of these staffers are time-based (not based on referrals or enrollment numbers), and that there are no other direct or indirect incentives related to enrollment which could create a conflict of interests.

Practices Generally Considered Problematic

1: site payments based on enrollment numbers.

Several years ago, it was not uncommon for sponsors to include recruitment-based incentive gifts or payments incorporated into study site contracts. These incentives could be seen in several forms:

• As a “per subject” payment for study costs which increased in amount after a certain enrollment target was reached (e.g., $2000/ subject for the first 10 subjects, $3000/subject for the next 10 subjects)
• As a bonus payment either to the site or directly to a member of the study team when an enrollment target was reached, or for the first site in a multicenter study which reached an enrollment target (e.g., first site to randomize 10 participants got a $5000 bonus to the study staff)

Sometimes there were efforts to make bonuses more acceptable by providing them as reimbursement for travel to a conference, or as equipment or educational materials for the study site or study team, (textbooks, etc).

Essentially, these kinds of bonus payments are now considered unacceptable. It is now recognized that providing direct financial incentives to the study staff for the enrollment of participants creates an unacceptable conflict of interests. Even without consciously doing so, the staff may encourage or pressure potential study participants to enroll, so that they can obtain the financial rewards. They may even be motivated — again, perhaps even without consciously doing so — to assess eligibility criteria less rigorously, or to be less critical in assessing the signs or symptoms of a potential participant that would otherwise be exclusionary or questionable, when rewards are promised.

Both sponsors and research sites, for the most part, now recognize this conflict and neither offer nor expect this kind of recruitment bonus. Recruitment plans that include these incentives are still occasionally seen, often when the study is being sponsored or managed by a less-experienced team, or when recruitment plans are developed by firms that specialize in marketing and commercial projects outside of the health sciences field, and when these teams have not thought through the conflicts these situations present.

2: Payments to referral sources based on successful enrollment of referrals (finder’s fees)

In some studies, the study site may encourage the referral of potential study subjects from other physicians or healthcare facilities. For example, a psychiatrist participating in a study for a new antidepressant might send a letter to local primary care physicians, suggesting that patients in the primary care practice who are not responding well to standard therapies may be candidates for the clinical trial, and that the primary care doctor provide information about the study to these patients.

Payments for successful referrals—referrals that result in enrollment of a study subject—are often referred to as “finder’s fees.” While there is no specific regulation that prevents the payment of finder’s fees, they are generally considered inappropriate because they create a conflict of interests. The promise of payment for successful enrollment may induce the referring physician to strongly encourage a patient to join the study even if the patient expresses doubts, or even to refer patients who aren’t really appropriate for the study but might slip through the screening process. These payments also conflict with the Code of Ethics of the American Medical Association, which prohibits referral payments to physicians, specifically stating that, “Offering or accepting payment for referring patients to research studies (finder’s fees) is also unethical.” 2

Conclusions

Study site recruitment practices have evolved over the last several years, with a broader overall view in the industry of the issues of conflict of interests and the protection of research participants from the impact of these conflicts. Most of the practices that historically raised concerns are rarely seen in the conduct of clinical trials today. Newer models of supporting recruitment efforts, such as supplementing site staff with additional staff focused on enrollment efforts, are generally considered to be ethically appropriate as long as payment is not based on recruitment efficacy, and the investigator retains oversight of all site activities.

• Guidance for Industry- Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, Department of Health and Human Services, Food and Drug Administration, October 2009. Section III(A)(4)(a), What Are an Investigator’s Responsibilities for Oversight of Other Parties Involved in the Conduct of a Clinical Trial?
• American Medical Association Code of Medical Ethics, Opinion 6.02; Feesplitting: Referral to Health Care Facilities

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• Methodology
• Open access
• Published: 22 August 2024

Patient and public involvement and engagement in the ASCEND PLUS trial: reflections from the design of a streamlined and decentralised clinical trial

• Muram El-Nayir 1   na1 ,
• Rohan Wijesurendra   ORCID: orcid.org/0000-0002-8261-8343 1   na1 ,
• David Preiss 1 ,
• Marion Mafham 1 ,
• Leandros Tsiotos 1 ,
• Sadman Islam 1 ,
• Anne Whitehouse 1 ,
• Sophia Wilkinson 1 ,
• Hannah Freeman 1 ,
• Ryonfa Lee 1 ,
• Wojciech Brudlo 1 ,
• Genna Bobby 1 ,
• Bryony Jenkins 1 ,
• Robert Humphrey 1 ,
• Amy Mallorie 1 ,
• Andrew Toal 2 ,
• Elnora C. Barker 2 ,
• Dianna Moylan 2 ,
• Graeme Thomson 2 ,
• Firoza Davies 2 ,
• Hameed Khan 2 ,
• Ian Allotey 2 ,
• Susan Dickie 2   na1 &
• John Roberts 2   na1  

Trials volume  25 , Article number:  554 ( 2024 ) Cite this article

Metrics details

Introduction

ASCEND PLUS is a randomised controlled trial assessing the effects of oral semaglutide on the primary prevention of cardiovascular events in around 20,000 individuals with type 2 diabetes in the UK. The trial’s innovative design includes a decentralised direct-to-participant invitation, recruitment, and follow-up model, relying on self-completion of online forms or telephone or video calls with research nurses, with no physical sites. Extensive patient and public involvement and engagement (PPIE) was essential to the design and conduct of ASCEND PLUS.

To report the process and conduct of PPIE activity in ASCEND PLUS, evaluate effects on trial design, reflect critically on successes and aspects that could have been improved, and identify themes and learning relevant to implementation of PPIE in future trials.

PPIE activity was coordinated centrally and included six PPIE focus groups and creation of an ASCEND PLUS public advisory group (PAG) during the design phase. Recruitment to these groups was carefully considered to ensure diversity and inclusion, largely consisting of adults living with type 2 diabetes from across the UK. Two members of the PAG also joined the trial Steering Committee. Steering Committee meetings, focus groups, and PAG meetings were conducted online, with two hybrid workshops to discuss PPIE activity and aspects of the trial.

PPIE activity was critical to shaping the design and conduct of ASCEND PLUS. Key examples included supporting choice for participants to either complete the screening/consent process independently online, or during a telephone or video call interview with a research nurse. A concise ‘initial information leaflet’ was developed to be sent with the initial invitations, with the ‘full’ information leaflet sent later to those interested in joining the trial. The PAG reviewed the content and format of participant- and public-facing materials, including written documents, online screening forms, animated videos, and the trial website, to aid clarity and accessibility, and provided input into the choice of instruments to assess quality of life.

Conclusions

PPIE is integral in ASCEND PLUS and will continue throughout the trial. This involvement has been critical to optimising the trial design, successfully obtaining regulatory and ethical approval, and conducting the trial.

Peer Review reports

ASCEND PLUS is an ongoing randomised placebo-controlled trial assessing the effects of oral semaglutide on cardiovascular and other outcomes in people with type 2 diabetes and no history of heart attack or stroke (NCT05441267). ASCEND PLUS will recruit approximately 20,000 participants in the UK. Potential participants are sent an invitation by post and the trial requires no in-person visits. Study medication is mailed directly to participants’ homes. This design represents a shift from the traditional concept of face-to-face interaction between research staff and participants at a clinical site and has become more common in recent years, perhaps accelerated by the COVID-19 pandemic [ 1 ]. Decentralised direct-to-participant designs, including that of ASCEND PLUS, offer the possibility to expand participation in clinical trials and increase the generalisability of results [ 1 ].

The ASCEND PLUS trial design was developed with extensive patient and public involvement and engagement (PPIE), to ensure that the participant experience is as good as it can be, the safety and wellbeing of the participants is protected, recruitment to the trial is successful, and the engagement and adherence of participants is maintained. ASCEND PLUS commenced recruitment in March 2023, and the estimated primary completion date of the trial is 2028.

PPIE is increasingly recognised as a key element in the development of all research [ 2 ], including clinical trial proposals and protocols. PPIE can harness the valuable insights of those living with and affected by a disease or health condition, and ensure that the trial findings are relevant to the needs of patients, and their relatives and carers [ 3 ]. “Involvement” can be defined as activities and research carried out “with” or “by” members of the public or patients, rather than “to”, “about”, or “for” them. In this instance, this refers to the active involvement of patients and members of the public in the development of the trial design and the conduct of the trial [ 4 ]. In contrast, “engagement” focuses on how the trial findings can be shared with patients and the public in a two-way process that encourages communication and interactions with researchers [ 4 ]. Despite the recognition of the importance and potential value of PPIE in clinical trials, implementation remains variable at present with inconsistency between trials [ 5 ].

Here, we aim to report the process and details of PPIE activity during the planning and initiation of ASCEND PLUS, evaluate how this helped to shape the final trial design, reflect critically on successes and aspects that could have been improved, and draw out themes and learning relevant to the implementation of PPIE in future trials.

Methods and results

Theoretical considerations.

The revised Guidance for Reporting the Involvement of Patients and the Public (GRIPP-2) long-form checklist [ 6 ] was used to guide the drafting of this report (see Supplementary Table 1).

Resourcing of PPIE activities

PPIE in ASCEND PLUS was organised by dedicated PPIE officers working within the communications team alongside the core trial team comprised of investigators, trial managers, and administrative staff at the Nuffield Department of Population Health at the University of Oxford (which sponsors the trial). An appropriate level of funding was available in the trial budget for PPIE activity, and all PPIE representatives were able to claim monetary compensation for their time, lived experience, and contribution, in line with guidance from the National Institute for Health and Care Research (NIHR) [ 7 ] and accepted best practice. Any out-of-pocket expenses (such as travel) incurred by PPIE representatives were reimbursed in full, and refreshments were provided at in-person meetings.

Format of PPIE activities

PPIE activity in ASCEND PLUS consisted of several linked components, beginning early in the design phase of the trial and is planned to continue through to trial completion and dissemination of the results.

Firstly, a series of six patient and public focus groups were convened to address specific issues. These focus group meetings largely involved people living with type 2 diabetes and included people from diverse backgrounds from across the UK.

Secondly, a trial-specific Public Advisory Group (PAG) was established. The PAG is responsible for providing feedback, advice, and opinions on many different aspects of ASCEND PLUS over the entire lifecycle of the trial.

Thirdly, in order to ensure patient involvement in the design and conduct of ASCEND PLUS at a strategic level, two members of the PAG who are individuals living with diabetes were also invited to join the Trial Steering Committee.

Steering Committee meetings, focus groups, and PAG meetings were largely conducted online using remote meeting software. Two in-person PPIE workshops were convened in Oxford. This combination of online and in-person meetings has been suggested to be favourable in a previous mixed methods study [ 8 ].

Recruitment and selection of focus groups and the PAG

The recruitment and selection of the focus groups and the PAG was carefully considered to ensure inclusivity and representation, for features including age, sex, and ethnicity. People living with type 2 diabetes were prioritised, given that ASCEND PLUS is a trial in this population.

The six focus groups were organised with support from the Nuffield Department of Population Health’s Public Advisory Group and four external organisations (Table  1 ). Each focus group was drawn from a specific geographic location (Leicester, Oxford, the north of England [two groups], Wales, and Scotland), to provide coverage of the areas of the UK in which ASCEND PLUS plans to recruit. The focus group based in Leicester was from the Centre for Ethnic Health Research and consisted of individuals of South Asian, Black Caribbean, and Black African ethnicity. The size of, and strategy used to achieve diverse representation within, each group was usually determined by the groups themselves.

Members of the PAG were invited from an existing departmental public advisory panel and the focus groups described above. The PAG was chosen to comprise a diverse group of patients and the public.

Involvement of PPIE panels and the PPIE advisory group in the research proposal

During the design phase of ASCEND PLUS, the six online PPIE focus groups (described above) were convened to address specific issues. Given the remote design of the trial with no in-person visits, the main topics discussed were the consent model and the recruitment/invitation methods. There was also discussion about other aspects of the trial design, including the active run-in, in which all participants receive the active drug prior to randomisation. These concepts were serially developed across the six focus groups, which took place between June and September 2021, with revisions made to the study design in response to the feedback received prior to the application for ethical approval.

Two people living with diabetes were next invited to join the Steering Committee. These individuals attended the first Steering Committee meeting in June 2021 and will continue to attend Steering Committee meetings until the completion of the trial. These patient and public contributors are members of the Steering Committee, contribute to discussions at meetings, and can vote on any decisions made by the Committee. They are also the joint senior authors of this publication (SD and JR).

The trial PAG was then assembled, including SD and JR amongst the members. The PAG contributed in detail to the design and review of all patient-facing study material, the online forms and videos used for the trial, and the trial website. This activity was organised through emails and online group meetings, as well as one face-to-face workshop in Oxford. The PAG will continue to contribute during the remainder of the trial, for example by reviewing planned patient newsletters and advising on local activities to aid recruitment. The PAG will also input on the interpretation of the trial results in due course, and specifically on their presentation and dissemination to patients and the public.

Impact of PPIE on ASCEND PLUS design and conduct

The six PPIE focus groups were critical to shaping the design and conduct of ASCEND PLUS. Full details of the composition and date of each of the six focus groups, the subjects discussed, and the feedback and impact are summarised in Table  1 .

Initially, it had been planned to invite all participants to complete self-directed online screening and consent, with an option of a telephone or video call if needed. A clear theme that emerged in the focus groups was support for choice in how participants interact with the trial: i.e. either online completion of study assessments on their own device (with the option to speak to a research nurse or study doctor at any time) or completion of study assessments during interviews with a research nurse. Therefore, recording of informed consent also needed to include both an online consent option (that can be completed by a participant independently) and the option to give consent during a telephone or video call with a research nurse. It was also felt to be important that participants can switch between these two methods of participation at any stage if they wish to. The exception to this concept was for non-English speakers, in whom a telephone or video call with a research nurse (aided by a translator) was recommended to ensure adequate understanding. In light of this feedback from the focus groups, the trial procedures were modified. The updated trial design now asks potential participants to indicate on the initial reply form which method (self-directed online versus telephone/video call with a research nurse) they prefer. Options have also been added to allow participants to change their trial interaction method during the course of the trial.

Another key impact on design and conduct of the trial resulted from feedback that the patient information leaflet was very long, due to the need to contain multiple items deemed mandatory by regulatory bodies. The focus group supported provision of an abbreviated “initial information leaflet” (rather than the “full” participant information leaflet) with the invitation letter, with the “full” patient information leaflet [ 9 ] subsequently supplied to those individuals who had declared interest in participating after reviewing the abbreviated leaflet.

The PPIE focus groups supported the proposed invitation method for ASCEND PLUS. In brief, this is conducted with the support of the NHS DigiTrials recruitment support service who undertake a search of electronic medical records to identify individuals who are potentially eligible (without individual patient consent at this stage). The name, address, and postcode of these individuals are then passed securely to a mailing house (who also handle patient letters for the NHS) who then send out study invitation letters. The details of potential participants are not disclosed to the ASCEND PLUS study team unless and until the participant returns the reply form, which includes the participant’s name and the details they add to it (such as telephone number, or email address). The reply form also contains a unique identifier which the ASCEND PLUS team send to NHS DigiTrials to obtain the participant’s name, address, sex, date of birth, NHS number, and GP surgery details from NHS records. The positive feedback from the PPI focus groups regarding the use of healthcare data in this way was cited in the application for regulatory approval. This recruitment method was supported by the Health Research Authority (HRA), who also followed advice from the Confidentiality Advisory Group (an independent body which provides expert advice on the use of confidential patient information). A separate data protection leaflet which is supplied to prospective participants covers all aspects of how data about ASCEND PLUS participants is processed [ 10 ].

The ASCEND PLUS PAG also undertook a detailed review of the three leaflets discussed above (initial information leaflet, full participant information leaflet, data protection leaflet), the trial invitation letter, and the study treatment information leaflets (one of which is included with each pack of study treatment mailed to a participant). Recommended text and content changes were made accordingly, ensuring that the text of each document remained consistent with trial processes. This extensive PPIE review and consultation process has resulted in documents which are easier to understand and more inclusive. This also included feedback about accommodating people with visual impairments. Examples of specific changes made to the text of study documents are shown in Fig.  1 .

Examples of specific changes made to the text of the ASCEND PLUS participant information leaflet after PPIE input

The PAG were then involved in co-developing an animated video to support the self-directed online consent process. The PAG initially contributed to the development of the script and then provided feedback on the images used in the storyboard, with many of the specific points raised implemented in the final version. For example, the images of potential participants in the video were updated to ensure greater diversity, and a border line was drawn on a map of the UK to highlight the geographical areas in which ASCEND PLUS plans to recruit.

The PAG was instrumental in the selection of quality of life questionnaires included in ASCEND PLUS. Whilst inclusion of the EQ5D questionnaire is commonplace due to its importance to the National Institute for Health and Care Excellence (NICE), several options existed for an additional questionnaire to capture diabetes-specific quality of life. The Problem Areas in Diabetes (PAID), Patient Health Questionnaire 9 (PHQ-9), Diabetes-Dependent Quality of Life questionnaire (ADDQoL), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were all considered. PAG members ranked the questionnaires separately on whether they thought they collected a meaningful and relevant assessment for people with diabetes, and whether participants would be willing to complete them. The PAG members were also separately asked to consider the feasibility of participants completing the 36-Item Short Form Survey questionnaire (SF-36) compared to the 12-item version (SF-12). Following detailed feedback from the PAG, the SF-12 and the PAID questionnaire were included in the final ASCEND PLUS protocol.

The PAG also reviewed the text and format of the questions included in the draft screening form (to be completed either by participants on their own devices or by research nurses in conversation with participants) and provided detailed feedback. A number of changes were implemented based on this, including changes to the order in which questions are asked and revisions to the working of particular questions to make them easier to understand.

A summary of PPIE in ASCEND PLUS is included in a dedicated page on the trial website, which also includes a video of two public contributors discussing their experience [ 11 ]. This activity, and the impact that it has had on the final design of ASCEND PLUS, is also summarised in Fig.  2 .

Summary of Public Advisory Group activity and impact in ASCEND PLUS

Impact of PPIE on individuals involved, and wider impact

The impact of PPIE in ASCEND PLUS on the individuals involved and the wider impact was considered in detail at a workshop convened on 26 November 2022, which included ten members of the PAG as well as investigators, trial managers, research fellows, and PPIE officers from the Nuffield Department of Population Health.

The context and process of PPIE in ASCEND PLUS were considered in some detail. Themes that emerged in this discussion included the fact that PAG members reported an overall highly positive experience. They commented that on-boarding for new members worked well and that the process had been well organised, with all members having a clear idea of upcoming tasks with regular updates from the study team. Having a single point of contact (the PPIE team at the Nuffield Department of Population Health) to coordinate the PPIE for the study was felt to be a major advantage. The logistical aspects of PAG group meetings were discussed and the format of online meetings scheduled in the evenings or at weekends was felt to be beneficial in avoiding travel time and allowing individuals the flexibility of contributing from their own home. Many meetings took place during periods of COVID-19 lockdowns, and being able to hold online meetings enabled these to go ahead and brought people together at a time of isolation. The benefits of in-person events (such as the PPIE workshop) were also discussed, and it was felt that some aspects, such as the ability to arrive early for social discussion and remain behind after the main meeting to ask questions and have private conversations, could also be implemented using the existing features offered by major online meeting platforms.

The inclusive nature of the PPIE process in ASCEND PLUS was praised. Specifically, discussion focused on the decision to actively encourage the involvement of contributors without previous PPIE experience, as well as the expectation in PAG meetings that everyone is listened to equally and that there are “no silly questions”. Members of the PAG also reflected that external feedback on ASCEND PLUS documents (created with their input) has been very positive. For example, the Departmental Information Governance lead commented that the ASCEND PLUS data information leaflet was the best such example they had seen in their experience of advising on multiple trials over a number of years. Similarly, the process of conducting PPIE in ASCEND PLUS has been used as an exemplar in the MSc in Clinical Trials postgraduate course that is run by the Nuffield Department of Population Health at the University of Oxford for students from across the world.

Some areas that could have been improved were also identified. Occasionally, too much information could be presented in PAG meetings, and key questions cropping up towards the end of a meeting might have meant that they received less attention than they should have. It was also highlighted that technology can be a barrier for some people, particularly those lacking the digital skills or hardware to be able to participate in online meetings. For example, printed materials may need to be offered as not all individuals will have access to a printer. In a few cases, deadlines for responding to tasks were shorter than ideal, and it was recommended that circulation of slides and materials should be undertaken well in advance of a meeting to allow members enough time to consider them carefully. Finally, it was suggested that it would have been helpful to have a “global overview” of the planned PAG activities so that members had an idea of what had been completed already and what would be coming up next.

In terms of the effect on themselves as individuals, PAG members reported that they had found participation in PPIE activities for ASCEND PLUS highly enjoyable and reported that there was more “behind-the-scenes” activity than they had initially expected. There was consensus that it was highly rewarding being part of helping to create a study that may have a huge impact on people’s lives, and in ensuring that the study is accessible to people from all walks of life including groups who are traditionally under-represented in research. From a personal perspective, some members reported that they had found participation intellectually stimulating and that it helped them to keep up to date with diabetes research, and be more confident when talking about research in general.

Finally, it is recognised that this manuscript only presents qualitative reflections on PPIE in ASCEND PLUS. ASCEND PLUS is still early in recruitment at the present time, and presentation of quantitative data on recruitment and retention would not be particularly meaningful in the absence of a relevant control. Of note, a sub-study is planned to specifically evaluate consent in ASCEND PLUS, given the decentralised trial design.

Study design of ASCEND PLUS and the relevance to the PPIE strategy

At the outset of ASCEND PLUS, a number of challenges and opportunities were identified that would be critical to the success of the trial, including:

Gaining approval from the relevant bodies for an innovative, streamlined trial design that has no in-person visits and requires a non-traditional participant consent process.

Recruitment of a large number of people (20,000), aged 55 and over, living with type 2 diabetes from across the UK, who have not yet experienced a heart attack or stroke. In addition, ethnic diversity among trial participants is highly desirable, to ensure a trial population broadly representative of that of the wider UK.

Implementation of a trial where all interactions with participants would be conducted directly using innovative patient-centred web-based technology, supplemented by telephone, video-call contact and mailed letters.

A decentralised enrolment and consent process that is sufficiently flexible and adaptable to suit all participants, irrespective of preference for self-directed online interaction versus a telephone/video call with a research nurse.

A lengthy participation timescale of 5 years.

The role of PPIE was particularly critical in ASCEND PLUS, helping to optimise the trial design in the context of each of these points. As discussed in the above sections, various aspects of the trial design were altered in line with the public contributors’ feedback, sometimes in quite a major way such as the decision to allow choice in the method of interaction with the study.

Contextual and process factors influencing PPIE in ASCEND PLUS

PPIE in ASCEND PLUS has included several distinct phases, including six focus groups, the construction of a trial-specific PAG, and inclusion of two members of the PAG on the trial Steering Committee.

PPIE activity in ASCEND PLUS has been greatly enhanced by the recruitment of enthusiastic and dedicated members to the focus groups and PAG, coordination and organisation by experienced and professional PPIE officers, the willingness and desire of the trial investigators to modify the trial design in response to PPIE feedback, and adequate resourcing for PPIE activity in the trial budget. The use of digital technology and online meetings aided the efficiency and inclusivity of the process.

Some areas of difficulty were identified. The tight trial timeline meant that occasionally PAG members were under pressure to meet challenging deadlines for review of various materials, and some online sessions perhaps contained too much information. Adequate resourcing of PPIE activity is key to spreading the load on each individual member.

Influence of PPIE on the final ASCEND PLUS study design

PPIE greatly enhanced the final ASCEND PLUS study design. The changes made in response to the PPIE scoping exercises made the trial more inclusive, most notably in influencing the decision to give all participants a free choice in the method by which they interact with the study. The PPIE activity also heavily influenced almost all of the written and online material for the trial, making this more accessible and understandable, and also available in different formats and to those with visual impairment. Specifically, the experience afforded by individuals living with diabetes was highly valuable when considering the nature of the trial and the target population. The impact of PPIE activity on the study was evaluated by direct comparison of the final trial design to the initial proposals (with some examples included here), and by qualitative discussion with relevant stakeholders in a dedicated workshop convened for this purpose.

Learnings and recommendations for future large-scale clinical trials

Comprehensive and early PPIE is critical to gain input on all aspects of the proposed trial design and to optimise the relevance and acceptability to people living with diabetes. This involvement should start well before regulatory submissions, in order to allow time for changes to be made in response to PPIE group feedback. Involvement of dedicated and professional PPIE officers should be strongly considered to streamline the process, and adequate resourcing of PPIE activity is essential. Careful consideration should be given to how recruitment to focus groups and advisory groups is undertaken, making sure that assembled panels are inclusive and representative, and are able to work in a cohesive group and provide constructive comments and feedback in a timely manner. Feedback on participant- and public-facing supporting material such as information leaflets, animations, and the trial website helps to make these accessible and should improve recruitment and adherence, as well as the experience of recruited individuals. Inclusion of public contributors on the trial Steering Committee is important to ensure PPIE input to decision-making during the course of the trial. A summary of these recommendations is outlined in Fig.  3 . Finally, ASCEND PLUS is a UK-based trial, and there may be limited applicability to different healthcare systems and cultural contexts, or in resource-limited settings.

Learnings and recommendations for PPIE in future large-scale clinical trials

ASCEND PLUS is a large-scale trial with an innovative, streamlined design with a non-traditional participant consent process and no in-person study visits. Extensive PPIE has proven integral to the design and initiation of ASCEND PLUS and will continue throughout the trial. This involvement has been critical to optimising the trial design, successfully obtaining ethical and regulatory approvals, and conducting the trial.

Availability of data and materials

Not applicable.

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Acknowledgements

The authors gratefully acknowledge the input from Parminder Hothi and other present and past members of the ASCEND PLUS Public Advisory Group who chose to remain anonymous and who are therefore not named as co-authors of this publication.

ASCEND PLUS is coordinated and sponsored by the University of Oxford and run with support from the National Institute for Health and Care Research. Novo Nordisk produces oral semaglutide and is providing the treatment for the study free of charge. Novo Nordisk has given a grant to the University of Oxford to help with the cost of running of the study but is not directly involved with either coordinating the study or analysing the results.

Author information

Muram El-Nayir, Rohan Wijesurendra, Susan Dickie, and John Roberts contributed equally to this work.

Authors and Affiliations

Clinical Trial Service and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK

Muram El-Nayir, Rohan Wijesurendra, David Preiss, Marion Mafham, Leandros Tsiotos, Sadman Islam, Anne Whitehouse, Sophia Wilkinson, Hannah Freeman, Ryonfa Lee, Wojciech Brudlo, Genna Bobby, Bryony Jenkins, Robert Humphrey & Amy Mallorie

Public Advisory Group; ASCEND PLUS Clinical Trial, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK

Andrew Toal, Elnora C. Barker, Dianna Moylan, Graeme Thomson, Firoza Davies, Hameed Khan, Ian Allotey, Susan Dickie & John Roberts

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Contributions

ME and RW: Lead authors of the manuscript with regular involvement in PAG meetings. DP and MM: Chief investigators of the ASCEND PLUS trial and the initiators of PPIE involvement throughout. Major contributors in writing and reviewing the manuscript. LT, SI, AW, SW and HF: PPIE officers for the ASCEND PLUS trial with substantial involvement in the recruitment and organisation of PAG meetings and collation of input obtained. RL, WB, RH, AM, BJ and GB: ASCEND PLUS Clinical & Administrative team involved in organisation of PAG meetings. AT, ECB, DM, GT, FD, HK and IA: PAG members who were major contributors in writing and reviewing the manuscript. SD and JR: Senior members of the PAG, who oversaw the writing of this manuscript. Major contributors in writing and reviewing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rohan Wijesurendra .

Ethics declarations

Ethics approval and consent to participate.

The ASCEND PLUS clinical trial has been approved by the Research Ethics Committee.

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Competing interests.

The authors declare that they have no competing interests.

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El-Nayir, M., Wijesurendra, R., Preiss, D. et al. Patient and public involvement and engagement in the ASCEND PLUS trial: reflections from the design of a streamlined and decentralised clinical trial. Trials 25 , 554 (2024). https://doi.org/10.1186/s13063-024-08393-2

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Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: a retrospective population-based cohort study

• Cecilia Pynaker 1 ,
• Jacqui McCoy 1 ,
• Jane Halliday 1 , 2 ,
• Sharon Lewis 1 , 2 ,
• David J. Amor 1 , 2 , 3 ,
• Susan P. Walker 4 , 5 &
• Lisa Hui 1 , 4 , 5 , 6

On behalf of the PALM cohort study group

BMC Pediatrics volume  24 , Article number:  536 ( 2024 ) Cite this article

Metrics details

There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-based paediatric cohort for long term developmental follow up.

An Australian state-wide research database was screened for pregnant individuals who had a prenatal chromosomal microarray (CMA) between 2013–2019 inclusive. Following linkage to laboratory records and clinical referrer details, hospital records were manually reviewed for study eligibility. Eligible participants were mother–child pairs where the pregnancy resulted in a livebirth, the mother was able to provide informed consent in English (did not require a translator) and the mother was the primary caregiver for the child at hospital discharge after birth. Research invitations were sent by registered post at an average of six years after the prenatal diagnostic test. Statistical analysis was performed in Stata17.

Of 1832 prenatal records examined, 1364 (74.5%) mother–child pairs were eligible for recruitment into the follow up cohort. Of the 468 ineligible, 282 (60.3%) had ‘no live pregnancy outcome’ (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons. TOP rates varied by the type of fetal CNV detected: 49.3% (109/221) for pathogenic CNVs, 18.2% (58/319) for variants of uncertain significance and 3.3% (42/1292) where no clinically significant CNV was reported on CMA. Almost 77% of invitation letters were successfully delivered (1047/1364), and the subsequent participation rate in the follow up cohort was 19.2% (201/1047).

Conclusions

This study provides Australia’s first population-based data on perinatal outcomes following prenatal diagnostic testing with CMA. The relatively high rates of pregnancy loss for those with a prenatal diagnosis of a CNV presented a challenge for establishing a paediatric cohort to examine long term outcomes. Recruiting a mother–child cohort via prenatal ascertainment is a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond.

Trial registration

ACTRN12620000446965p; Registered on April 6, 2020.

Peer Review reports

Chromosomal microarray analysis (CMA) can interrogate the human genome to a higher resolution than G-banded karyotyping [ 1 ]. This has enabled the detection of submicroscopic deletions and duplications, termed copy number variants (CNVs), which can be benign or pathogenic depending on their location and gene content. CMA is well-established as the gold-standard first-tier diagnostic test for paediatric patients with an unexplained developmental disability, intellectual disability or congenital anomalies, providing 15–20% higher diagnostic yield than G-banded karyotyping [ 2 , 3 , 4 ].

Alongside paediatric care, CMA has also revolutionised prenatal care. It has been 10 years since CMA replaced G-banded karyotyping as the recommended diagnostic test for fetuses with an ultrasound abnormality because of its superior diagnostic yield [ 5 , 6 , 7 ]. CMAs can detect pathogenic copy number variants (pCNV) linked to established syndromes, but also CNV of uncertain clinical significance (VUS). VUS are CNVs that often involve non-disease causing genes, may not have been previously identified or described, or for which there is limited information on genotype–phenotype correlation due to incomplete penetrance and variable expressivity.

In the Australian state of Victoria, there has been an increase in the proportion of prenatal diagnostic tests analysed with CMA, from 39.4% in 2013 to 93.1% in 2021, regardless of indication for testing [ 8 ]. Concurrently, the absolute number of fetuses diagnosed with a pCNV has increased over the past decade, from 25 pCNVs in 2013 to 61 pCNVs in 2022 in the background of a declining number of prenatal diagnostic procedures [ 8 ]. The most frequent pCNVs in our population are 22q11.2 deletion (DiGeorge syndrome), 4p16.3 deletion (Wolf-Hischhorn syndrome), and 5p15.33 deletion (cri-du-chat syndrome) [ 9 ]. These account for 13.5%, 3.9%, 3.0% of pregnancies with a pCNV respectively. However, the vast majority of pCNVs are rare, which makes counselling on long term childhood outcomes difficult, especially when ascertained before birth when the phenotype is incomplete.

A VUS is diagnosed in approximately 5% of fetuses following chorionic villus sampling or amniocentesis [ 8 ]. These VUS can be challenging as there is often no prenatal phenotype to guide CNV interpretation. The limited data available in the literature are commonly skewed towards cases diagnosed postnatally, possibly biased towards the more severe end of the phenotypic spectrum [ 10 , 11 , 12 ]. In Australia, there are currently no guidelines for the routine follow up and assessment of children with a prenatally diagnosed VUS. Furthermore, as genomic databases and clinical interpretation guidelines are updated some prenatal VUS are subsequently reclassified as either pathogenic or benign [ 13 ]. This highlights the challenge of providing appropriate long term care, as children may not only be lost to follow up after the newborn period, but may also carry a nonextant genetic diagnosis throughout childhood due to changes in scientific knowledge [ 12 , 14 ].

The PrenatAL Microarray (PALM) is a nationally-funded cohort study of mother–child pairs who have had a prenatal diagnosis with a chromosomal microarray (CMA) from 2013 to 2019 in the Australian state of Victoria. In brief, this cohort study of children- with and without a prenatally-ascertained CNV- aims to examine their developmental, social-emotional and health outcomes in early childhood through a range of parent completed questions, in person cognitive assessments, and clinical paediatric review [ 15 ]. The full protocol has been previously published in this journal [ 15 ].

In this paper, we report the perinatal outcomes of fetuses that had a prenatal chromosomal microarray (potential PALM participants, with and without a CNV), including rates of termination of pregnancy (TOP) and spontaneous perinatal losses following prenatal diagnosis. We also present the challenges of creating a representative paediatric cohort of children from a prenatal cohort.

Study population

This was a population-based study set in the Australian state of Victoria. Victoria has approximately 78,000 births per year with a median maternal age of 31.5 years [ 16 ]. All pregnant individuals are offered screening for fetal structural anomalies and chromosomal conditions, with an uptake of 83.6% state-wide [ 17 ]. Between 2013–2021, 80.9% of prenatal diagnostic tests were analysed by CMA [ 8 ]. TOP is lawful on maternal request up to 24 weeks, and after 24 weeks if two medical practitioners deem it “appropriate in all the circumstances” [ 18 ].

Maternity healthcare in Australia operates through a dual public–private system. Public care, funded by Medicare, offers subsidized services in public hospitals. Private care, covered by private health insurance or out-of-pocket, provides additional options such as choosing obstetricians and amenities in private hospitals. In Australia, approximately 75% of births occur in a public hospital.

Eligibility criteria for paediatric cohort

Participants were eligible if: the pregnancy resulted in a livebirth, they were the primary-caregiver for the child at hospital discharge, resident in the Australian state of Victoria, and able to provide informed consent in English (did not require a translator).

Data sources

Multiple sources were utilised to identify and pre-screen potential study participants.

Victorian prenatal diagnosis database

The Victorian Prenatal Diagnosis Database (VPDD) is a population-based research dataset that collects all chromosome testing results from amniotic fluid and chorionic villus samples (CVS) [ 8 ]. The VPDD was screened for pregnant individuals who underwent prenatal diagnosis with CMA from January 2013 to December 2019. Clinical laboratories classified prenatal CNVs in accordance with the guidelines of the American College of Medical Genetics (ACMG) and other established guidelines [ 19 , 20 , 21 ]. CNVs were classified as ‘pathogenic’ when they encompassed a region implicated in a well-described abnormal phenotype, as documented in multiple peer-reviewed publications. ‘Likely pathogenic’ variants were CNVs that met the ACMG definitions of a CNV ‘described in a single case report but with well-defined breakpoints and phenotype, both specific and relevant to the patient findings’, or CNV interval ‘with very compelling gene function that is relevant and specific to the reason for patient referral’. ‘Cases’ included pregnancies with a pathogenic or likely pathogenic CNV (pCNV) and variant of uncertain significance (VUS). ‘Controls’ were pregnancies that had a primary clinical indication other than an ultrasound abnormality and had ‘no clinically significant genomic imbalance’ reported on CMA. These included positive (‘high chance) screening result (non-invasive prenatal testing, combined first trimester screening, or second trimester serum screening), and other testing indications (such as advanced maternal age, maternal request).

Due to the modifier of a structural anomaly or known genetic condition on childhood outcomes, ‘controls’ with a clinical indication of a fetal structural abnormality, family history of a chromosomal condition or a single gene condition were excluded. However, there were some controls where the ultrasound abnormality was a secondary indication after a primary indication of a positive screening result. These were predominantly soft markers (increased nuchal translucency, hypoplastic nasal bone). Further details will be available in the next phase of the PALM study and any controls with a major structural abnormality on antenatal ultrasound excluded from analysis.

Results of single gene testing were not available for the entire cohort. These results were only available for the final consented PALM study participants and will not be reported here.

Clinical laboratories that submitted the cases and controls to the VPDD internally reidentified records and obtained the name of the public maternity hospital or private clinical referrer. Follow up was different for these two groups:

Public hospital medical record review

Hospital medical records were manually reviewed for perinatal outcome and study eligibility. Perinatal outcomes were coded as either miscarriage (spontaneous pregnancy loss < 20 weeks’ gestation), stillbirth (infant born with no signs of life ≥ 20 weeks’ gestation), TOP, neonatal death (death within 28 days of birth), infant death (death within 2 years of birth), or live birth.

A minimum de-identified dataset was collected for all individuals screened containing: hospital name, maternal postcode, test date, gestational age, clinical indication, CNV classification, perinatal outcome, parity, and study eligibility status. Maternal postcode was mapped to the corresponding local government area and assigned the relevant Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) allocated by the Australian Bureau of Statistics from 2016 Census data [ 22 ].

Private clinical referrers

Private clinicians were contacted by phone and/or email and asked to pre-screen their patients for study eligibility and send an invitation letter to eligible participants. No minimum dataset was collected for these patients as pre-screening was performed at the clinician’s discretion.

Study recruitment

Study invitation letters were sent by registered post between November 2021 and June 2023. Each contained a participant information and consent form, hard-copy questionnaire booklet, and replied paid envelope. Registered post enabled tracking of research letters, including proof of mailing and signature on delivery. The public roll of the Australian Electoral Commission (AEC) was used to check the details of participants whose post were returned to sender. Participants had the option to complete a hard copy or online consent form and questionnaire. Completed hard copies were returned using the provided replied paid envelope, while the online version, hosted in Research Electronic Data Capture (REDCap), were accessed via a QR code in the invitation letter [ 23 , 24 ].

Protocol amendments

Pandemic impacts.

In response to the COVID-19 pandemic in 2020, the study protocol was updated to include alternative online child assessments. Due to pandemic-related disruptions, a 12-month extension was requested due to delays in recruitment, participant assessments, and obtaining approvals for new regional sites.

Low recruitment rate

In response to a low recruitment rate, the study protocol was amended. Participants were: (i) sent two reminder letters, and (ii) offered an AUD$110 gift card in appreciation of their time. The first reminder was sent three weeks after the initial study invitation (if successfully delivered), and the second reminder three weeks after the first reminder. Ethics Committee approval for all amendments was obtained.

Statistical analysis

Statistical analysis was performed in Stata17 using chi-squared test for proportions with p  < 0.05 considered significant [ 25 ]. Wilson score method was used to calculate 95% confidence intervals using Epitools [ 26 ].

Ethics approval

This study received Human Research Ethics Committee approval from the Royal Children’s Hospital on April 8, 2020 (Reference no. 60542) and Mercy Health on September 15, 2020 (Reference no. 2020–046).

Pre-screening of potential participants

During the 7-year study period 8184 prenatal diagnostic tests were performed by CMA; a fetal CNV was reported for 1029 samples (12.6%, 95%CI: 11.9–13.3%), and ‘no clinically significant CNV’ reported in 7155 samples (87.4%, 95%CI: 85.7–88.1%). Of these, 4316 with ‘no clinically significant CNV’ were excluded due to an indication of an ultrasound abnormality, family history of a chromosomal condition, or a single gene condition.

Figure  1 illustrates the pre-screening and recruitment of participants with and without a copy number variant.

Study flowchart of the pre-screening and recruitment of participants. Abbreviations: CNV, copy number variant; pCNV, pathogenic copy number variant; VUS, copy number variant of uncertain significance. † In total, 14 participants were recruited into the study through a private obstetrician or general practitioner (data not shown)

The personal identifiers of the 2458 potential cases and controls were provided to the eight relevant hospitals and were manually reviewed for eligibility criteria. Only 74.5% ( n  = 1832) had a known birth outcome documented in the hospital records. The remaining missing birth outcome data was due to patients delivering in a different hospital to the one in which the prenatal diagnostic procedure was performed.

Of those with a known birth outcome ( n  = 1832), 1364 (74.5%) were eligible for recruitment (‘potential participants’) and 468 (25.5%) were ineligible. Of the 468 ineligible, 282 (60.3%) had ‘no live pregnancy outcome’ (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons (Table  1 ).

Perinatal outcomes by CMA result

Birth outcomes varied significantly by the type of fetal CNV detected and are presented in Table  2 . Fetuses with a pathogenic CNV had a higher TOP rate compared with those with a VUS (49.3% vs. 18.2%, p  < 0.05) or ‘no clinically significant’ CNV (3.3%, p  < 0.05).

Perinatal outcome by indication for prenatal diagnosis

The perinatal outcomes of pregnancies with and without a CNV varied by indication for prenatal diagnosis (Table  3 ). For pregnancies with a pCNV or VUS the most common indication for prenatal diagnosis was an ultrasound abnormality, 54.8% (121/221) and 62.4% (199/319) respectively. A TOP occurred in 56.2% (68/121) of cases with a pCNV and an ultrasound abnormality. In comparison, when there was a VUS and an ultrasound abnormality, a TOP occurred in 30.6% (61/199) of cases. Almost two percent of pregnancies with ‘no clinically significant genomic imbalance’ and a high chance screening result resulted in a TOP (17/1067). These did not have an ultrasound abnormality.

Responders and non-responders

A total of 3304 research letters were sent to 1364 eligible patients over the 20-month study period (1607 invitations (including repeats), 893 first reminders, 804 s reminders) (Fig.  1 ). Initially, a third of all study invitations were returned to sender due to incorrect address (31.9%, 435/1364). An updated address was found for 43.2% (188/435) of these using the AEC public electoral roll. Overall, 1047 participants were successfully contacted (1047/1364, 76.8%).

The rate of informed consent to participate in the PALM study among those who were successfully contacted (‘responders’) was 19.2% (201/1047) (Fig.  1 ).

Comparison of cases and controls

Data collected through examination of hospital medical records were used to compare the 1832 ‘potential participants’ (with a known birth outcome) stratified by CNV status (cases vs. controls).

There were no consistent patterns of difference in sociodemographic characteristics between cases and controls in their study eligibility or ability to be contacted via mail (see Supplementary Table 1 and Supplementary Table 2 for details). A slight difference in response rate was observed with 23.8% of cases responding compared with 17.8% of controls (Table  4 ).

Compared with non-responding controls, participating controls were significantly more likely to be of higher socioeconomic status and lower parity. There was no evidence of any differences between responders and non-responding cases (Table  4 ).

Private practice referrers

A substantial proportion of patients were referred for their diagnostic procedure by a private referrer rather than a public hospital (1132/3868, 29.3%, Fig.  1 ). These 1132 patients were referred by 497 private clinicians. Of these, 304 clinicians (associated with 874 patients) could be contacted by phone and/or email; 28 clinicians (9.2%; associated with 119 patients (13.6%)) agreed to pre-screen their patients for study eligibility; 14 patients were ultimately recruited through this method. Data from the 119 patients screened by private referrers were not collected and were excluded from this analysis as pre-screening of potential participants was performed at the discretion of the private referrer.

Regional participants

One in five patients who had a prenatal diagnostic procedure in a tertiary hospital was referred from a regional hospital (175/850, 20.6%). To assist recruitment and minimise selection bias by location, the protocol was amended to include data collection from the three largest referring regional health services (representing 156/175 regional patients). It took on average 20-months from ethics amendment approval to site governance approval. The additional burden of adding these three sites resulted in an additional 9 participants (all cases).

Recruitment rate

Overall, the 201 mother–child pairs were recruited into the PALM childhood outcome study, comprising 144 controls and 57 cases (10 pCNVs, 47 VUS). This cohort represented 2.5% of the initial 8184 prenatal diagnosis cases pre-screened from the Victorian Prenatal Diagnosis Data Collection. This was lower than 8.7% (719/8184) recruitment rate estimated in the original study protocol [ 15 ].

Principle findings

CMA has been instrumental in improving the diagnostic yield of prenatal diagnosis, but published data on the perinatal and paediatric outcomes of fetal CNVs are scarce due to their rarity. We conducted a lengthy and thorough manual linkage process to retrospectively recruit 201 mother–child pairs for a prospective childhood outcome study from a starting data source of re-identifiable prenatal diagnostic test results. This complex process was necessary to overcome the challenges of maintaining patient privacy and traversing siloed medical record information across health services and research institutes.

Results in the context of what is known

Overall, the rates of TOP for the pCNVs in our cohort were at the lower end of the range reported in the literature. We observed a 49.3% TOP rate for pCNVs overall and a 56.2% TOP rate for pCNVs with an ultrasound abnormality. This compares with TOP rates for pCNV ranging from 50–100% in other studies [ 13 , 14 , 27 , 28 , 29 , 30 , 31 , 32 ]. Higher rates have been report for pCNVs with an ultrasound abnormality (either structural or soft marker) (76.2–100%) in China, France, and Israel [ 13 , 29 , 30 , 31 , 32 ].

Similarly, for VUS we observed a 18.2% TOP rate for VUS overall and a 23.1% rate for VUS with an ultrasound abnormality. Again, this aligns with the lower end of reported TOP rates for VUS from 11.0–44.9% [ 14 , 29 , 30 , 31 , 33 , 34 ], with higher rates for de novo VUS (50.8–58.0%) [ 13 , 34 ] and fetuses with an ultrasound abnormality (17.1–37.5%) [ 13 , 29 , 30 , 31 , 34 ]. There are many methodological factors that may contribute to the different TOP rates for pCNV and VUS that preclude meaningful direct comparisons between studies. These factors include highly variable cohort sizes, study inclusion criteria, clinical testing pathways, CNV classification systems, health system and patient factors, availability of TOP, and timing of prenatal diagnosis.

Clinical and research implications

Paediatrics cohorts established from prenatal genomic testing populations are rare due to logistical and ethical challenges, yet they are crucial for obtaining long-term outcome data. A previous cohort of this nature examined the childhood outcomes of children prenatally diagnosed with confined placental mosaicism in the Australian state of Victoria [ 35 ]. By utilising the same prenatal diagnosis dataset this paediatric cohort was not biased towards children with an established clinical phenotype. Despite contacting participants 5.5 years after prenatal diagnosis, the study achieved a recruitment rate of 76%. This is almost four times the response rate achieved in our study (19.1%). It is unknown what factors contributed to the higher recruitment rate but one factor could be the clinician-patient relationship as the treating doctor facilitated the contact between the participant and the research team, rather than a hospital departmental representative as in our study. Moreover, despite modifying the study protocol to minimise exposure to COVID-19 (such as offering virtual assessments), the pandemic might have negatively influenced patient attitudes towards participating in research studies [ 36 ].

There are only two other studies that have reported paediatric outcomes of children with a prenatal diagnosis of a CNV [ 13 , 37 ]. Shi et al. prospectively followed up 109 children with a prenatally diagnosed VUS up the age of 2–4 years. Five children apparently showed clinical signs or phenotypic features of disease, but the clinical assessments were not described in detail. Muys et al. retrospectively recruited 85 mother–child pairs with a pCNV or VUS (‘cases’) and 123 with no or a benign CNV (‘controls’). The response rate of 15.8% (208/1312) was lower than our results, even though their study had lower participant burden (parental questionnaire only). However, these response rates may not be comparable. Muys et al. did not perform extensive pre-screening to determine perinatal outcomes: several participants were ineligible due to a perinatal or neonatal death. Had we not performed our extensive pre-screening step, 282 women who experienced a perinatal loss would have been invited to participate in our childhood outcome study. Also, Muys et al. did not report the number of research invitation letters successfully delivered, only the total number sent. Use of registered post and manual follow up at the AEC public roll enabled us to determine the number of potential participants successfully contacted. Of note 21.3% (43/201) of our final cohort were contacted following use of the AEC to update contact addresses, demonstrating the value of this additional step.

Strengths and limitations

This is one of the largest studies to manually determine the perinatal outcomes of pregnancies with and without a prenatally diagnosed CNV. Through this process, we have successfully established a paediatric cohort and prospectively conducted detailed cognitive and clinical assessments on each child. Data analysis is currently underway, with public dissemination of results expected in 2024.

Another one of our strengths was the attention paid to patient psychological safety through manual record review and the exclusion of patients who had experienced a perinatal loss or infant death. We thereby averted potential distress for 282 families by removing them from our study invitation list. However, the extensive pre-screening procedures at multiple maternity hospitals and the siloed nature of Australian health records pose substantial resource and administrative barriers to future research of this type.

One of the limitations of our cohort is the missing birth data on one quarter of potentially eligible patients due to private and regional referral patterns. This finding highlights the challenges in tracing participants and engaging with hospitals for population-based research studies.

Another limitation of this study is that our ethics approval did not permit us to retain data on perinatal outcomes by specific CNVs due privacy concerns with potentially identifying information. We have previously reported the most common CNVs in our population from 2012 to 2018 [ 9 ]. The three most frequent pathogenic CNVs were 22q11.2 deletion syndrome, 4p16.3 deletion, and 5p15.33 deletion. The three most frequent VUS were 15q11.2 del, 22q11.2 duplication and 1q21.1 duplication. Further details including perinatal outcomes and ultrasound abnormalities are available in that publication.

Future directions

Establishing systems that enable the routine paediatric follow up of prenatally diagnosed genetic abnormalities are essential for understanding the full phenotypic spectrum of CNVs. In particular, there are no standard recommendations regarding long term follow up of children with VUS. Our cohort will provide long term outcome data on the developmental outcomes of children with VUS that may help guide future clinical care.

One of the barriers to collecting long term outcomes from genomic CNVs is the limitations of current congenital anomaly coding systems such as the International Classification of Diseases 10 th Revision (ICD-10). The ICD-10 has very few specific genetic diagnostic codes as it is based on phenotypes and organ systems. More locally, our state-wide Victorian Congenital Anomalies Report reports the population prevalence and birth outcomes for common autosomal trisomies but not CNVs (pathogenic or VUS) [ 38 ]. Expanding the reporting of congenital anomalies to encompass a broader spectrum of genomic variants would offer a more comprehensive understanding of the impact of prenatal diagnosis and enable us to perform better quality linkage studies for long term outcome data.

This study provides Australia’s first population-based data on perinatal outcomes including termination of pregnancy following prenatal diagnostic testing with CMA. Three-quarters of fetuses with a VUS and less than half of fetuses with a pCNV resulted in a livebirth. Our establishment of a mother–child cohort via prenatal ascertainment was a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author to researchers from a recognised academic institution upon reasonable request.

Abbreviations

Australian Electoral Commission

Chromosomal microarray

Copy number variant

Chorionic villus sampling

Human Research Ethics Application

Human Research Ethics Committee

Murdoch Children’s Research Institute

National Health and Medical Research Council

PrenatAL Microarray

Pathogenic copy number variant

Termination of pregnancy

Victorian Prenatal Diagnosis Data collection

Variants of uncertain/unknown significance

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Acknowledgements

We thank the associate and site investigators in the PALM study group: Ms Joanne Kennedy (Murdoch Children’s Research Institute, Royal Women’s Hospital), Ms Fiona Norris (Victorian Clinical Genetics Services), Ms Lucy Gugasyan (Monash Pathology), Ms Emma Brown (Monash Pathology), Dr Suzanne Svobodova (Monash Pathology), Dr Matthew Regan (Monash Medical Centre), Ms Helen Kincaid (Monash Medical Centre), Dr Anand Vasudevan (Royal Women’s Hospital and Western Health), Ms Susan Fawcett (Royal Women’s Hospital), Ms Melissa Graetz (Mercy Hospital for Women), Prof Joanne Said (Western Health), Dr Lisa Begg (Box Hill Hospital, Eastern Health), Dr Nicole Yuen (Bendigo Health), Dr Natasha Frawley (Grampians Health Ballarat), and Dr Geraldine Masson (Barwon Health Geelong).

This study is being funded by a NHMRC Clinical Trials and Cohort Studies grant for 2020–2022 (NHMRC APP1186862). The funding body has had no role in the study design, in the writing of the protocol or in the decision to submit the paper for publication.

LH receives salary support from a Medical Research Future Fund investigator grant (APP1196010) and the University of Melbourne.

The PALM study is sponsored by MCRI. The contact on behalf of the sponsor is LH.

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Authors and affiliations.

Reproductive Epidemiology Group, Murdoch Children’s Research Institute, Parkville, VIC, Australia

Cecilia Pynaker, Jacqui McCoy, Jane Halliday, Sharon Lewis, David J. Amor & Lisa Hui

Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia

Jane Halliday, Sharon Lewis & David J. Amor

Neurodisability and Rehabilitation Group, Murdoch Children’s Research Institute, Parkville, VIC, Australia

David J. Amor

Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Parkville, VIC, Australia

Susan P. Walker & Lisa Hui

Mercy Hospital for Women, Heidelberg, VIC, Australia

Northern Health, Melbourne, VIC, Australia

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• Joanne Kennedy
• , Fiona Norris
• , Lucy Gugasyan
• , Emma Brown
• , Suzanne Svobodova
• , Matthew Regan
• , Helen Kincaid
• , Anand Vasudevan
• , Susan Fawcett
• , Melissa Graetz
• , Joanne Said
• , Lisa Begg
• , Nicole Yuen
• , Natasha Frawley
•  & Geraldine Masson

Contributions

LH and JH conceived the original concept for this study. LH was the lead writer for the study protocol and funding application, with intellectual input from all members of the chief investigator team (JH, DA, SL, SP). CP and JM are salaried members of the PALM study team. Data collection was performed by CP and JK; CP and LH prepared the first draft of the manuscript. All authors read, provided intellectual input and approved the final version of this manuscript.

Corresponding author

Correspondence to Lisa Hui .

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Ethics approval and consent to participate.

Ethics approval was granted by the Royal Children’s Hospital Human Research Ethics Committee (reference number 60542) and Mercy Health Human Research Ethics Committee (reference number 2020–46). All participating parents provided written informed consent.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Supplementary Information

12887_2024_5012_moesm1_esm.docx.

Supplementary Material 1: Supplementary Table 1. Sociodemographic characteristics of eligible and ineligible participants. IRSAD, Index of Relative Socioeconomic Advantage and Disadvantage.

12887_2024_5012_MOESM2_ESM.docx

Supplementary Material 2: Supplementary Table 2. Sociodemographic characteristics of cases and controls by ability to be contacted by mail. IRSAD, Index of Relative Socioeconomic Advantage and Disadvantage.

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Pynaker, C., McCoy, J., Halliday, J. et al. Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: a retrospective population-based cohort study. BMC Pediatr 24 , 536 (2024). https://doi.org/10.1186/s12887-024-05012-6

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Received : 07 February 2024

Accepted : 13 August 2024

Published : 22 August 2024

DOI : https://doi.org/10.1186/s12887-024-05012-6

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• Prenatal diagnosis
• Chromosomal microarray analysis
• Copy number variants
• Variant of uncertain significance
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• Cohort studies
• Paediatric population
• Feasibility studies

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