Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am talking with Atasi Poddar. She is a health science policy analyst within FDA’s Office of Medical Policy in the Center for Drug Evaluation and Research, or CDER. She will share some insights with us on an important FDA guidance titled, Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs. Our discussion today will focus on important points about this guidance document for patients, including information about clinical trials. Welcome, Atasi! Thank you for speaking with us today.
Before we discuss the guidance, Atasi, could you explain what clinical trials are?
Yes. Clinical trials are research studies conducted in human volunteers to evaluate whether a new medical product is safe and effective for patients. Usually, the clinical trial will include three phases: phase 1, phase 2, and phase 3. In early phases, fewer than 100 participants are enrolled, and in later phases, when there is more information and understanding about the drug, the number of participants is increased to between one hundred and several thousand.
Before bringing any new drug to the U.S. market, sponsors must conduct clinical trials to determine whether it is safe and effective to use in the general U.S. population.1 A sponsor can be an individual, a pharmaceutical company, a government agency, an academic institution, a private organization, or any other organization that takes responsibility for the clinical trial. I would like to mention two important points; first, participation in clinical trials is voluntary, which means participants choose to be involved. And if you participate in a clinical trial, you may choose to stop participating at any time. Second, FDA does not conduct clinical trials.2
Are clinical trials required by FDA?
Yes. Clinical trials are essential to the drug development process.3 They are also required by law. If a sponsor wants to market a new medical treatment to the U.S. public, the sponsors submit clinical trial study designs and participant data to get FDA’s approval for marketing new drugs. FDA evaluates this information to decide whether the new medication is safe and effective for wider use in the general population for the purpose for which the drug is to be approved.4
Why is participant diversity important for clinical trials?
People in the United States differ by sex, age, race, ethnicity, location, and many other characteristics. They may also have various diseases, or could be pregnant, overweight, or underweight. These different groups of people may respond to a given medication in different ways. For these reasons, it is important that clinical trials include representatives of the different groups of people who will use the medication, so that when it is being evaluated or tested, we can have a better understanding about how well it works and how safe it is in those groups.
This information helps both healthcare providers and patients. For example, if your healthcare provider knows that the drug is not going to work for you or in a certain group of patients, they will not prescribe it for you or anyone in that patient group.
What are eligibility criteria and why are they important?
Eligibility criteria are the requirements that a volunteer must meet to participate in a clinical trial. In other words, they outline characteristics to be shared by all study participants. The criteria are determined by the sponsor of each study and may include characteristics such as age, sex, gender, medical history, current health status, presence of the disease or condition being treated, severity of the disease, or the absence of certain diseases.
One of the goals of eligibility criteria is to exclude people for whom the risk of a serious side effect of the drug is more than the benefit of participating in the trial. For example, a person with kidney disease may not be able to participate in a trial if a medication’s expected side effect is that it may worsen the kidney disease. Eligibility criteria are also important for generating accurate and meaningful study results.
Can you discuss how eligibility criteria are applied in practice today?
When a new drug is being developed, the sponsor determines the eligibility criteria based on the purpose and type of study to be performed. There are some eligibility criteria that have become commonly accepted over time and are used for different clinical trials.
This practice of using the same criteria repeatedly across different trials may sometimes have the unintended consequence of excluding certain populations from trials without a strong clinical or scientific justification. These excluded populations may be older adults, pregnant individuals, participants with cancer or HIV infection, and others. If participants are excluded without good reason, we may miss out on fully understanding important safety and effectiveness information about the new medication for all people who will take the drug, if it is approved by FDA.
Other than eligibility criteria, are there any other challenges that might limit participation in clinical trials?
Beyond the criteria I just mentioned, another limitation may be lack of easy access to clinical trial sites and locations. The need to make frequent visits to specific sites could be burdensome for participants who live far from research facilities, such as those in rural or remote locations; or for older adults, children, people with disabilities, and people with cognitive impairments who may require transportation or other help from caregivers.
Now that we have the background information, can you tell us briefly what this guidance is about?
FDA published this guidance in November 2020 as part of its ongoing commitment to promoting the diversity of participants in clinical trials that test the safety and efficacy of new medical products. Recommendations in the guidance are for sponsors responsible for initiating and conducting clinical trials.
The guidance document presents four sets of recommendations that sponsors can apply to ensure participants in clinical trials are diverse.
- First, broaden the eligibility criteria for clinical trials and avoid unnecessary exclusions.
- Second, design clinical trials in ways that achieve participant diversity.
- Third, improve practices for recruiting participants to clinical trials.
- Fourth and finally, apply the recommendations for broad eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.
That is helpful. Now, can you share some examples of FDA’s recommendations for inclusion of specific population groups, like women?
Certainly. FDA recommends that sponsors of clinical trials include women in adequate numbers to detect any significant sex-related differences in response to the drug. When possible, sponsors should consider including pharmacokinetic sampling in women and those who become pregnant during a trial to establish the appropriate dosing of the drug for these individuals. Pharmacokinetic sampling involves checking a participant’s blood levels to see how the drug behaves in the body. Clinical trial sponsors can use the information from these types of tests to ensure safe and continued participation by taking into consideration each individual’s risks and anticipated benefits.
What about children? Should they be included in clinical trials?
When a new drug is approved, it may be important that physicians be able to prescribe the drug to children. FDA recommends that when appropriate, sponsors consider including children and teenagers in clinical trials involving adults. Early in drug development, sponsors should also consider creating a separate pediatric development program specific to children and teenagers. A sponsor’s plan to study pediatric patients should be based on a clear scientific rationale.
You mentioned earlier that clinical trials should include participants of different races and ethnicities to ensure a full understanding of how the drug works and how safe it is in different people. What recommendations does this guidance have for people of different races and ethnicities?
As I mentioned earlier, participants in clinical trials should match the patients who will take the approved drug. As we know, the United States is a melting pot, with people of different races and ethnicities. FDA recommends that sponsors include underrepresented racial and ethnic populations such as Black people, Asian people, people of Hispanic heritage, and Native American people or Pacific Islanders in trials to identify how a variety of people will respond to the new drug. Studying the drug in different people leads to a better understanding of the drug, which is helpful to everyone.
To enroll participants from diverse backgrounds, FDA also recommends that clinical trial sites should be located in areas with higher concentrations of underrepresented racial and ethnic patients and indigenous populations, as well as within neighborhoods where these populations receive their health care.
Participants might prefer healthcare providers of their own races and ethnicities, but this may not always be possible. Healthcare providers can be inclusive in their practices and care by instilling in all patients a genuine sense of belonging and value. FDA recommends that sponsors consider selecting diverse healthcare providers and study coordinators to assist with clinical trial recruitment and implementation.
You mentioned before that clinical trial participation could be burdensome for some participants who live far from research facilities or who might need help from their caregivers to get to and navigate the trial sites. Does FDA have any recommendations to make it easier for these people?
Yes. FDA recommends that sponsors consider flexibilities in visit times and cut back the frequency of in-person study visits, if possible and appropriate. Instead of having participants visit trial sites, sponsors can arrange for mobile medical professionals, such as nurses and blood collection workers, to visit participants at home or have participants visit their local clinics or labs. Another option could be to replace visits to clinical trial sites with electronic options, such as contacting participants by landline, mobile phone, secured email, social media platforms, or digital health technologies, if possible and appropriate. The electronic options can also be used to collect participants’ data in real-time.
Can you share how sponsors can engage with participants and communities to make trials more inclusive?
If I or others want to participate in a clinical trial, we will need to know if there is a trial available for the condition of interest. FDA recommends sponsors educate interested people about the trial and what participation in the trial would mean. Though English is the primary language in the U.S., all participants may not be fluent in English. So, to educate these participants, sponsors can share trial-related resources and information in multiple languages; and recruit research staff who speak different languages or interpreters for participants who speak little or no English. Sponsors can also seek feedback from participants or potential participants to gain valuable insights into patient challenges and burdens, and the degrees of risk they would be willing to accept in exchange for a potential benefit from participation in a clinical trial or to learn more about their disease.
Engaging with the potential participants’ community is also important. Sponsors can talk to patients, focus groups, and community advisory boards to better understand the needs of the potential participants. They can also speak to medical societies, healthcare providers, and disease registry staff. In addition, sponsors can hold events in trusted locations, such as places of worship or community centers; social places of business, such as barbershops and beauty salons; and at public gatherings, such as cultural festivals, carnivals, and parades.
Sponsors should remain engaged with participants and their communities after the clinical trial ends. They can also share clinical trial updates to maintain and strengthen relationships with the communities from which they recruited participants.
Can sponsors make use of social media platforms?
Yes, sponsors can make use of the various platforms. Here is an example from the guidance on social media use. A traditional referral center for clinical trial participation may not be accessible to some participants because the location is far from where they live or work. In this case, sponsors instead may consider using online/social media recruitment strategies to identify potential participants.
Let’s change gears a bit. You’ve told us that the guidance has recommendations for rare diseases. First, what are rare diseases?
A rare disease is a disease or condition that affects less than 200,000 people in the United States. As the name suggests, the smaller the number of patients who have these diseases, the more challenging it is to study them and find new treatments. Rare diseases are very diverse, may affect many organs, and vary in the way they manifest and progress. Also, many rare diseases are genetic and may present early in life, in infants or juveniles, or later in life, in adults. Patients with rare diseases may live all over the world and the symptoms of their diseases may prevent them from traveling far.
Because of these unique attributes and challenges, sponsors need to make special efforts to ensure that the clinical trials for rare diseases are also diverse.
How can sponsors make clinical trials for rare diseases more diverse?
Early in the medication development process, sponsors can engage with patient advocacy groups, as well as experts on rare disease, and patients with rare disease, to ask for their suggestions on the trial designs, procedures, and other aspects. If patients know their suggestions are being considered, they may be more likely to enroll in and support the trials.
After early-phase studies, when medically appropriate and scientifically sound, sponsors may include participants from the early-phase clinical trials in the late-phase trials or longer-term studies. This is to ensure that participants have access to the drug for as long as possible prior to approval, if they can tolerate it and are continuing to experience benefits. For example, sponsors may consider recruiting patients who received a placebo in the earlier trials to receive the study drug in the longer-term study. By the way, a placebo is a treatment that has no active properties, such as a sugar pill, that is used for comparison with the trial medication to determine how well the medication works and how safe it is.
How can someone learn more about a clinical trial that they may want to participate in?
Patients are encouraged to talk to their healthcare providers to learn about clinical trials that may be beneficial for them. They, and interested members of the public, can also visit several websites to learn about clinical trials that are recruiting participants. For example, Clinicaltrials.gov is a database of clinical studies occurring in the U.S. and other countries in the world. Patients can also check the websites of advocacy organizations to find information about clinical trials.
What are some take-home messages from this guidance for patients?
FDA wants patients to know how important it is that clinical trial participants reflect the diversity of the people across our nation who will be taking the medication, if approved. People of different racial and ethnic groups, sexes, ages, abilities, locations, and more may respond differently to medications, so it is important that clinical trials provide the best opportunities to fully understand the medications’ safety and efficacy in all people who will ultimately use them. This understanding also allows science and drug development to move forward toward a future of better treatments.
Everyone should be aware that clinical trials are available to them. You may consider participating in a clinical trial if you are willing, and it is safe for you to do so. If you think a clinical trial might be right for you, talk with your healthcare provider and engage with advocacy groups and other organizations to learn more about clinical trials and eligibility criteria.
Atasi, thank you for speaking with us today about the final guidance on enhancing the diversity of clinical trial populations. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this guidance.
To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.