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Last month, NIH announced a revision (NOT-OD-18-116) to a decades-old policy originally conceived in response to concerns that children were not appropriately included in clinical research. These changes broaden the policy to address inclusion of research participants of all ages, and as discussed at the last Advisory Committee to the NIH Director meeting, will apply beginning in 2019 to all NIH-supported research involving human subjects. Our goal is to ensure that the knowledge gained from NIH-funded research is applicable to all those affected by the conditions under study.
To get here, NIH solicited feedback from experts and the public through a Request for Information and a workshop held over the summer. We heard from many of you, from pediatricians, geriatricians, primary care providers, statisticians, publishers, bioethicists, and people from the general public. Among the concerns raised were that many trials include poorly-justified age-based exclusions (Cherubini 2011, Cruz-Jentoft 2013), and that older adults, who carry a disproportionate burden of disease, are often underrepresented in clinical trials. For example, while nearly a third of US cancer patients are 75 years or older, less than 10% of patients in cancer trials are in this age range (Hurria 2014).
After considering input and in accord with the 21st Century Cures Act, our policy now requires people of all ages, including children under 18 years and older adults, be included in clinical research studies unless there are scientific or ethical reasons not to include them. We outline when certain age groups may be excluded and note that grantees are now required to annually report on the age at enrollment of their participants along with sex/gender, race, and ethnicity.
So, for application due dates on or after January 25, 2019 (yes, one year from now), if you propose a study involving human subjects, you must have a plan describing how participants across the lifespan will be included and justify the proposed age range of participants. Reviewers will consider whether the proposed age range is appropriate in the context of the specific scientific aims. Should the study be funded, keep in mind that your progress reports will include de-identified individual-level participant data on sex/gender, race, ethnicity, and age at enrollment (in units ranging from hours to years). Ongoing NIH-funded research (type 5 awards) are exempt from this policy, but the policy will apply if you are submitting a competitive renewal application on or after January 25, 2019.
We understand that sometimes research should exclude certain participants. For example, if the disease does not occur in the excluded group, or the knowledge sought is already available on the excluded group, then this may be an appropriate justification to limit who is in your study. We also recognize that there are situations where participation of certain groups would be unethical, or laws or regulations bar the inclusion of a specific group in research. The Guide notice describes situations in which exclusion of individuals based on age may be justified. Keep in mind that the age distribution of participants should be appropriate in the context of the science.
We look forward to working with you in the implementation of these high priority inclusion policies, which are designed to assure that our funded research will better help us make informed health and health care choices going forward.
This is important to consider, but we also need to consider follow up for potential undesired results in subjects after the funding is completed.
This is a very welcome change in policy and long overdue. It has been difficult in HIV research for example to explain to the community why older adults are excluded when they are also burdened by the disease.
Thank you for this important revision. Can you clarify whether inclusion will be expected to reflect age distribution for the condition; for instance, if 1/3 of US cancer patients are >75 yo, will investigators have to enroll a similar proportion, or can they simply indicate that they didn’t exclude such patients? If it’s the latter, the impact may be minimal. Also; to fully capitalize on the new policy, is it possible to request pre-planned analyses stratified by age? For instance, in the case of cancer, it would be most helpful to know the effectiveness/side effects of the approach in those above age 70/75 years vs. those below this age. Function and frailty are also of fundamental importance in this regard. Thanks again.
Answer to Q1: The goal of the Inclusion Across the Lifespan policy is to ensure that study results are generalizable to those affected by the condition under study. The policy indicates that applications must address the age-appropriate inclusion or exclusion of individuals in the proposed research project. Therefore, your application should include a rationale for selecting the specific age range justified in the context of the scientific question proposed. While the prevalence or incidence of the condition in individuals across the lifespan is an important consideration when determining age-appropriate inclusion, there is not a specific requirement that enrolled participants reflect the age distribution/proportion for the specific condition under study.
Answer to Q2: While NIH is not requiring subgroup analyses by age, as discussed in an Open Mike blog last year, NIH encourages investigators to consider relevant biological variables such as sex, age, BMI, and underlying health conditions, when designing their study, conducting analyses, and reporting results.
What about pregnant women. This is a difficult area, but there is not much of an evidence base because of the lack of clinical trials
Thank you for raising the issue of inclusion of pregnant women in clinical research. We agree that there is a serious lack of evidence to, for example, inform the use of therapies used by either pregnant or lactating women. the Eunice Kennedy Shriver National Institute of Child Health and Human Development is leading a congressionally mandated Task Force that will report to the HHS Secretary, by fall of 2018, its recommendations to begin to address those gaps in knowledge. We hope this report will spur further work in this critical area.
Does anyone know where we can find an example of this section?
NIH does not typically provide examples of applications. We suggest referring to the application guide instructions and following up with your Program Officer with specific questions.
I’m not a program officer, but maybe this site will help?
https://grants.nih.gov/grants/how-to-apply-application-guide.html