New Inclusion Policy Promises Better Representation Of All Ages In Clinical Research

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The National Institutes of Health (NIH) wants a better representation of people of all ages in clinical studies it funds, especially those affected by age-related and other various medical conditions, frailty, physical or cognitive impairments and those on multiple medications.

The NIH Inclusion Across the Lifespan policy, which was developed in response to requirements in the 21st Century Cures Actwent into effect in January. The new policy mandates that participants of all ages be included in human subjects research, unless there is a scientific or ethical reason for exclusion of any age category.

According to Barbara Radziszewska, health scientist administrator for the Division of Geriatrics and Clinical Gerontology (DGCG), “the inadequate inclusion in clinical trials of older adults, especially those affected by age-related conditions, has been amply documented across many disease areas, including those that disproportionally affect older people. Participants enrolled in clinical trials are frequently younger and healthier than the typical population affected by a given disease or condition.”

In a recent blog post, Radziszewska said some studies impose “arbitrary upper age limits of enrolled participants,” and others “use exclusion criteria that disproportionally affect older people, such as multiple morbidities, polypharmacy, frailty and physical or cognitive impairments.”

These restrictions, she says, “reduce the relevance of the data collected in clinical trials to real-life patients in clinical settings,” leaving “critical gaps in the evidence base and in clinical guidelines for older, more complex patients.”

National Institute on Aging (NIA) and NIH staff has been conducting ongoing research and analysis of this issue for several years. The 21st Century Cures Act called for NIH to convene a workshop focused on the inclusion of pediatric and older adult populations in clinical research, including clinical trials. The workshop was held in 2017 and resulted in several recommendations for change.

Some of the organizations that responded to the NIH’s Request For Information for that workshop included Florida Breast Cancer Foundation, Federation of American Societies for Experimental Biology, Public Responsibility in Medicine and Research, The American Geriatrics Society and The Gerontological Society of America.

According to the NIH, the purpose of the Inclusion Across the Lifespan policy is “to ensure that the knowledge gained from NIH-funded research is applicable to all those affected by the conditions under study.”

The recommendations of the Inclusion Across the Lifespan Workshop acknowledged that in order to generate the best evidence possible from clinical research and to ensure that all communities benefit equally from advances in treatment, management, or prevention of disease, “it is important for clinical research and trials to include participants who adequately represent those with the disease or condition under study.”

But according to the NIH, this is often not the case because “investigators often exclude children (individuals under age 18) or older adults (individuals ages 65 and older) either explicitly, by limiting the age range of eligible participants in their exclusion criteria, or implicitly, by excluding those with co-morbid conditions or polypharmacy use, both of which are common in older populations.”

As a result, many interventions are inadequately tested in the very old and the very young, Radziszewska said. The NIH has been trying to resolve the issue for the last three decades by instituting policies to ensure that participants in NIH-supported clinical research are representative of affected patient populations.

“Beginning in the 1980s and early 1990s, policies and legislation required the inclusion of women and minorities,” the workshop summary states. “NIH issued a policy requiring the inclusion of children in 1998 and in 2015 revised the definition of children from under 21 to under 18. Most recently, the 21st Century Cures Act—signed into law in December 2016—requires NIH to collect data on the inclusion of participants in clinical trials by age.”

Workshop participants were charged with considering inclusion on a broad spectrum, across government research funding agencies (GRFs), regulatory agencies, publishers and the scientific community. They heard from investigators, experts and clinicians who discussed the challenges and barriers to including children and older adults in clinical research as well as to identify strategies that would produce more age-inclusive clinical trials.

Radziszewska said she and NIA Deputy Director Dr. Marie A. Bernard recently analyzed data on subject inclusion in Phase III clinical trials from 1965 to 2015, focusing on diseases that are the most frequent causes of hospitalization and/or disability in older adults. She said the analysis “revealed striking evidence for the need to include more older adults.”

“We found that 33% of the studies had arbitrary upper age limits, and 65 percent of the trials reported data of participants who were younger than the typical population affected by the disease under study,” she wrote. “In addition, many clinical trials excluded participants based on multimorbidity and polypharmacy.”

The new policy will require investigators in the aging research community who seek grants from the NIH for research involving human subjects to:

  • Consider age as a variable in study design and recruitment plans.
  • Submit a plan to include individuals within an age range that is appropriate for the goals of the study. If investigators plan to exclude participants based on age, they must provide rationale and justification.
  • Include anonymized data on individual participants’ age at enrollment, as well as sex or gender, race and ethnicity in progress reports.

Radziszewska said the policy does allow for acceptable reasons to exclude certain age ranges, which will be assessed by the Scientific Review Groups.

“The expanded inclusion policy presents a new set of challenges to the scientific community, as it has implications for study design and recruitment planning,” Radziszewska wrote. “Although the implementation of the new policy may necessitate increasing the planned sample size to overcome the additional variability introduced by more inclusive enrollment policies, the expected result is well worth the additional effort and expense, given the urgent need to address critical gaps in the evidence base on the diseases and conditions of later life. This is a solid step in the right direction for improving clinical care for the nearly 50 million U.S. adults over age 65.”

An article published in Perspectives in Clinical Research (PICR) by Dr. Premnath Shenoy and Anand Harugeri, both of Regulatory Affairs and Patient Safety at AstraZeneca Pharma India Ltd., addressed the issue of elderly patients’ participation in clinical trials in 2015.

The authors wrote that while the elderly make up the lion’s share of patients for certain health conditions including cancer, cardiovascular disease, arthritis and Parkinson’s disease, among others in most parts of the world, and furthermore the elderly make up the majority of patients for many medications treating chronic conditions, “typically, clinical trials conducted in adult population include patients between the ages of 18 and 64 years.”

“However, drugs should be studied in all age groups and trial participants should be representative of the patient population receiving the therapy in daily medical practice,” the authors wrote. “Elderly patients are poorly represented in clinical trials.”

Although persons aged 65 years and older represent only about 13% of the population, they consume nearly one-third of all medications, the authors wrote. Further, geriatric patients can respond differently from younger patients to drug therapy. “Age-related physiological changes can affect pharmacokinetics and pharmacodynamics of the drug,” they wrote.

And geriatric patients are more prone to adverse effects which can be severe and have more serious consequences than in the younger population, they wrote. “Not all pharmacotherapeutic outcomes that can occur in the geriatric population can be predicted from nongeriatric populations. Therefore, to assess the benefits and risks of a drug that will be used in elderly, these patients should be appropriately represented in clinical trials.”

The U.S. Food and Drug Administration (FDA) also encourages more participation and diversity in clinical trials.

While the FDA does not ordinarily conduct clinical trials, it relies on the data from them to determine whether medical products are safe and effective.

“Overall, few people actually sign up for and participate in trials, and those who do participate don’t always represent the U.S. population,” the FDA states. “Participation is especially low for certain populations, including adults age 75 or older and people from certain racial and ethnic groups.”

Simply put, diversity in clinical trials helps the FDA do its job. “Clinical trials, and the people who volunteer to participate in them, are essential to help the development of ways to fight illnesses. To make sure that the FDA has a full picture of the risk or benefit of a medical product, patients enrolled in a trial should be representative of the types of patients who are likely to use the medical product if it is approved or cleared by the FDA.”

Certain populations can be more at risk for certain diseases—such as diabetes and heart disease—than others, and people of diverse groups can respond very differently to medical products. With diversity in clinical trials, information on those differences can then be included on medical product labels to help doctors and patients make treatment decisions about safe and effective use in everyone who uses them.

The FDA has a dedicated section on its website for patients that provides information and tools to encourage clinical trial participation. This section includes information that focuses on people of different ages, races, ethnic groups and genders.

The FDA’s Office of Women’s Health, along with the National Institutes of Health (NIH) Office for Research on Women’s Health, launched an initiative last year to raise awareness among women and share best practices for clinical trials.

And the FDA’s Office of Minority Health also has tools to encourage patients and their health care providers to learn about trials, including public service announcements (PSAs) on the FDA’s “Minorities in Clinical Trials” webpage.)

The NIH also keeps a list of ongoing trials, so potential participants can search for studies at clinicaltrials.gov.

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