Question

there is the interesting scientific data on the population response to the virus (children vs. adult vs. elderly) - how would a clinical trial be affected if enrolling adults vs. elderly? and how the generalizability of the findings be applicable?

Answer 1

During drug development, inclusion of broad patient populations in clinical trials helps provide evidence that the investigational medical products will be safe and effective in the full range of patients likely to use the product if the product is approved. Eligibility criteria determine who can participate in clinical trials and, at times, this results in the enrollment of study populations that may not represent the broader patient populations that use approved products. Over the past few decades, there have been policy initiatives to increase the inclusion of particular subgroups in clinical trials, including women and older adults, and to ensure that all eligibility criteria are scientifically justified. This includes initiatives by the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) that emphasize the importance of inclusive eligibility criteria. Despite these efforts, challenges and barriers that limit participation in clinical trials remain.

Eligibility criteria are a critical component of clinical trials, as they define the patient population under investigation. These criteria are often tailored to allow assessments of the effectiveness of a treatment in a well-defined population. Inclusion criteria specify the characteristics required for study entry, such as stage of disease or specific pathophysiological characteristics. They typically identify a population in which it is expected that the effect of the drug can be shown. An obvious example is identifying patients with a specific mutation that is targeted by the treatment,

where the drug is likely to be effective only in those patients with the disease who have the mutation. More broadly, it is usual to not only include patients who have the disease to be treated, but those who also have a threshold severity of disease and do not have certain other conditions, or who are not using medications that could mask the effect. Exclusion criteria specify characteristics that disqualify patients from participation and often include factors such as comorbidities or concomitant treatment or factors that could mask the effect of the intervention. However, if these criteria exclude a subgroup that will eventually receive the drug once approved (e.g., people with comorbidities), relevant effects of the drug on that subgroup will not be detected. Broader inclusion criteria and less-restrictive exclusion criteria will lead to a study that provides more information about the product’s effects in the population most likely to use the product if it is approved.

When designing clinical trials, there is tension between balancing the desire to minimize heterogeneity (“noise”), which can mask a finding of the effect, and the desire to generate data that are generalizable to a broader patient population that is likely to be treated. Narrow eligibility criteria can result in (1) a homogenous sample of subjects, limiting the variability in a study population, and (2) controlling for confounding factors, maximizing the probability of detecting a treatment effect if one exists. On the other hand, narrow eligibility criteria can diminish the understanding of the riskbenefit of the study treatment relevant to the patient population likely to take the drug if the drug is approved. Sponsors must balance the need to generate evidence of effectiveness to support a regulatory decision while obtaining evidence in the population most likely to utilize the treatment.

Balancing these scientific considerations and designing clinical trials that both generate substantial evidence of effectiveness for regulatory approval and inform the safe and effective use of medical products in patient populations that will be exposed to them after approval will continue to be a challenge for stakeholders across the full spectrum of drug development, regulation, and use.

Ethical and Scientific Considerations that Can Lead to Exclusion

Whether the benefits of enrolling in a study outweigh the potential risks is also a primary consideration for determining eligibility criteria. Older adults and patients with organ dysfunction or multiple chronic conditions may be excluded from clinical trials because of concerns about potential adverse impacts arising from comorbidities and concomitant medications. Ethical considerations may lead to the exclusion of children, adolescents, and pregnant and lactating women in clinical trials. On the other hand, exclusion of such patients provides no information about a drug’s benefits and risks in such patients, but they may use the drug if it is approved. Therefore, it is important to consider on a caseby-case basis whether such exclusions are truly necessary

Older adults

Older adults and patients with organ dysfunction or multiple chronic conditions may be excluded from clinical trials because of concerns about potential adverse impacts arising from comorbidities and concomitant medications. Ethical considerations may lead to the exclusion of children, adolescents, and pregnant and lactating women in clinical trials. On the other hand, exclusion of such patients provides no information about a drug’s benefits and risks in such patients, but they may use the drug if it is approved. Therefore, it is important to consider on a caseby-case basis whether such exclusions are truly necessarya drug improves clinically meaningful health outcomes for the Medicare population. Without the inclusion of adults over age 65 in clinical trials, it can be challenging to determine the strength and generalizability of the evidence for the Medicare population. Since the early 1980s, FDA has developed guidance (finalized in 1989) on including the elderly (patients over age 65) in clinical trials;9 and an ICH-E7 guidance10 also urges this with a recent amendment to encourage inclusion of patients over age 75. There have been renewed efforts to include older adults in clinical trials. The 21st Century Cures Act requires NIH to examine barriers to including older adults in clinical trials and identify ways to design age-inclusive trials. Beginning in 2019, applications for research must describe plans for including individuals across the lifespan, with scientific justifications for both the age range specified in the context of the study and any exclusions. NIH must also collect data on clinical trial participants by age.11 Under FDA regulations, new drug applications must include effectiveness and safety data presented by gender, age, and racial subgroups and, when appropriate, other subgroups of the population of patients treated, such as patients with renal failure or patients with different levels of severity of the disease (21 CFR 314.50(d)(5)(v)).

Children, Infants, and adolescent -Changes to U.S. drug laws to strengthen regulatory oversight for these subgroups have often been in reaction to tragic cases of harm from drugs and biologics. For example, (1) the Biologics Control Act was passed in 1902 following the deaths of 22 children from contaminated diphtheria antitoxin and smallpox vaccine; (2) the Federal Food, Drug and Cosmetic Act of 1938 legislation followed the deaths of over 107 persons, many of whom were children, caused by a preparation of the antibiotic sulfanilamide that was formulated in diethylene glycol (antifreeze), and (3) the passage of the Kefauver-Harris Drug Amendments of 1962, which created a requirement that drugs be shown effective prior to their marketing, followed the thalidomide tragedy that led to thousands of birth defects in Europe. Legislation was established to define additional safeguards to limit the risk to children in research if there is no prospect of direct benefit (21 CFR 50, subpart D). An unintentional outcome of these additional safeguards is a lack of early drug testing in children, leading to reduced knowledge about the safety and effectiveness of these medications for children, and language in labeling that may discourage pediatric use. Federal efforts have sought to address these issues by incentivizing the inclusion of children, infants, and adolescents in clinical trials. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) havesignificantly increased the inclusion of children in research, but often only after approval of the drug based on data from adult populations.12 Investigators should consider children when designing adult trials (e.g., evaluating exposureresponse, incorporating endpoints that are applicable to all ages) to support extrapolation of efficacy from adults to adolescents and/or younger children when appropriate.

The elderly population is a large and the fastest-growing portion of the population worldwide. 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. Furthermore, 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. Elderly patients are poorly represented in clinical trials. Hence, there is inadequate evidence and knowledge about responses of geriatric patients to medications. Regulatory authorities in developed countries urge to avoid arbitrary upper age limits and advise researchers and industry not to exclude elderly people from clinical trials without a valid reason. Since last few years Indian regulatory authority has been stipulating upper age limit for studies conducted in India. The Central Drugs Standard Control Organization (CDSCO) will be doing a great contribution to the researchers if it changes its view on stipulating upper age restrictions in clinical studies. This article describes the need for including elderly patients in the clinical trials in order to garner data from geriatric patients who form major medication users in most of the chronic diseases.

ELDERLY POPULATION AND CLASSIFICATION

The elderly population is the fastest-growing portion of the population in advanced nations. Globally, the elderly population (aged ≥60 years) is expected to increase to more than 2 billion in 2050.[3] The present population aged ≥65 years in India accounts to 5.3% of the total population. By the year 2025, it is expected that 7.2% of Indian population will contain people aged ≥65 years.

Gerontologists have recognized very different conditions that people experience as they grow older. In developed countries, most people in their 60s and early 70s are still fit, active, and able to care for themselves. However, after 75, they will become increasingly frail, a condition marked by serious mental and physical debilitation. Gerontologists have defined elderly sub-groups as young-old (65–74 years), middle-old (75–84 years), and very old (≥85 years).

The cut-off age for elderly in India is 60 years. Low life expectancy of the Indians compared to developed countries, the normal age for retirement, age boundary for senior citizenship, and literature reports support 60 years as the cut-off age for the elderly in India.[6] However, increasing the life expectancy of Indian population may point toward upsurge in the cut-off age for the elderly in India in the future.

AGING AND PHARMACOLOGY

Aging has a significant effect on the responses to pharmacological interventions. Age-related physiological and pathological changes play a major role in altering pharmacological actions of drugs. Age-related changes in hepatic and renal functions significantly affect the absorption, distribution, metabolism, and excretion of the drugs. Age-related changes in bioavailability may be secondary to changes in absorption or gut wall and hepatic metabolism. Gastric acid secretion decreases with aging.[7] Aging is associated with slowing of gastric emptying, decreased peristalsis, and slowing of colonic transit which influence the Tmax and Cmax than the area under the curve. The active transport of some nutrients is impaired with aging. Gastrointestinal blood flow is probably diminished in the elderly and affects the absorption of drugs.[7] Decrease in albumin with aging increases the unbound concentrations of many drugs.[8] Due to aging-related possible increase in α1-acid glycoprotein, concentration of some unbound drugs like lignocaine decreases.[9] Age-related changes such as an increase in body fat and a decrease in body water may influence volumes of distribution of drugs. Changes in body composition lead to an increased concentration of water-soluble drugs and a prolonged elimination of lipid soluble drugs.

Both Phase I and Phase II of drug metabolism in liver convert drugs into more water soluble molecules to ease the elimination. Phase I metabolism in the liver is affected in the elderly. Hence, decreased the clearance of drugs that undergo Phase I metabolism is expected. Metabolism could also be impaired due to a reduction in liver size and blood flow with aging. Glomerular filtration rate declines with age. Hence, age-dependent decrease in total clearance is expected for drugs that are eliminated by kidneys. The use of standard doses of these drugs may result in increased plasma concentration and increased risk of adverse drug reactions in elderly. The efficacy of renally eliminated drugs is usually increased in states of reduced renal functions.

The relationship between aging and pharmacodynamic effects of drugs are less well-established. Age-related up-regulation and down-regulation of pharmacological receptors are probable. Pharmacodynamic changes can vary among drugs, including the drugs from the same class. In elderly, the central nervous system shows an increased sensitivity to antipsychotic drugs due to the age-related increase in monoamine oxidase activity. Aging brain loses a significant number of active cells and some degree of brain atrophy is common. There is also a reduction in cerebral blood flow and a selective decline in some nerve pathways. The elderly patients are more sensitive to drugs that have anticholinergic effects due to age-related loss of cholinergic neurons and exacerbation of cholinergic deficit by these drugs. The elderly patients’ exhibit increased sensitivity to coumarin anticoagulants due to age-related decline in the hepatic synthesis of vitamin K-dependent clotting factors.

ELDERLY AS CLINICAL STUDY SUBJECTS

Typically, clinical trials include patients aged between 18 and 65 years. However, the study population should ideally reflect the population that will be treated in the real world, particularly if it's studying a drug that will be used by elderly patients. It is just and apt that elderly patients are adequately represented in clinical trials for treatments for the above-listed conditions. There are several benefits of elderly patients’ participation in clinical trials

Table

Benefits of elderly patients’ participation in clinical studies

There is inadequate evidence and knowledge about responses of geriatric patients to medications. The older patient population is poorly represented in clinical trials, with up to 35% of published trials excluding older people. In a recent commentary, it was contended that the crisis of aging must be addressed by the development of broad expertise and research into geriatric pharmacology. It has been found that the elderly are underrepresented in cancer clinical trials, more pronounced in trials for early-stage cancers than in trials for late-stage cancers.

In USA, though the elderly aged ≥65 years account for 61% of all new cancer cases and 70% of all cancer deaths, in the clinical trials active between 1993 and 1996, the elderly comprised only 25% of oncology trial participants.study audited 226 clinical research proposals recording exclusion of patients based on an arbitrary upper age limit and found that significant proportion (13.7%) of clinical trials excluded patients based arbitrarily on an upper age limit.However, none (9.8%) of the trials submitted by geriatricians excluded patients based solely on age. The mean upper age limit used over all trials as a cut-off was 69.2 years. Over 50% trials submitted by neurology/psychiatry excluded patients based on an upper age limit

Although elderly patients represent the majority of the heart failure (HF) population, and have a worse prognosis compared to younger cohort commonly included in trials, targeted treatment strategies have been insufficiently developed for them. The elderly HF phenotype is characterized by an increased prevalence of HFpEF, with a greater burden of cardiac and noncardiac co-morbidities. The present knowledge is limited by the enrollment of patients with HF with reduced EF in most trials, with the exclusion of those with increased frailty.

People are living longer and expect that treatments will cure and improve their quality of life. Hence, there is a clear need for evidence-based pharmacotherapy of elderly patients. To deny them this opportunity runs counter to the precepts of medical practice and could even be considered unethical. In a survey of nine EU countries, the majority (87%) of the medical professionals believed that excluding people on age grounds alone was unjustified and over 70% agreed that not having enough older people in clinical trials resulted in difficulties for older patients

REGULATORY VIEW ON ELDERLY IN CLINICAL STUDIES

The scientific, ethical, and regulatory principles that determine the conduct of clinical trials in younger individuals apply equally to older people. In addition, the development of drugs to be used in elderly requires an awareness of physiological, pathophysiological, and sociological considerations. This has inevitably meant that the drug development process must increasingly recognize the importance of identifying and developing therapeutic targets relevant to elderly. However, there are several reasons why elderly are underrepresented in clinical trials .

Table

Reasons for under-representation of elderly patients in clinical studies

The International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use (ICH) called for including elderly in clinical trials for all therapies intended for adults. “Studies in Support of Special Populations: Geriatrics,” issued by ICH in 1994 urged clinical trial protocols to avoid arbitrary upper age limits. It also recommended not excluding elderly from trials even if they have other ailments, since doing so prevents uncovering interactions of multiple drugs or diseases.

Federal laws require that cancer trials enroll representative samples of women and members of a minority group. No such law for representative samples of elderly exists today. A 7 years review of elderly patients’ enrollment in cancer drug registrations by U.S. Food and Drug Administration (USFDA) found statistically significant under-representation of the elderly. The USFDA guidance advises researchers not to exclude trial participants solely on the basis of age, and also urges inclusion of an appropriate representation of elderly patients in clinical trials to measure safety and effectiveness in older patients, and to allow comparisons with their nonelderly patients.

European medicines agency has described a strategy for geriatric medicines. Five of the 10 new medicinal product dossiers reviewed by Committee for Human Medicinal Products included specific studies for the elderly and all of them analyzed the results for patients aged ≥65 years.[18] Governmental officials, industry, health professionals, and other stakeholders from across Europe are working to improve the translation of research into practice by specifically addressing the lack of clear, accessible evidence about new technology, including medications for elderly people.