The Graying of Clinical Trials

Patients 65 years of age and over are underrepresented in clinical trials, even though in many therapeutic categories they are the primary drug consumers. But, writes, Sydney Rubin, there are few practical or ethical obstacles to including elderly patients in trials that cannot be overcome.

Thanks to efforts of groups like the Society for Women’s Health Research, considerable attention has been focused over the last 20 years on bias in biomedical research, specifically the inclusion of women and minorities in clinical trials. Previously, clinical trials were almost exclusively designed by middle aged white men for middle aged white men and such bias put the health of American women and minorities at risk, SWHR has said.

Today, a similar problem is faced by older people. Broadly speaking, patients 65 years of age and over are underrepresented in all phases of clinical trial, even though in many therapeutic categories they are the primary drug consumers. The disparity between participation in trials by older patients and market need is enormous and growing. Sponsors of clinical trials must open the door to including more elderly patients because failing to do so will have enormous adverse consequences for global public health – and pharmaceutical industry profits.

“The world is on the cusp of a staggering rise in the number of old people, and they will live longer than ever before,” an article in The Economist reported in May. Those tracking the graying of the globe say that over the next 20 years the global population over 65 will almost double, from 600 million to 1.1 billion. People will work and be active longer and policies in many sectors are changing to reflect the evolving demographic.

All the way back in 1994, the International Conference on Harmonisation (ICH) made a compelling case for including older patients in trials, noting that drugs tested on younger populations don’t always work the same in the elderly. Knowing this, physicians face a tough choice between treating elderly patients off label with insufficient data on dosing ranges, side effect profiles and drug-drug interaction or denying them the treatment entirely.

Case in point: Only 42 of 4,000 patients in a trial for recombinant tissue plasminogen activator were older than 80 years old. So, the EMA approved the drug for patients 80 and under. Older patients in the EU needing treatment for thrombolysis in stroke could only receive the medication off label and their chance of having access to the drug depends on the hospital and in which country they live.

Healthcare professionals recognize the problem and a recent survey of medical professional in nine EU countries found:

· More than 70% agreed that not having enough older people in clinical trials creates difficulties for older patients, and

· Eighty-seven percent believe that excluding people on age grounds alone was unjustified.

Indeed, aging populations in developing nations are so much more active and healthy than previous generations that the World Health Organization in 2006 called on policymakers to redefine old age. Although many trials set a ceiling of 65 years of age for participants, WHO points out that 75 is the new 65 – so perhaps the ceiling should be raised.

Older adults suffer the greatest health burdens in the Western worlds with disproportionally higher rates of cancer, cardiovascular disease, dementia, arthritis and Parkinson’s disease. Yet, literature reviews demonstrate the disparity between trial participation by older patients and disease burden:

· The elderly account for 60% of all new cancer cases but only 36% of patients over 65 participate in cancer trials, according to a study published in 2004 in the Journal of Clinical Oncology.

· In antidepressant treatment trials, only 9-11% included older adults, despite depression being most prevalent in the elderly, according to a study on “Increasing the participation of elderly in clinical trials” published in November 2008 by the Medical Research Council.

· Thirty-five percent of research published over one year, 1996-1997, excluded the elderly for no justifiable scientific reason, a 1997 study in the British Medical Journal reported.

Those IHC guidelines in 1994, “Studies in Support of Special Populations: Geriatrics,” suggest protocols should not ordinarily include arbitrary upper age cutoffs. Drugs should be studied in all age groups, including the elderly. And, patients entering clinical trials should be reasonably representative of the population that will later be treated by the drug. Geriatric patients should be included in Phase III in meaningful numbers sufficient to allow comparison of drug response in older patients to that of younger ones – all according to IHC guidelines.

The EMA agreed with IHC in a 2011 report and expanded their position in February 2013 as part of recommendations on the ethical aspects of clinical trials in older people. In between, in 2012, the FDA issued a question and answer document building on the ICH work, calling for “an appropriate representation of the geriatric population.” The guidance is clear. So why aren’t more elderly being included in clinical trials?

The challenges include:

· Medical factors, such as comorbid conditions, reduced life expectancy and a higher risk of adverse events related to pharmacokinetic and pharmacodynamics changes related to aging.

· Scientific factors, such as the need to manage withdrawal from a trial due to cognitive deterioration.

· Socioeconomic factors, such as a lack of support at home to support protocol compliance and problems with transportation.

· Ethical challenges, such as the need to take extra care ensuring informed consent with frail and vulnerable patients.

In addition, study design and recruitment may become more complicated when older patients are involved. But all these challenges are surmountable and a good clinical trials partner can help companies broaden trials to include this important population.

Given our graying demographic, sponsors need to extend the clinical trial age limit to 75 and adjust to new market realities while adhering to regulatory guidance. This means:

· Ensuring that the ages of trial participants reflect the age strata of the potential consuming patient population. In many cases, this means including a significant group of people over 65.

· Designing studies to accommodate the elderly, breaking those out with comorbidities and medications and adding laboratory evaluations, as needed.

· Preparing to justify age-related exclusion criteria.

· Tailoring outcomes measures to the population under study. Outcome measures for the elderly should include quality of life and may need to include effects on cognition, balance and falls, incontinence and weight loss, according to a study published in 2013 in The Journal of Nutrition, Aging & Health (“Guidance Synthesis. Medical Research for and with Older People in Europe: Proposed Ethical Guidance for Good Clinical Practice.”)

· Assuming that all adults are capable of providing informed consent unless proven otherwise.

There are few practical or ethical obstacles to including elderly patients in trials that cannot be overcome. Regulators and the marketplace both favor providing a base of evidence on the use of products in patients over 65. Doing so has become a regulatory recommendation, an ethical imperative and, above all, a business opportunity.

Sydney Rubin is Chief Communications Officer of inVentiv Health