Graham McClelland, PhD

	Today’s demographic shift to an ageing global population has led to a higher prevalence of age-related physiological changes and disease, leading to multimorbidity and polypharmacy. Therefore, dosage adjustments for the elderly are often necessary. Despite efforts to tailor doses, adverse drug reactions are still more prevalent in the elderly than the general population; these are often avoidable. Furthermore, the older population has historically been underrepresented in clinical research, despite regulatory guidance requiring their inclusion so as to establish age-related differences in safety and effectiveness and thus safe dosage recommendations can be specified with confidence.

	The significant demographic shift to an ageing population has been driven by two major factors. Firstly, a decrease in fertility has been experienced in virtually all regions of the world. Nearly 50% of the global population today live in countries with a fertility rate of less than 2.1 live births per woman, compared to less than a quarter of countries in 1990.¹ 

	Secondly, an increase in life expectancy has been experienced by all regions. The world average life expectancy at birth is 72.6 years today and is projected to increase to 77.1 years by 2050.¹ The accuracy of projected figures, however, depend upon continued advances in the treatment of disease, and the absence of catastrophic events, such as war or epidemics. The highest average life expectancy of 83.2 years is in Australia and New Zealand, followed by 78.7 years in Europe and the USA. However, significant disparities still remain between countries, with the lowest average life expectancy being 61.1 years in Sub-Saharan Africa. 

	The International Conference on Harmonization (ICH) originally issued their E7 guidance on studies in geriatric patients in 1993² (revised in 2008.³) ICH E7 arbitrarily defines a geriatric population as comprising patients aged 65 years or older and states that they should be “included in the Phase III database (and in Phase II, at the sponsor's option) in meaningful numbers. The geriatric subpopulation should be represented sufficiently to permit the comparison of drug response in them to that of younger patients.”

	In 2011, an analysis of 251 trials investigating heart failure

concluded that “despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.” 

	The present research has examined whether medicines currently being licensed are now including sufficient elderly patients to meet the needs of the ever-ageing global population.

	This project focused specifically on the FDA approved drug database

by reviewing new molecular entities (NMEs) approved during the three-year period between June 2016 and May 2019. A two-part approach was adopted: firstly, the statements used in the 

subsection within each approved drug label were categorized and analyzed to assess the extent to which older subjects are represented in the clinical studies. The standard FDA categories 

, plus as an additional category for those NMEs with inconsistent dose recommendations, were used, as are summarized in Table 1.

	Table 1: Categories of geriatric dose recommendations adopted for this research.

	Secondly, the therapeutic indications for which the drugs were approved were assessed to indicate the extent to which the pharmaceutical industry is developing medicines for diseases that are particularly experienced by the elderly (i.e., age-related diseases). Thus, the therapeutic indication of each approved NME during the three-year period were classified as to whether the indication was considered to be age-related or not, according to proposals that resulted from thestudy of the Global Burden of Disease 2017 by Chang et al

, in which they classified 92 out of 293 global diseases as being age-related. Wethen further subdivided our results into each disease area. 

	89 NMEs were approved in the three-year period under study, seven of which were developed specifically for populations other than the elderly. 

	As illustrated in Figure 1,the remaining 82 approved drug applications included a 

subsection, in which 32 percent (n=26) did not include a sufficient number of elderly subjects in their clinical studies, 54 percent (n=44) included a sufficient number  of elderly patients, but did not find any significant differences between younger and older patients, and 11 percent (n=9) included a sufficient number of patients and did find differences between the two groups. Only percent (n=1) of drugs were developed specifically for the elderly population, while two percent (n=2) of drugs had ambiguous , or overlapping, statements and so were categorized as having an “Inconsistent” 

	Figure 1: Pie chart illustrating distribution of new medicines according to geriatric dose recommendations. 

	Figure 2: Disease categories and statement categories for diseases classified as “age related”

	As shown in Figure 2, during the three-year period under review, the pharmaceutical industry has indeed developed drugs for age-related diseases such as cancer, but, no drugs have been approved to treat any age-related cardiovascular diseases and only two for neurodegenerative diseases, despite the high burden of these diseases in the elderly population.

	New medicines that were developed for non-age-related disease indications are shown in Figure 3.

	Figure 3: Disease categories and statement categories for the diseases classified as “nonage related”

	The pharmaceutical industry is currently including older subjects in many of trials of NMEs, particularly with those new drugs which are more likely to be treating diseases that are prevalent in the elderly. However, the elderly population is still underrepresented, with almost a third of newly registered drugs included an insufficient number of elderly in clinical trials, thus leading to uncertainties regarding safety and effectiveness for prescribers. 

	There are several tactics that can, and perhaps should, be always adopted to increase the participation of elderly subjects in clinical trials, as were proposed by Ryan Bailey in 2018

, where he specifically recommended that trial organizers should:

		Reconsider age limits and avoid an all-or-none mentality to enrolling geriatric subjects.

		Learn from other efforts to recruit marginalized populations.

		Engage patient advocacy groups that focus on elderly patients. 

		Learn what is already expected from agencies like the FDA

when it comes to inclusivity. [Similarly, the EMA actively promotes the greater inclusion of elderly in clinical trials

		Design studies to examine effectiveness (demonstrating that a treatment produces desired results in “real-world” circumstances) not just efficacy (demonstrating that a treatment produces desired results in ideal conditions).

	The results from this project have indicated that there should be greater focus on the R&D of new medicines to unmet medical needs of the elderly. While there have recently been a number of oncology drugs suitable for the treatment of cancers in the elderly, there has been a lack of any new treatments for dementia, congestive heart failure, and the management of chronic pain in this population.

, is a Visiting Professor and can be reached at 

, MSc, is a former postgraduate student at the Institute of Pharmaceutical Sciences, King’s College London, UK.

		World Health Organization. Global strategy and action plan on ageing and health. Sep 2015. Available at: 

https://www.who.int/ageing/events/world-report-2015-launch/en/

		ICH E7: Studies in Support of Special Populations: Geriatrics. Jun 24, 1993. Available at: 

		ICH E7(R1): Studies in Support of Special Populations: Geriatrics. Oct 23, 2008. Available at: 

		Cherubini A, Oristrell J, Pla X, Ruggiero C, Ferretti R, Diestre G, Clarfield A M, Crome P, Hertogh C, Lesauskaite V, Prada G-I, Szczerbinska K, Topinkova E, Sinclair-Cohen J, Edbrooke D, Mills GH. The persistent exclusion of older patients from ongoing trials regarding heart failure. Arch Intern Med 2011;171(6):550-556.

		Drugs@FDA: FDA Approved Drug Products. Available from: 

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

		FDA Code of federal Regulations Title 21, Volume 4, Revised April 1, 2019. Available from: 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201

		Chang AY, Skirbekk VF, Tyrovolas S, Kassebaum NJ, Dieleman JL. Measuring population ageing: an analysis of the Global Burden of Disease Study 2017. Lancet Public Heal. 2019;4(3):e159–67.

		Bailey R. “The importance of age diversity in clinical trials”.

http://www.appliedclinicaltrialsonline.com/importance-age-diversity-clinical-trials

		FDA patient guidance on diversity in clinical trial participation. Available at: 

https://www.fda.gov/patients/clinical-trials-what-patients-need-know/diversity-clinical-trial-participation

		NIH Policy and Guidelines on the Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects. Dec 19, 2017. Available at: 

https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html

		EMA guidance in medicines for older people.  Available at: 

https://www.ema.europa.eu/en/human-regulatory/research-development/medicines-older-people

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The elderly population is still underrepresented in clinical trials, with nearly a third of newly registered drugs included an insufficient number of elderly participants, leading to uncertainties regarding safety and effectiveness for prescribers.

Graham McClelland, PhD

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