The European Medicines Agency (EMA) has published a new Questions and Answers document (EMA/CHMP/ICH/604661/2009 ) relating to the ICH E7 Guidance - Studies in Support of Special Patients: Geriatrics (CPMP/ICH/379/95) . The existing ICH E7 guideline outlines the need to include geriatric patients in clinical trial design in recognition of the increasing aging population in the ICH regions of Europe, Japan and the USA. The guideline outlines the definition of a geriatric patient, provides advice on how many geriatric patients to include in a trial and discusses pharmacodynamic studies in detail, as well as providing advice on drug-drug interaction studies in geriatric patients. The new Q & A document further clarifies the need to include geriatric patients in the clinical database, how to incorporate geriatrics into a trial design and what parameters should be addressed that are specific to the aging population.
The differences between the geriatric and non-geriatric populations in terms of drug efficacy, drug safety, pharmacokinetics, pharmacodynamics and drug-drug interactions can be very large. Not only do changes in age-related physiology alter the safety and efficacy profile of the drug in the elderly population, but the use of concomitant medication for the treatment of other indications is common in geriatric patients and may affect the body’s response to the drug. Frequently, these differences in response to a drug cannot always be predicted from studies in non-geriatric patients. Therefore, as the number of elderly patients rises, it is increasingly important to include patients over the age of 65 in clinical trials for conditions that are known to also affect this age group.
While the current ICH E7 guideline suggests including a minimum of 100 geriatric patients in clinical trials to study drugs for diseases that are not unique to geriatric populations, the Questions and Answers document specifies that studies should "include more than 100 geriatric patients in the Phase 2 and 3 databases". These patients should cover the entire geriatric spectrum, with no upper cap on age. Preferably, geriatric patients should be included in the same study as non-geriatric patients.
It is also important not to exclude geriatric patients with co-morbidities and concomitant therapies from the trial, as care in randomisation should allow any findings to be attributed to either the investigational drug or to other factors. Recruitment of such patients can be challenging and in some cases it can be appropriate to collect data after marketing. The need for, and adequacy of, data in these patients should be discussed in the marketing authorisation application (MAA). If there has been insufficient enrolment of geriatric patients, specific plans to collect data post-marketing should also be discussed and presented in the MAA.
Specific age-related adverse events and efficacy endpoints should be actively monitored in geriatric patients during the trial, such as effects on cognitive function, balance and falls, urinary incontinence or retention, weight loss and sarcopenia. Disease-specific guidelines should also be referred to for more advice on the evaluation of safety and efficacy in geriatric patients.
Data on geriatrics should be presented in the MAA for different age groups (e.g. <65, 65-74, 75-84 and >85) within the geriatric population, so that the consistency of the drug product efficacy and safety can be compared to the non-geriatric population. If a single trial has not recruited enough geriatric patients to do this, the data from multiple trials can be pooled. Obviously, any further analysis must consider consistency across the studies.
The pharmacokinetic data should also be evaluated to identify age-related differences that are independent of differences in weight and/or renal and hepatic function. Population pharmacokinetics may be used to obtain this information if adequate numbers of over 65 (or over 75) are included in the trials during the entire clinical development of the medicinal product. Alternatively, a direct comparison of PK data in the geriatric patients versus the younger patients may be undertaken within one of the studies. The Q & A document recommends seeking advice from the regulators with regard to the specifics of the trial design to assess the pharmacokinetics and drug-drug interactions in geriatrics.
The new Questions and Answers document lays out strong grounds for inclusion of significant numbers of geriatric patients in clinical studies and provides advice on the number of patients to recruit, the parameters to be assessed and suitability of trial design in order to allow a meaningful analysis of the data collected. This guidance should always be read in conjunction with the ICH E7 guideline and will be implemented as of July 2010.
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EMA/CPMP/ICH/379/95 ICH Topic E7 Studies in Support of Special Populations: Geriatrics
EMA/CHMP/ICH/604661/2009 Studies in Support of Special Populations: Geriatrics - Questions and Answers
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