EMA Public Consultation on – ‘Points to consider on frailty: Evaluation instruments for baseline characterisation of clinical trialOlder-Person populations’

  • Start of public consultation: 21 December 2015
  • Deadline for comments: 31 May 2016
  • Provide comments using this TEMPLATE
  • Send comments to: geriatrics@ema.europa.eu

Summary

Older persons are large drugs consumers for a number of chronic diseases, but despite this they have often been excluded from clinical trials. The ICH E7 Question and Answers advocates that it is very important to ensure, to the extent possible, that the population included in the clinical development program is representative of the target patient population and that in the marketing application, depending on the numbers of patients, data should be presented for various age groups (for example <65, 65-74, 75-84 and > 85) to assess the consistency of the treatment effect and safety profile in these patients with the non-geriatric patient population. It is recognised, however, that chronological age alone is a suboptimal predictor of susceptibility to adverse outcomes.
Article 6 of the Clinical Trials Regulation ((EU) No 536/2014) requires a justification for the gender and age allocation of subjects and, if a specific gender or age group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and justification for these exclusion criteria.
Reasons for exclusion often have been poorly justifiable, and have included predefined arbitrary upper age limits, lists of different comorbidities or polypharmacy. Such frequent exclusion has generated a situation of “evidence biased”, as opposed to evidence based medicine for older adults. This selection bias is even more evident for the frail elderly, who account for a large proportion of older persons at risk. Important elements to be considered in the development of a new medicine for use in the older population include the recruitment of sufficient numbers of elderly in appropriate age ranges (particularly the very elderly) for Pharmacokinetics (PK) as well as PK/PD analyses, the use of an age- appropriate measure of renal function, and awareness of and openness to testing covariates reflecting biological rather than chronological age. The very elderly often exhibit enhanced PD sensitivity and thus exploration of the minimum effective dose is key to improving tolerability. Better characterisation of this growing segment of the population, following a standardized approach, might also help the evaluation of efficacy and safety of drugs in the post authorisation phase, and perhaps in defining enrolment criteria for future studies in the pre authorisation phase(1, 2).

To try to address this point, the EMA Geriatric Medicines Strategy included the following action:

  • The Agency should perform a search among available documentation and other scientific data to identify available and validated instruments/methods (e.g. scales) which can be used to examine effect and safety in “frail” patients.
  • In August 2011 the Committee for Medicinal Products for Human Use (CHMP) requested the GEG (Geriatric Expert Group) to perform such a search, and this Points to Consider document is the result of that work.

A standardized characterisation of frailty is potentially useful for risk stratification and to improve the description of the characteristics of older populations involved in clinical trials. If such frailty scales could be routinely introduced to characterise the baseline demographics of the population enrolled in a clinical trial for a drug with highly prevalent use in the older population, this would enhance the knowledge of the benefit/risk balance of the product in the target population.

These Points to Consider are intended to provide guidance only for the evaluation of the baseline frailty status of patients (typically, but not exclusively aged > 65 yrs.) enrolled in a clinical trial or other clinical investigation (e.g. registry), and to supplement the requirements of ICH E7 Questions and Answers.
The following aspects of frailty are considered; physical frailty, cognitive dysfunction, malnutrition and multi-morbidity, with scales recommended categorising patients in these domains on the basis of their frailty status. Different scales focusing on specific aspects may be selected for a clinical development program to investigate the frailty status, according to the therapeutic area and the Pharmacodynamic (PD) profile of the medicinal product under investigation. However, the Short Physical Performance Battery (SPPB) is identified as the scale providing the overall best predictive value for the baseline characterization of the (physical) frailty of older people enrolled in a clinical trial. This document provides an overview of validated and therefore recommended instruments for characterisation of patient profiles for frailty and related states including cognitive impairment, malnutrition and multimorbidity. Those most relevant instruments can be selected to best match the product in development and the patient population to be studied. The development and validation of alternative / additional scales to better characterise specific populations is encouraged.

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