nidhi.saxena@xcelloninstitute.com Clinical Trials in Geriatrics Nidhi Saxena Xcellon Institute nidhi.saxena@xcelloninstitute.com Introduction  Those aged 65 years or above  Increase in prevalence of large number of physical and health related problems with age  Increased use of prescription and non-prescription drug  Long duration of treatment and poly-pharmacy is common in elderly  Altered physiological function altering the response of drugs.  Drug used to treat condition where increased age is a risk factor, older people should be oversampled in studies designed to test there efficacy nidhi.saxena@xcelloninstitute.com Fact  Elderly population are under-represented in trials of treatments for conditions that predominantly affect older people.  Limited data available for geriatrics from studies, resulting in a late recognition of serious side effects  eg. benoxaprofen (Opren) was withdrawn from the market after the report of death of 5 elderly patients.  According to the Guidelines-  Trials of the efficacy of interventions need to cover the age groups who are affected nidhi.saxena@xcelloninstitute.com Polypharmacy  Multiple drug prescription is common in elderly.  Reasons:  Prevalence of many diseases is age related and several may co-exist in the same patient  Adequate response from single drug is not possible  Increased utilization of fixed dose drug combination for the optimum management of a number of conditions.  To counteract or minimize the risk of side effects.  Patient are also being targeted by pharmaceutical companies (direct-to- consumer advertising) nidhi.saxena@xcelloninstitute.com Interactions in relation to multiple drug prescribing  ADRs are common in the elderly  Multiple drug prescription  Drug to drug interactions  Inappropriate drug combination  Drug interactions represent a change in either the magnitude or the duration of action  This may enhance or reduce the efficacy of one or both of the drugs or a new effect may appear  Interaction may be pharmaco-kinetic or pharmaco- dynamic nidhi.saxena@xcelloninstitute.com Altered Pharmaco-kinetics in the Elderly  Elderly patients may also develop drug-related problems even when their medication is confined to a single agent or non-interacting multiple agents  Altered pharmaco-kinetic and pharmaco-dynamic  Absorption  GIT  Reduced acid secretion in stomach  Decreased gastric emptying  Diminished splanchnic blood flow  Decreased gastrointestinal mobility  Altered hepatic function resulting in change in bioavailability. nidhi.saxena@xcelloninstitute.com Altered pharmaco-kinetics in the Elderly  Distribution:  Body composition:  decrease in lean body mass and body water  increase in adipose tissues  Protein binding:  Decrease serum albumin level  Decrease binding capacity of weakly acidic drugs  eg. salicylates, phenytoin  Increase serum acid glycoprotein  Basic drug such as lidocaine displays increased protein binding. nidhi.saxena@xcelloninstitute.com Altered pharmaco-kinetics in the Elderly  Metabolism:  Reduced phase I oxidative drug metabolism  Phase 2 reaction is altered only in the individual who have suffered injury or have undergone surgery  Enzyme activity is depressed  Reduced hepatic blood flow  eg. propranolol, clomethiazole nidhi.saxena@xcelloninstitute.com Altered pharmaco-kinetics in the Elderly  Renal Excretion:  Diminished renal functional capacity and renal reserve  Structural changes include:  Decrease renal weight  Thickening of the intra-renal vascular intima  Reduction in the number of glomeruli with increased sclerosis within those remaining and infitration by chronic inflammatory cell and fibrosis in the stroma  Altered renal tubular function  Impaired handling of water, sodium and glucose  Decreased creatinine production nidhi.saxena@xcelloninstitute.com Altered pharmaco-dynamics in the Elderly  Altered sensitivity to the medication  eg. increased responsiveness to warfarin  Increased sensitivity to benzodiazepines  Altered homeostatic mechanism due to impaired baro-receptor function  reduction in number of -adrenoceptor  Decline in the function of renin-angiotensin system, but ACE inhibitors will cause a greater reduction in BP nidhi.saxena@xcelloninstitute.com Regulation  ICH E7- Studies in support of special populations: Geriatrics  General Principle  Patients entering clinical trials should be reasonably representative of the population that will be later treated by the drug  Scope:this guidelines is directed towards:  New Molecular Entities that are likely to have significant use in the elderly  New formulation &new combinations of established medicinal products  when expectation of common conditions are likely to be encountered & are not dealt with in current labelling.  When they alter the geriatric patient’s response  New uses that have significant potential applicability in geriatrics. nidhi.saxena@xcelloninstitute.com Guidelines Cont..  Clinical Experience:  Geriatric patients should be included in the Phase 3 database (and in Phase 2,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.  For drugs used in diseases not unique to, but present in the elderly, a minimum of 100 patients would usually allow detection of clinically important differences.  For drugs to treat relatively uncommon diseases, smaller numbers of the elderly would be expected.  disease to be treated is characteristically associated with aging (e.g., Alzheimer's disease) geriatric patients should constitute the major portion of the clinical database. nidhi.saxena@xcelloninstitute.com Guidelines Cont….  Pharmacokinetic Studies:  important to determine whether or not the pharmacokinetic behavior of the drug in elderly subjects or patients is different from that in younger adults  to characterize the effects of influences, such as abnormal renal or hepatic function, that are more common in the elderly even though they can occur in any age group.  Formal PK Studies:  done either in healthy geriatric subjects or in patient volunteers with the disease to be treated by the drug.  initial PK study can be a pilot trial of limited size conducted under steadystate conditions to look for sizable differences between older and younger subjects or patients.  A larger, single-dose PK study of sufficient size to permit statistical comparisons between geriatric and younger subjects' or patients‘ pharmacokinetic profiles is also acceptable. nidhi.saxena@xcelloninstitute.com Guidelines Cont….  PK Screening Approach:  Sponsors may opt, instead of conducting a separate PK evaluation of the elderly, to utilize a pharmacokinetic Screen in conjunction with the main Phase 3  It is important:  to record time of dosing prior to blood concentration measurements, and relation of dosing to meals,  to examine the influence of demographic and disease factors, such as gender renal function, presence of liver disease, gastrointestinal disease or heart disease,  body size and composition, and concomitant illnesses.  Advantage:  it can assess the effects, not only of age itself, but also of other factors associated with age (altered body composition, other drugs, concomitant illness) and their interactions. nidhi.saxena@xcelloninstitute.com Eligibility  Explicit Exclusion:  Elderly people is explicitly excluded from cl. Trials  Age-based exclusion was more common  When the treatment under investigation was invasive  When the situation is not improving  Operating an upper age limit for trials has been used to limit the problem of co-morbid conditions and drug interactions common with elderly  Physiological and functional characteristics of the patient is importa t f r drug interaction. nidhi.saxena@xcelloninstitute.com Eligibility  Implicit:  Exclusion criteria other than age limit  Process of patient selection and recruitment mostly aims to produce a homogeneous study population  Tight eligibility criteria may aim to produce very similar participants  True homogeneous group of patient is difficult  When treatment trials are specifically designed for elderly people, exclusion criteria is overly stringent leading to participation of non- representative population. eg. Excluding patient with behavioral problem in Alzheimer's disease.  Narrow range also misses potential to identify subgroups of pt. Responding well to the test drug. nidhi.saxena@xcelloninstitute.com Eligibility  Advantage of wide eligibility criteria:  Easier screening and recruitment.  Large trials are more feasible and economical  Large study sizes reduce random error, providing more reliable overall result  Wider applicability or results.  Greater clinical and public health impact  Greater opportunity to test subgroup hypothesis nidhi.saxena@xcelloninstitute.com Informed Consent  Patient information necessary for informed consent  Diagnosis  Available treatments and treatment on trial  Potential risks and benefits of treatment  Concept of a clinical trial (including randomization, use of placebo, double-blind procedures  Discomforts of inconveniences associated with assessments  Number of follow-up visits or extra travel for trial. nidhi.saxena@xcelloninstitute.com Difficulties in taking Informed Consent  Vulnerable population  Need to have sufficient understanding to give consent without coercion.  Clinical trial design is complex  Patient may not understand it fully to give true informed consent  Increasing prevalence and incidence of dementia with advancing age  Level of confidence that can be placed on how the potential participant's interests are accurately represented by their caregiver in the role of proxy. nidhi.saxena@xcelloninstitute.com Follow Up  Factors influencing exit of the participant from the study before the final outcome assessment  Greater risk of developing co-morbid conditions  cognitive impairment,  need for other drug treatments  Advanced planning by allowing realistic rate of loss to follow up when calculating sample size  Flexible timing of follow-up visits may prevent the unnecessary loss of data  Use of community pharmacists in drug trials might assist treatment compliance  Medication discontinuation because of depressive symptoms, low self-rated health nidhi.saxena@xcelloninstitute.com Conclusion  Eligibility criteria should be wide  Use multiple recruitment strategies  Involves clinicians and service providers throughout.  Design the consent documentation and process carefully  Minimize trial burden on participants  Be realistic nidhi.saxena@xcelloninstitute.com Thank You