Postmarket Surveillance -Adverse Event Reporting in the Office of Generic Drugs

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1 Postmarket Surveillance -Adverse Event Reporting in the Office of Generic Drugs Integration Communication Collaboration John R Peters, MD Director, Division of Clinical Review Office of Generic Drugs 1

2 Disclaimer The opinions and information in this presentation are those of this presenter, and do not represent the views and/or policies of the U.S. Food and Drug Administration. 2

3 Drug Price Competition and Patent Restoration Act (Hatch-Waxman) There were 3 basic mandates to generic drug approval provided by this act: 1. generic approvals must be based on scientific considerations and minimize duplicative testing 2. all generic and brand name drugs must meet the same quality criteria for manufacturing 3. generic versions of drugs must be equivalent to a degree, calculated statistically, which ensures that therapeutically equivalent drugs have the same clinical effect and no greater chance of adverse effect Generic Drugs are now approximately 84% of the prescription drugs administered to patients. 3

4 Generic Drugs in Clinical Use Therapeutic Equivalence = Substitutability This decision is based on the Pharmaceutical Equivalence (same API, same dose form and route of administration) and Bioequivalence in the context of Clinical Use (delivery to the same site of action for the same indication). Only when both factors are equivalent can the product be acceptable as a generic equivalent. 4

5 Definition A clinical endpoint bioequivalence study is: a clinical study utilizing a patient population o two products containing same active moiety (chemically equivalent) same dosage form (pharmaceutically equivalent) o drug administration delivers the active moiety to the site of action clinical effect is evaluated o a predetermined clinical endpoint evaluates comparative clinical effect o statistical analysis determines therapeutic equivalence o an inference regarding bioequivalence of the two products is made The general design of these studies is a blinded, randomized, balanced, parallel study. A placebo arm is usually included in these studies in order to demonstrate that the study is sufficiently sensitive to identify a clinical effect. 5

6 Negative Definition A clinical endpoint bioequivalence trial is not: a study of safety or efficacy a non-inferiority trial It is a quantitative comparison of a clinical (therapeutic) effect. Comparison of therapeutic effect (not efficacy) allows for the inference that the test and reference products are bioequivalent 6

7 Brief Background The Randomized Controlled Clinical Trial has matured over centuries to be the Gold Standard for demonstration of safety and efficacy of pharmaceutical products. The Clinical Endpoint BE Study is not the same thing! only evolving in earnest since the late 1970s dependent on a clinical biomarker biomarker serves as a surrogate for the therapeutic effect not as reliable, reproducible, nor unbiased as the PK BE study statistically it is analyzed as 2 one-sided tests (unlike the simplified one-sided approach in non-inferiority trials) 7

8 Randomized Controlled Trial vs Clinical Endpoint BE Study For an NDA drug Safety and Efficacy must be established. This requires a randomized clinical trial. For an ANDA drug Bioequivalence must be demonstrated. There are 4 options to do this: in vivo pharmacokinetic study in vivo pharmacodynamic study in vivo clinical endpoint bioequivalence study in vitro methodology The Clinical Endpoint BE study is the poorest of the 3 in vivo options for establishing BE. 8

9 FDA, CDER Office of Generic Drugs NDA vs ANDA: Regulatory Requirements NDA: Adequate and well-controlled studies to demonstrate safety and efficacy ANDA: Same active drug substance in same amount as in the RLD Acceptable inactive ingredients Bioequivalent to RLD Same label as RLD No pre-review of data Formulation differences must not impact therapeutic safety or efficacy. 9

10 FDA, CDER Office of Generic Drugs Biomarker as Surrogate? For a biomarker to serve as a surrogate for the effect of an intervention on a clinical endpoint at the population level, more is required than just the ability of the marker measured on an individual to predict that individual s clinical endpoint. The extent to which a biomarker is appropriate for use as a surrogate endpoint in evaluating a new treatment depends on the degree to which the biomarker can reliably predict the clinical benefit of that therapy, as compared to a standard therapy. ----De Gruttola, VG. et al., Considerations in the Evaluation of Surrogate Endpoints in Clinical Trials: Summary of a National Institutes of Health Workshop, Controlled Clinical Trials, 2001, 22:

11 How good is the clinical endpoint? What is needed: Knowledge of biological mechanism of the disease process Knowledge of the mechanism of action of the therapeutic agent Genomic evaluation of clinical endpoints Statistical model of surrogacy tested over multiple studies Classical and Bayesian statistical methods may be appropriate Requires continual testing for validity Requires continual updating of surrogates The selected endpoint must be quantifiable in order to statistically evaluate for bioequivalence. 11

12 Limitations of Clinical Endpoint Bioequivalence Study Biological systems are intrinsically variable Unknown intersubject variability within reference population Diseases are variable Validated biomarkers are limited Rating scales are subject to considerable bias Clinical endpoints may not accurately reflect therapeutic equivalence Time of measurement (end of trial) may not accurately reflect equivalence Clinical studies are very expensive People do stupid things and invalidate measurements 12

13 Clinical Considerations for Clinical Endpoint BE Studies The OGD Clinical Reviewer must research: Pathophysiology of the disease Site of action of API Presumed mechanism of action Nature of excipients Critical clinical endpoints Surrogate endpoints and/or biomarkers How clinical endpoints are identified Pivotal studies for RLD approval Post-market safety issues Issues discussed during approval process 13

14 Safety Considerations for Clinical Endpoint BE Studies The Clinical Reviewer must research the safety profile: PK relationship to the therapeutic/toxic effects PD relationship to the therapeutic/toxic effects Highest safe dose in healthy volunteers Elimination half-life Drug-Drug interactions 14

15 How do we decide? Recommendations based on the studies from the RLD updated to the most recent recommendations Markers and endpoints modified for T/R comparison Communicate with OND to remain current on validated markers and endpoints Use placebo groups where clinically ethical and feasible Publish detailed, updated Guidance Documents Review of clinical literature Review of current standard of care recommendations 15

16 Critical Basics Biomarker Excipients Quantifiability Patient Considerations Test of Cure 16

17 When to do a Clinical Endpoint BE Study drug products that have negligible systemic uptake there is no identified pharmacodynamic measure the site of action is local Local action is defined broadly as action at the surface to which the drug is applied rather than to which it is delivered in some body fluid (blood, bile, lymphatic fluid). These surfaces may include skin, mucosal surfaces of the eye, nose, lung, gut, bladder, rectum and vagina. The indication for the drug and pathophysiology of the disease guide us to the known or proposed site of local action. The chosen clinical endpoint or surrogate provides us with the measure of clinical effect. 17

18 Core of the Clinical Endpoint BE Study Dose Target Population Target Indication Biomarker Statistical Analysis Time of Assessment 18

19 Considerations in Planning a Clinical Study of Bioequivalence Knowledge about the pathophysiology of the disease to be studied: proposed disease mechanism criteria for diagnosis stages of the disease recommended therapies at different stages known indicators for therapeutic responders known indicators for increased risk profile Monitoring strategies in the clinician s office Are there validated disease scores? Is there an easily measureable surrogate marker? Can that marker be adequately quantified for comparison? If it is not possible to include a placebo arm in the study: o what is known of the background rate of placebo response? o Is there a rate of spontaneous resolution? What is the current Standard of Care for this disease, and will your study provide acceptable care as required in clinical ethics? 19

20 Considerations in Planning a Clinical Study of Bioequivalence What is known about the reference drug? site of action known mechanism of action or proposed mechanism of action Is the active component the parent drug or a metabolite(s) or both? Are there specific metabolites that are important to the safety profile? For a locally acting drug will it be necessary to demonstrate comparability of local irritation or sensitization resulting from the drug product? If the product is a transdermal patch, are overlays used and will adhesion studies be required? 20

21 Considerations in Planning a Clinical Study of Bioequivalence What is known about your proposed formulation? is it qualitatively and quantitatively the same as the reference product? are there important physicochemical characteristics (e.g. particle size, particle distribution, melting point, viscosity)? other efficacy considerations about the formulation (such as ph for locally acting gastrointestinal (GI) products)? other safety considerations (such as different excipients or novel excipients)? What is known about the toxicology of all excipients in the clinical context of expected use? 21

22 Considerations in Planning a Clinical Study of Bioequivalence What is known of the proposed clinical endpoint? Is the proposed endpoint valid for all drugs treating the disease of interest? Is the proposed endpoint valid regardless of the specific mechanism of action for any drug treating this same condition? Is the proposed endpoint equally valid during asymptomatic phases of a chronic disease, particularly if the disease has relapsing and remitting phases? If the gold-standard clinical assessment surrogate endpoint cannot be quantified, is the proposed alternate clinical endpoint at least as good as the standard followed in clinical practice? Are there genomic considerations for choice of endpoint or patient inclusion criteria? 22

23 Considerations in Planning a Clinical Study of Bioequivalence For drugs with multiple indications, which indication will be most sensitive to potential differences in therapeutic effect between the test and reference products? Is there an indication that can be more accurately diagnosed? Is there an indication that has well defined stages and clear characteristics with improvement or cure? Is there a more obvious marker for therapeutic effect in one of the indications? Are there more specific or validated scoring systems for improvement or cure in one of the indications? 23

24 Summary Pathophysiology Toxicology Pharmacology Medical Ethics Regulatory Requirements 24

25 Questions? 25

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