1. DSaRM Advisory Committee May 19, 2005 Postmarketing Studies: OND Perspective Julie Beitz MD, Deputy Director, Office of Drug Evaluation III, Office of New Drugs Julie Beitz MD, Deputy Director, Office of Drug Evaluation III, Office of New Drugs

2. DSaRM Advisory Committee May 19, 2005 2 Product Risk Assessment Occurs throughout a product’s life cycle When embarking on the development plan for a new product, sponsors and regulators need to consider: –What safety information should be generated pre-approval; in particular, what specific safety risks should be explored pre-approval? –What safety information may be reasonably delayed to postmarketing studies? Occurs throughout a product’s life cycle When embarking on the development plan for a new product, sponsors and regulators need to consider: –What safety information should be generated pre-approval; in particular, what specific safety risks should be explored pre-approval? –What safety information may be reasonably delayed to postmarketing studies?

3. DSaRM Advisory Committee May 19, 2005 3 Size of the NDA or BLA Safety Database* It is not possible to identify all safety concerns pre-approval After approval, new safety concerns may become apparent –Large numbers of patients exposed chronically, including those with co-morbid illness or prescribed concomitant medications Size of safety database depends upon*: –Product use: chronic or acute? –Intended population: healthy subjects on a large scale, or the seriously ill? –Are alternative therapies available? *Guidance for Industry: Premarketing Risk Assessment, March 2005 It is not possible to identify all safety concerns pre-approval After approval, new safety concerns may become apparent –Large numbers of patients exposed chronically, including those with co-morbid illness or prescribed concomitant medications Size of safety database depends upon*: –Product use: chronic or acute? –Intended population: healthy subjects on a large scale, or the seriously ill? –Are alternative therapies available? *Guidance for Industry: Premarketing Risk Assessment, March 2005

4. DSaRM Advisory Committee May 19, 2005 4 Size of the NDA or BLA Safety Database* For acute or short-term use or use in life-threatening illness –Number of exposed subjects should be individualized For chronic, long-term use in non-life-threatening illness –1500 subjects (300-600 for 6 mos and 100 for 1 yr) exposed in multiple dose studies to relevant doses –>1500 exposed subjects if: Concern about late developing adverse events Need to quantify the rate of a specific low frequency adverse event Benefits are small The product may add to existing morbidity in the treated population *Guidance for Industry: Premarketing Risk Assessment, March 2005; ICH E1A, March 1995 For acute or short-term use or use in life-threatening illness –Number of exposed subjects should be individualized For chronic, long-term use in non-life-threatening illness –1500 subjects (300-600 for 6 mos and 100 for 1 yr) exposed in multiple dose studies to relevant doses –>1500 exposed subjects if: Concern about late developing adverse events Need to quantify the rate of a specific low frequency adverse event Benefits are small The product may add to existing morbidity in the treated population *Guidance for Industry: Premarketing Risk Assessment, March 2005; ICH E1A, March 1995

5. DSaRM Advisory Committee May 19, 2005 5 The Fundamental Challenge Given the limitations of the premarket safety assessment, rigorous postmarketing safety assessment is critical for characterizing a product’s risk profile and for making informed decisions about risk minimization

6. DSaRM Advisory Committee May 19, 2005 6 Presentation Outline How are postmarketing studies regulated? What can we learn from different types of studies? What are some important considerations in designing or reviewing them? What are some dilemmas in interpreting them? What challenges do regulators face? How are postmarketing studies regulated? What can we learn from different types of studies? What are some important considerations in designing or reviewing them? What are some dilemmas in interpreting them? What challenges do regulators face?

7. DSaRM Advisory Committee May 19, 2005 7 Postmarketing Studies - Definition “…delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.” (312.85)

8. DSaRM Advisory Committee May 19, 2005 8 Required Postmarketing Studies Accelerated Approval (1992) –Confirm clinical benefit for products approved based on surrogate endpoints; safety data are also collected Animal Efficacy Rule (2002) –Confirm clinical benefit and assess safety for products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances Pediatric Research Equity Rule (2003) –Assess safety and efficacy and support dosing for pediatric patients Accelerated Approval (1992) –Confirm clinical benefit for products approved based on surrogate endpoints; safety data are also collected Animal Efficacy Rule (2002) –Confirm clinical benefit and assess safety for products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances Pediatric Research Equity Rule (2003) –Assess safety and efficacy and support dosing for pediatric patients

9. DSaRM Advisory Committee May 19, 2005 9 Other Postmarketing Studies Requested by FDA –Sponsor voluntarily commits to conducting study(ies) after approval –A schedule for study completion is agreed upon before approval of the application –FDA tracks status of studies, posts updates on its website, and reports summary statistics annually in FR Requested by other regulatory authorities Conducted at the initiative of the sponsor, NIH or other investigators –With or without input from FDA Requested by FDA –Sponsor voluntarily commits to conducting study(ies) after approval –A schedule for study completion is agreed upon before approval of the application –FDA tracks status of studies, posts updates on its website, and reports summary statistics annually in FR Requested by other regulatory authorities Conducted at the initiative of the sponsor, NIH or other investigators –With or without input from FDA

10. DSaRM Advisory Committee May 19, 2005 10 Categories of Serious Adverse Events* Events that are readily attributable to treatment –Hematologic, hepatic, renal, dermatologic or pro-arrhythmic Events that are not readily attributable to treatment –Myocardial infarction or stroke in the elderly –Immune defects in AIDS or cancer –Sudden death in schizophrenia –Large controlled studies are often needed *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005 Events that are readily attributable to treatment –Hematologic, hepatic, renal, dermatologic or pro-arrhythmic Events that are not readily attributable to treatment –Myocardial infarction or stroke in the elderly –Immune defects in AIDS or cancer –Sudden death in schizophrenia –Large controlled studies are often needed *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005

11. DSaRM Advisory Committee May 19, 2005 11 Investigating Safety Signals* Safety signal: a concern about an apparent excess of adverse events compared to what would be expected After a safety signal is identified, a careful case level review should be conducted If the signal represents a potential safety risk: –Develop a synthesis of all available safety information –Assess the benefit-risk balance of the product for users as a whole and for at-risk populations –Consider how best to investigate the signal further through additional studies *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005 Safety signal: a concern about an apparent excess of adverse events compared to what would be expected After a safety signal is identified, a careful case level review should be conducted If the signal represents a potential safety risk: –Develop a synthesis of all available safety information –Assess the benefit-risk balance of the product for users as a whole and for at-risk populations –Consider how best to investigate the signal further through additional studies *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005

12. DSaRM Advisory Committee May 19, 2005 12 General Advice to Sponsors* Consider all available methods to evaluate a particular safety signal Choose the method best suited to the particular signal and research question Communicate with FDA as plans progress *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005 Consider all available methods to evaluate a particular safety signal Choose the method best suited to the particular signal and research question Communicate with FDA as plans progress *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005

13. DSaRM Advisory Committee May 19, 2005 13 Types of Studies Preclinical toxicological studies Clinical studies –Pharmacokinetic studies –Pharmacoepidemiologic studies –Controlled clinical studies Long-term controlled safety studies Each can provide unique information –Mechanistic considerations –Magnitude, severity, and change in risk over time –Factors that can enhance or diminish the risk Preclinical toxicological studies Clinical studies –Pharmacokinetic studies –Pharmacoepidemiologic studies –Controlled clinical studies Long-term controlled safety studies Each can provide unique information –Mechanistic considerations –Magnitude, severity, and change in risk over time –Factors that can enhance or diminish the risk

14. DSaRM Advisory Committee May 19, 2005 14 Preclinical Toxicological Studies Purpose –Predict potentially serious toxicity that might occur in humans –Assess suspected or documented toxicities observed in humans during development or after approval Dilemmas –Not all adverse events in humans are predicted by animal studies –Not all adverse events in humans are confirmed after the fact in animals Purpose –Predict potentially serious toxicity that might occur in humans –Assess suspected or documented toxicities observed in humans during development or after approval Dilemmas –Not all adverse events in humans are predicted by animal studies –Not all adverse events in humans are confirmed after the fact in animals

15. DSaRM Advisory Committee May 19, 2005 15 Reasons for False Positive/Negative Animal Studies Very large doses are used May saturate pharmacological mechanisms Lead to irrelevant toxicities Subjective adverse events are not detectable in animals Immunologic effects are difficult to detect in animals Rare events in humans will rarely be observed in animals as few animals are evaluated Very large doses are used May saturate pharmacological mechanisms Lead to irrelevant toxicities Subjective adverse events are not detectable in animals Immunologic effects are difficult to detect in animals Rare events in humans will rarely be observed in animals as few animals are evaluated

16. DSaRM Advisory Committee May 19, 2005 16 Pharmacokinetic Studies Purpose –Select optimal dosage strength, form, and regimen –Assess factors that can enhance or diminish absorption, distribution, metabolism and excretion –Monitor the course of patients experiencing adverse events –Determine bioequivalence of new formulations Dilemmas –Timing of studies and populations studied are often debated –It is not possible to assess all factors that may affect blood or tissue levels –Not all factors that affect pK parameters can be quantified Purpose –Select optimal dosage strength, form, and regimen –Assess factors that can enhance or diminish absorption, distribution, metabolism and excretion –Monitor the course of patients experiencing adverse events –Determine bioequivalence of new formulations Dilemmas –Timing of studies and populations studied are often debated –It is not possible to assess all factors that may affect blood or tissue levels –Not all factors that affect pK parameters can be quantified

17. DSaRM Advisory Committee May 19, 2005 17 Pharmacokinetic Studies: Study Design Considerations Was a baseline for study subjects established? Sufficiently long crossover period to prevent carryover effects? Were study subjects compliant with diet? Good analytical method to measure product concentrations? Appropriate number of samples and optimal timing of collection? Degree of protein binding in various clinical situations? Differences in activity or receptor binding of optical isomers and metabolites? Dosage strengths/forms studied similar to those to be marketed? Was a baseline for study subjects established? Sufficiently long crossover period to prevent carryover effects? Were study subjects compliant with diet? Good analytical method to measure product concentrations? Appropriate number of samples and optimal timing of collection? Degree of protein binding in various clinical situations? Differences in activity or receptor binding of optical isomers and metabolites? Dosage strengths/forms studied similar to those to be marketed?

18. DSaRM Advisory Committee May 19, 2005 18 Pharmacokinetic Studies: Interpretation Issues For each study, have the appropriate assumptions been made? –Pharmacokinetic models used –Rate limiting steps –Presence or absence of metabolites When considering several studies, are appropriate studies being compared? –Populations studied –Study conditions (fasted vs. fed) –Formulations studied –Assay methods used For each study, have the appropriate assumptions been made? –Pharmacokinetic models used –Rate limiting steps –Presence or absence of metabolites When considering several studies, are appropriate studies being compared? –Populations studied –Study conditions (fasted vs. fed) –Formulations studied –Assay methods used

19. DSaRM Advisory Committee May 19, 2005 19 Pharmacoepidemiologic Studies* Purpose –May be the only practical choice to characterize uncommon or delayed adverse events –Identify important co-morbidities or co-therapies as risk factors –Examine the natural history of a disease –Explore drug use patterns Dilemmas –What is the optimal design and size? –How many studies are needed? –How best to minimize bias and account for confounding? *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005 Purpose –May be the only practical choice to characterize uncommon or delayed adverse events –Identify important co-morbidities or co-therapies as risk factors –Examine the natural history of a disease –Explore drug use patterns Dilemmas –What is the optimal design and size? –How many studies are needed? –How best to minimize bias and account for confounding? *Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005

20. DSaRM Advisory Committee May 19, 2005 20 Controlled Clinical Studies Purpose –Phase 2: Assess effectiveness and “determine the common short- term side effects and risks associated with the drug.” [312.21(b)] –Phase 3: Assess safety and effectiveness needed to “evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labelling.” [312.21(c)] –Postmarketing: Assess safety and effectiveness: In populations not previously studied (new uses) New dosing regimens Longer treatment durations Purpose –Phase 2: Assess effectiveness and “determine the common short- term side effects and risks associated with the drug.” [312.21(b)] –Phase 3: Assess safety and effectiveness needed to “evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labelling.” [312.21(c)] –Postmarketing: Assess safety and effectiveness: In populations not previously studied (new uses) New dosing regimens Longer treatment durations

21. DSaRM Advisory Committee May 19, 2005 21 Controlled Clinical Studies Dilemmas –A large number of patients - representing appropriate demographic subsets and risk groups - needs to be enrolled to observe a relatively uncommon adverse event –If inclusion criteria are set too narrowly, study findings may not be relevant to general clinical settings –Studies in phases 2/3 typically do not test specified hypotheses about safety Dilemmas –A large number of patients - representing appropriate demographic subsets and risk groups - needs to be enrolled to observe a relatively uncommon adverse event –If inclusion criteria are set too narrowly, study findings may not be relevant to general clinical settings –Studies in phases 2/3 typically do not test specified hypotheses about safety

22. DSaRM Advisory Committee May 19, 2005 22 NDA/BLA Materials for Clinical Review Integrated Summary/Analysis of Safety Adverse event tables Case report forms for dropouts or patients who experienced serious adverse events Individual patient adverse event data and laboratory listings Narrative summaries of deaths, serious adverse events, and events leading to dropout Other documents –Reports of specific safety studies –Coding dictionaries –Source documents for auditing purposes Integrated Summary/Analysis of Safety Adverse event tables Case report forms for dropouts or patients who experienced serious adverse events Individual patient adverse event data and laboratory listings Narrative summaries of deaths, serious adverse events, and events leading to dropout Other documents –Reports of specific safety studies –Coding dictionaries –Source documents for auditing purposes

23. DSaRM Advisory Committee May 19, 2005 23 Controlled Clinical Studies: Adverse Events* Assess drug-relatedness –For common events, compare rates for product vs. placebo –For rare events, the expected rate = 0, so even a few cases could represent a safety signal For events that seem drug-related, explore: –Dose-dependency –Time to onset, severity of events –Time course of events –Demographic interactions –Drug-drug, drug-disease interactions *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005 Assess drug-relatedness –For common events, compare rates for product vs. placebo –For rare events, the expected rate = 0, so even a few cases could represent a safety signal For events that seem drug-related, explore: –Dose-dependency –Time to onset, severity of events –Time course of events –Demographic interactions –Drug-drug, drug-disease interactions *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005

24. DSaRM Advisory Committee May 19, 2005 24 Controlled Clinical Studies: Adverse Event Reporting Over-reporting –Study design: excessive dosing, frequent assessments, study duration long enough to introduce other factors –Overzealous investigators or patients’ awareness heightened –Improper coding Under-reporting –Study design: infrequent or poorly timed assessments, inappropriate parameters monitored, follow-up too short –Investigators attribute event to underlying disease –Event not recognized by investigators or patients –Improper coding Over-reporting –Study design: excessive dosing, frequent assessments, study duration long enough to introduce other factors –Overzealous investigators or patients’ awareness heightened –Improper coding Under-reporting –Study design: infrequent or poorly timed assessments, inappropriate parameters monitored, follow-up too short –Investigators attribute event to underlying disease –Event not recognized by investigators or patients –Improper coding

25. DSaRM Advisory Committee May 19, 2005 25 Controlled Clinical Studies: Laboratory Abnormalities* Analysis of central tendency Outliers Dropouts or dose reductions for laboratory abnormalities Dose-dependency, time to onset, time course Potential for severe hepatotoxicity Potential for QT/QTc prolongation –Thorough QT/QTc study** *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005 **ICH E14 Draft, June 2004 Analysis of central tendency Outliers Dropouts or dose reductions for laboratory abnormalities Dose-dependency, time to onset, time course Potential for severe hepatotoxicity Potential for QT/QTc prolongation –Thorough QT/QTc study** *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005 **ICH E14 Draft, June 2004

26. DSaRM Advisory Committee May 19, 2005 26 Controlled Clinical Studies: Special Populations Neonates and young pediatric patients –Were doses adequately adjusted for weight? –Was the stage of development of physiologic functions, metabolic pathways considered? –Were potential adverse effects on growth, neurocognitive development considered? –Was the frequency of testing, imaging, or blood sampling adequate? Geriatrics –Were renal function, muscle mass considered? –Was the impact of altered homeostatic mechanisms considered? Neonates and young pediatric patients –Were doses adequately adjusted for weight? –Was the stage of development of physiologic functions, metabolic pathways considered? –Were potential adverse effects on growth, neurocognitive development considered? –Was the frequency of testing, imaging, or blood sampling adequate? Geriatrics –Were renal function, muscle mass considered? –Was the impact of altered homeostatic mechanisms considered?

27. DSaRM Advisory Committee May 19, 2005 27 Long-Term Controlled Safety Studies* Purpose –Assess/compare rates of adverse event rates across groups Helpful when event is more common with cumulative exposure –Facilitate attribution of adverse events to the product Helpful when the event occurs relatively commonly in the treated population, or could be part of the disease being treated Dilemmas –Timing of studies relative to product approval –Sample size, study duration and “simple” safety endpoints *Guidance for Industry: Premarketing Risk Assessment, March 2005 Purpose –Assess/compare rates of adverse event rates across groups Helpful when event is more common with cumulative exposure –Facilitate attribution of adverse events to the product Helpful when the event occurs relatively commonly in the treated population, or could be part of the disease being treated Dilemmas –Timing of studies relative to product approval –Sample size, study duration and “simple” safety endpoints *Guidance for Industry: Premarketing Risk Assessment, March 2005

28. DSaRM Advisory Committee May 19, 2005 28 Controlled Clinical Studies: Pooling Safety Data* Pooling safety data from different studies can improve the precision of an incidence estimate –Good for low frequency events –Permits exploration of effects within subgroups –Can obscure important differences between studies Most appropriate to pool data from studies with similar designs Still important to explore the range of incidences across the studies being pooled *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005 Pooling safety data from different studies can improve the precision of an incidence estimate –Good for low frequency events –Permits exploration of effects within subgroups –Can obscure important differences between studies Most appropriate to pool data from studies with similar designs Still important to explore the range of incidences across the studies being pooled *Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005

29. DSaRM Advisory Committee May 19, 2005 29 Summary of Challenges It is not possible to identify all safety concerns prior to product approval Studies of approved or new uses may generate safety information that: –Needs to be placed in context with what is already known –May impact the benefit-risk balance for labeled indications –May need to be applied to: Other members of a product class Other dosage forms It is not possible to identify all safety concerns prior to product approval Studies of approved or new uses may generate safety information that: –Needs to be placed in context with what is already known –May impact the benefit-risk balance for labeled indications –May need to be applied to: Other members of a product class Other dosage forms