1. Risk Assessment Public Meeting - 4/9/03 1 Premarketing Risk Assessment Special Conditions Robert J. Temple, M.D. Associate Director for Medical Policy Center for Drug Evaluation and Research Food and Drug Administration

2. Risk Assessment Public Meeting - 4/9/03 2Background You’ve already heard a discussion of some of the most important general issues in pre-marketing assessment, including The size of the safety data base and characteristics of the drug and its effects, its proposed use, and the intended population that could affect the sizeThe size of the safety data base and characteristics of the drug and its effects, its proposed use, and the intended population that could affect the size Characteristics of an ideal safety data base, including adequate duration, a diverse population, and better dose-response information than we typically see. The last is particularly important for drugs with a high rate of drug-induced adverse effects or “biomarkers” of injury (CPK, TA, UA, K changes)Characteristics of an ideal safety data base, including adequate duration, a diverse population, and better dose-response information than we typically see. The last is particularly important for drugs with a high rate of drug-induced adverse effects or “biomarkers” of injury (CPK, TA, UA, K changes)

3. Risk Assessment Public Meeting - 4/9/03 3 Background (cont.) A good search for “individualization” factors, such as drug-drug interactions, drug- demographic relationships, and drug-disease relationships, including routine population PKA good search for “individualization” factors, such as drug-drug interactions, drug- demographic relationships, and drug-disease relationships, including routine population PK Comparative data when it would be particularly importantComparative data when it would be particularly important

4. Risk Assessment Public Meeting - 4/9/03 4 Special Considerations Evaluation of safety has some general principles, but as the paper indicates, that doesn’t mean one size fits all. In planning and monitoring development there needs to be constant attention to results of animal and human data, to suggestions of problems, and to population and drug-specific features that raise special concerns. When these occur, plans need to be modified. The concept paper identifies some of these

5. Risk Assessment Public Meeting - 4/9/03 5 Special Considerations 1.Is maintenance dose the same as the acute dose? A.Pharmacokinetic: Sometimes, long half-life drugs are started at high doses to get a prompt effect. Should the maintenance dose be lowered? –Astemizole. The 10 mg dose was close to the dose causing TdP (factor of <2). Maintenance could have been 3 mg (factor of about 6-7) –Fluoxetine. Drug and metabolites have half lives well over a week. Seems likely maintenance dose could be lower

6. Risk Assessment Public Meeting - 4/9/03 6 Special Considerations 1.Maintenance dose b.PD. Perhaps the drug induces PD changes that would allow lower or intermittent doses, or allow “drug holidays.” The drug could produce an undesired effect that might be mitigated by lower doses. –Alosetron. Observation of constipation in 30% of population starting with troublesome diarrhea suggests a “back-off” approach at first improvement might have avoided severe constipation

7. Risk Assessment Public Meeting - 4/9/03 7 Special Considerations 2.Titration: It is not common for drugs that are titrated to have actual comparisons of various methods. Too slow and too fast could both be problems.

8. Risk Assessment Public Meeting - 4/9/03 8 Special Considerations 3.“Subtle” adverse effects: Certain adverse effects are notoriously poorly studied in trials, such as effects on –sexual function –cognition –motor skills (driving) –mood These can become major issues (SSRI sexual function, depression with isotretinoin) and would be best studied in controlled trials as soon as there are hints of concern. They might, e.g., be dose related, respond to drug holidays, etc.

9. Risk Assessment Public Meeting - 4/9/03 9 Special Considerations 4.Pediatric - specific issues: This is now becoming clear with the explosion of peds studies, but children pose special issues of growth and neurocognitive development. It is also particularly useful to avoid mid-day dosing

10. Risk Assessment Public Meeting - 4/9/03 10 Special Considerations 5.Expanding the data base, the large simple safety study (LSSS), a study focussing on a small number of specified outcomes, generally with reduced routine data collection. Not as strange an idea as it once was: Pre-marketing studies (>10,000 patients) to evaluate a new antibiotic, a new COX-2 selective NSAID, and an antihypertensive (omapatrilat, concern about angioedema)Pre-marketing studies (>10,000 patients) to evaluate a new antibiotic, a new COX-2 selective NSAID, and an antihypertensive (omapatrilat, concern about angioedema) Similar studies are underway post-marketing (ziprasidone vs. olanzapine, salmeterol).Similar studies are underway post-marketing (ziprasidone vs. olanzapine, salmeterol). When might this be considered?

11. Risk Assessment Public Meeting - 4/9/03 11 Special Considerations 5.LSSS (cont.) To evaluate a troublesome safety signal, e.g., transaminitis with one or two bilirubin elevations, ambiguous extreme QT prolongations, that needs a larger databaseTo evaluate a troublesome safety signal, e.g., transaminitis with one or two bilirubin elevations, ambiguous extreme QT prolongations, that needs a larger database When a drug is to be used for long periods in asymptomatic people, to assess potential unexpected problemsWhen a drug is to be used for long periods in asymptomatic people, to assess potential unexpected problems To evaluate a larger, less restricted population for potential consequences of drug-drug or drug- demographic interactionsTo evaluate a larger, less restricted population for potential consequences of drug-drug or drug- demographic interactions

12. Risk Assessment Public Meeting - 4/9/03 12 Special Considerations 6.Keep blood or other tissue samples for potential later pharmacogenomic evaluation (serious events, better responses). Need to pay attention to consent issues Related (not in paper) is importance of capturing serious events and studying the individuals (blood levels at least). This is particularly emphasized in QT paper but is ok more general importance

13. Risk Assessment Public Meeting - 4/9/03 13 Always Evaluated Some matters always need assessment, notably QTc effectsQTc effects Evidence of hepatotoxicityEvidence of hepatotoxicity Polymorphic metabolismPolymorphic metabolism Drug-drug interactions, including new ones (inducers, inhibitors of glucuronidation, P-glycoprotein inhibitors)Drug-drug interactions, including new ones (inducers, inhibitors of glucuronidation, P-glycoprotein inhibitors) And, for biologics Immunogenicity, neutralizing AbsImmunogenicity, neutralizing Abs For live agents-virulence, transmissibility, genetic stabilityFor live agents-virulence, transmissibility, genetic stability Transplantation therapies - survival, function, host immunocompetenceTransplantation therapies - survival, function, host immunocompetence

14. Risk Assessment Public Meeting - 4/9/03 14 Medication Error Prevention Analysis (MEPA) PRE-MARKETING ASSESSMENT TO INCREASE THE “SAFE USE” OF DRUG PRODUCTS BY MINIMIZING MEDICATION ERRORS RELATED TO THE NAMING, LABELING, AND/OR PACKAGING OF THE PRODUCTPRE-MARKETING ASSESSMENT TO INCREASE THE “SAFE USE” OF DRUG PRODUCTS BY MINIMIZING MEDICATION ERRORS RELATED TO THE NAMING, LABELING, AND/OR PACKAGING OF THE PRODUCT

15. Risk Assessment Public Meeting - 4/9/03 15 PRE-MARKETING ERROR PREVENTION PROPRIETARY and GENERIC NAME ANALYSIS PROPRIETARY and GENERIC NAME ANALYSIS –for Sound and Look Alike similarities Expert and/or Focus GroupsExpert and/or Focus Groups Verbal Orders SimulationVerbal Orders Simulation Handwritten Orders SimulationHandwritten Orders Simulation Computer AnalysisComputer Analysis –Orthographic/Phonetic Overall Risk and Benefit AssessmentOverall Risk and Benefit Assessment

16. Risk Assessment Public Meeting - 4/9/03 16 PACKAGING Analysis of the packaging for its error potential:Analysis of the packaging for its error potential: –What are the inherent risks and benefits of choosing or not choosing a particular drug delivery package (e.g. ampule vs. syringe)?

17. Risk Assessment Public Meeting - 4/9/03 17 LABELS/LABELING Labeling AnalysisLabeling Analysis –Container label similarities within product line/class? –Similarities with other products? –Is Critical Information (e.g., drug name, strength, route of administration) clear for the end user? –Are the dosing instructions in the PI clear and easily understood?

18. Risk Assessment Public Meeting - 4/9/03 18 Conclusion We look forward to discussion We’re sure the experience of this audience can refine and expand the thoughts in the concept paper