1. Development and Approval of Drugs and Devices EPI260 Lecture 9 May 23, 2012 Richard Chin, M.D.

2. Overview Outline Overview Classification Case study Reporting requirements for FDA, EMEA, and others Signal detection REMS and postmarketing surveillance

3. Overview Patient Safety Safety is paramount Clinical research is risky IND is a specific exemption granted by the FDA Specific adverse event reporting requirements during clinical trials –Now harmonized Reporting requirements after marketing

4. Defining Adverse Events Adverse events, except targeted adverse events, are not predefined Safety is not opposite of efficacy, but rather the complement Statistical significance is not required for safety signal –Hard to predefine –Most studies not powered for safety events

5. Mapping Terms MI vs. angina vs. chest pain vs. anterior MI vs. sudden death Terms must be mapped to consistent terms MedDRA - the Medical Dictionary for Regulatory Activities –Hierarchical and cross referenced mapping system

6. Defining Adverse Events When does event begin and end? –Exacerbation of asthma –Reinfarction What about events that recur? –How many events? What events are emergent events? –Exacerbation of condition that existed at baseline Who determines causality? –Investigator –Sponsor –Adjudication committee

7. Adjudication Committees Standardizes adverse events Similar to DSMB Necessary and possible if there is a targeted adverse event Can be combined with outcome adjudication committee

8. Drug Effects

9. Additional Drug Effects Cumulative Interactions Harbinger events

10. Case Study: Zooming In and Out A promising drug for refractory seizures is being developed Unfortunately, it appears to have two drawbacks –Potential to cause arrhythmias –Potential to cause duodenal ulcers Therefore, the Phase III safety data is carefully examined to assess potential signal in those two categories

11. Initial reading Fortunately, neither concern seems to have been justified, as no signal is apparent

12. Illusion: Lumping Unfortunately, if the net for arrhythmias is cast more widely to include not just the term, “arrhythmia” but also “sudden death,” “palpitations,” “syncope,” (which can be other presentations of arrhythmia) then a signal becomes apparent 12% 23%

13. Lumping and Splitting For ulcers, no signal is apparent if the data is split too much or lumped too much But if we zoom to the right level, a clear signal comes into focus p = 0.02p = NS

14. Types of AEs Premarketing (clinical trial) –Individual –Trend analysis Postmarketing –Spontaneous –Trend analysis

15. Reporting Requirements During Trials Serious, Unexpected Adverse Events must be reported AS FAST AS POSSIBLE but no later than –7 calendar days if life threatening or fatal –15 calendar days if not life threatening or fatal New guidelines specify this applies to events “for which there is a reasonable possibility that the drug caused the adverse event “ Increased incidence of AE must also be reported

16. Adverse Event/Drug Reaction Definition Adverse Event: Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product Suspected adverse reaction : Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event.

17. Reasonable Likelihood A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group

18. Serious vs. Severe Not the same thing Serious (a)results in death (b)is life-threatening (c)requires hospitalization or prolongation of existing hospitalization (d)results in persistent or significant disability or incapacity, or (e)consists of a congenital anomaly or birth defect

19. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grade 1: Mild AE Grade 2: Moderate AE Grade 3: Severe AE Grade 4: Life-threatening or disabling AE Grade 5: Death related to AE

21. Unexpected Definition Not in the Investigator’s Brochure Not in the Package Insert or SPC Unclear: Addendum to the IB May be unexpected if changes occur in –Rate –Severity –Duration –Other

22. Emergent Adverse Event Definition Sometimes it is not clear when an event began Examples –Worsening of event –Event stops and restarts –Repeat of event Consistency is critical

23. Causality and Relatedness Categories –Unrelated –Possibly related –Related Assessed by investigator and by the sponsor When is patient considered to be off the drug? Often, sponsors have Safety Review Boards an DSMB but CMO has last word FDA guidelines – sponsor definition prevails ICH guidelines – either sponsor or investigator

24. Unblinding Per ICH guidelines, placebos may qualify as drug Most sponsors unblind and report only patients who were on drug

25. When Does Clock Start? Day 1 is the day of the sponsor has knowledge Sponsor includes anyone at the company, and anyone at the CRO or other agents of the company Knowledge occurs when –a suspected investigational medicinal product –an identifiable subject (e.g. study subject code number) –an adverse event assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship –an identifiable reporting source Clock stops on the day that the report is received by the regulatory agency

26. Follow-up Many sponsors follow SAEs to resolution At a minimum, the patients should be followed until end of study

27. Trend Analysis Frequency analysis is important Analysis by subgroups and risk factors is important Need to monitor event rates and patterns

28. How to Report Medwatch forms CIOMS forms EUDRA

30. Reporting Regulatory Authorities Investigators IRB/ECs Patients –Reconsent

31. Logistics Typical flow of information –P.I. reports to sponsor via EDC –Assigned to case worker in pharmacovigilance group –Data mapped and entered –Follow up information obtained –Medwatch or other form prepared –QC check –Regulatory files with authorities

32. SOPs and Documents Safety Reporting Agreements: Document outlining how the AEs will be processed between cosponsors or sponsor and CRO Annual Safety Reports Pharmacovigilance SOPs MedDRA updates

33. Reconciling Reconciling with Clinical Database –AE database often separate from clinical database –Reconciliation can be difficult Reconciling different versions of MedDRA

34. Approval and Postmarketing Risk minimization action plans (RiskMAPs) –strategic safety program100designed to meet specific goals and objectives in minimizing known risks of a product while 101preserving its benefits Risk Evaluation and Mitigation Strategies (REMS) –Timetable for Submission of Assessments –Additional Potential Elements A Medication Guide A patient package insert A communication plan to health care providers –Elements to Ensure Safe Use (ETASU)

35. Postmarketing Reporting SUSAR: Similar requirements for postmarketing period Literature Survey: Sponsors are required to monitor literature for AEs and report them Annual reports