The Role of Adverse Events in Evaluating the Abuse Potential of New Drugs

1. The Role of Adverse Events in Evaluating the Abuse Potential of New Drugs A. J. Allen, M.D., Ph.D., Sr. Med. Fellow Cochair, Lilly Drug Abuse Liability & Dependence (Safety) Advisory Committee Eli Lilly and Company Allenaj@Lilly.com

2. Financial Disclosures

3. Overview • General approach to evaluating drug safety • Goal of evaluating AEs from clinical trials as part of abuse potential evaluation • Some challenges to using adverse events to evaluate abuse potential • Learning from experience: • Suicidal ideation and behaviors • Learn from experience: Ezogabine (Potiga) • Some needs and proposals

4. General Approach to Evaluating Drug Safety

5. “Scientific knowledge is a body of statements of varying degrees of certainty – some more unsure, some nearly sure, none absolutely certain. Richard P. Feynman, Ph.D. The Pleasure of Finding Things Out Chapter 6, The Value of Science

6. General Approach To Evaluating Drug Safety • Preclinical – Toxicology • In vitro and in vivo animal studies provide preliminary signals of possible risks in humans • Phase I/II – Exploratory & Evaluate • Identify possible common adverse events in clinical trials • Includes specialized safety studies to evaluate possible common adverse events • Drug interaction, thorough QT and human abuse potential studies

7. General Approach To Evaluating Drug Safety (continued) • Phase III – Confirmatory (or not) • Characterize common adverse events in clinical trials – including specialized clinical pharmacology • Identify possible less common adverse events • Phase IV – Monitor, Evaluate & Mitigate • Identify possible rare & very rare adverse events • Clinical trials, including large simple trials • Non-trial approaches to human data • Pharmacoepidemiology approaches possible • Example: FDA’s Sentinel Initiative • REMS, RMPs

8. General Approach To Evaluating Drug Safety (continued) • Prospectively collected data is always preferable to retrospectively collected data • Retrospective data subject to multiple limitations (e.g., recall bias, memory lapses, other biases) • Given a choice, prospective studies are generally preferable to retrospective studies • Retrospective studies are hypothesis generating • Prospective studies are hypothesis testing

9. Some Challenges in Evaluating Drug Safety • Background frequency of adverse events in population being studied, especially • Rare events • Understudied populations • New onset of averse events vs. worsening of subclinical pre-existing adverse events/conditions • Heterogeneity of population • Small sub-group(s) at heightened risk • Mean changes vs. categorical measures & outliers

10. Recent FDA Rule Change on Safety Reporting • 2010 rule change and draft guidance • http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf • Problem per FDA: Tendency for sponsors to default to reporting uninformative individual cases primarily due to misapplication of the standard that there was a “reasonable possibility” that individual adverse events were “associated with the use of the drug.“ • Potential causality not assessed appropriately • FDA flooded with AE reports, many clearly not caused by drug

11. Recent FDA Rule Change on Safety Reporting (continued 2) • Solution per FDA: revise definitions • Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. • Adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions for which there is reason to conclude that the drug caused the event.

12. Recent FDA Rule Change on Safety Reporting (continued 3) • Solution per FDA: revise definitions (continued) • 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. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.

13. Recent FDA adoption of DSURs • DSUR = Development Safety Update Report • ICH E2F guidance • FDA guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073109.pdf • DSUR is a periodic report for a drug or biologic in development. It contains: • Safety information/data and analysis from ongoing and completed trials conducted by the sponsor • Significant other findings pertinent to safety of the drug – from any of a number of sources

14. Recent FDA adoption of DSURs (continued) • Includes “Summary of Important Risks (3.19)” • A concise, cumulative, issue-by-issue list of important identified and potential risks* (e.g., those that might lead to warnings, precautions, or contraindications in labeling) • Could provide the basis for the safety specification of a risk management plan (RMP) • Risks that have been fully addressed or resolved should remain in the summary and be briefly described, e.g., findings from toxicology studies or early clinical trials that were not borne out by later clinical data.

15. The Goal… • Appropriate and validated methods for evaluating adverse events from clinical trials during new drug/biologic development for the purpose of: • Detecting possible signals of abuse potential (phases I and II, suspected adverse drug reactions, potential risks) and • Confirming or refuting possiblesignals of abuse potential (phases III and IV, move from suspected to confirmed adverse drug reactions, identified risks – or not confirmed, resolved)

16. Some Challenges to Using Adverse Events to Evaluate Abuse Potential

17. Some challenges of using adverse events to evaluate abuse potential • Study population’s risk of abusing • Most phase I/II/III/IV trials exclude subjects with history of drug abuse/dependence • Despite this, small percentage (? maybe 10%) of study population likely to be at risk for drug abuse/dependence of specific class of drugs due to genetics, etc. • Human abuse potential studies specifically recruit a population with current/past history of drug abuse of specific class of drugs • Essentially 100% of subjects with phenotype • Implications

18. Some challenges (continued) • Language and culture • Even in English, terminology is often unclear • Limitations of MedDRA dictionary well known • Global studies often conducted in non-English speaking countries with different cultures • May be difficult to translate some terms/adverse events relevant to abuse potential • Different drug classes with distinct effects, and some overlap • For example: stimulants vs. sedative-hypnotics • Especially difficult problem for new drugs/biologics with novel mechanisms of action

19. Some challenges (continued 2) • Instrumentation (scales) • Scales need to be appropriate to the research question being asked and trial design • Including population being studied, language, culture, etc. • Scales developed for human abuse potential studies may not be useful instruments in other populations • Scales need to be appropriately validated • In addition to other forms of validity, need predictive validity – does the scale accurately predict abuse/lack of abuse by the population being studied? • Scales should not be overly burdensome and/or difficult for research subjects or investigators

20. Learning from Experience

21. Drugs and Suicidal Ideation/Behaviors • Historical concern with anti-depressants – attributed to partial improvement of depression • In early 1990s questions about SSRIs • In 2003, GSK pediatric anti-depressant trials raised topic again • FDA advisory committees in Feb. and Sept. 2004 on pediatric data • One FDA advisory committee on young adults in late 2006 • FDA problem: inconsistent data across companies

22. Columbia -Classification Algorithm for Suicide Assessment (C-CASA) • 1 Completed Suicide • 2 Suicide Attempt • 3 Preparatory Actions Toward Imminent Suicidal Behavior • 4 Suicidal Ideation • 5 Self-Injurious Behavior Intent Unknown • 6 Fatal Event: Not Enough Information • 7 Self-Injurious Behavior Without Suicidal Intent • 8 Other (Accident, Psychiatric, Medical) • 9 Nonfatal Event: Not Enough Information

23. Old Methodology for Conducting Meta-Analyses of Suicidal Ideation/Behaviors • Applied retrospectively to clinical trial data • Text string search of database fields for visits in window of time • Spontaneously collected AEs vs. other data • Remove clear false positive “hits” • Prepare data for review • Raw data (line listings) • One page patient summaries (OPPS) • Health care professionals blind to treatment assess cases and categorize using C-CASA criteria • Statistical analysis of categorized cases

24. New Methodology for Conducting Meta-Analyses of Suicidal Ideation/Behaviors • Problem: old methodology applied C-CASA criteria retrospectively to trial data and spontaneous AEs , many questions about results • Data not collected with this purpose in mind • FDA proposed response: prospectively solicit data on suicidal ideation/behaviors using instrument that maps to C-CASA • 2010 FDA Draft Guidance on Suicidality: Prospective Assessment of Occurance in Clinical Trials http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225130.pdf • Columbia Suicide Severity Rating Scale (C-SSRS)

25. Columbia Suicide Severity Rating Scale (C-SSRS) • Semi-structured clinician interview • Captures data in C-CASA categories • Developed and validated in the US in academic psychiatry study of depressed patients • Has been pressed into use in many industry trials globally… • Translated into other languages (but not validated) • Used in many foreign countries (but not validated) • Used in trials involving psychiatric and non-psychiatric diseases and clinicians (only validated for use by psychiatrists in depression)

26. Some Things to Consider…

27. More Things to Consider… • Spontaneous vs. solicited adverse events • Spontaneous captures “significant” events, but not “all” events • Lower baseline (less “noise”) – may allow for smaller sample to show difference between drug and placebo • C-CASA uses spontaneous events • Solicited captures “all” events • Higher baseline (more “noise”) – may require larger sample to show difference between drug and placebo • C-SSRS solicits Aes • Collecting both spontaneous and solicited AEs in the same trial creates challenges • Need to collect spontaneous before solicited, BUT… • Reconciling #s (especially if different people collect each)

28. Ezogabine (Potiga) • Anti-convulsant for adjunctive use • Novel mechanism of action (potassium channel opener) • Preclinical studies in rats and monkeys showed decrease in locomotor activity, decrease in muscle tone and ataxia • In rats trained to self-administer cocaine, substitution of ezogabine did not maintain self-administration • Phase I AE data: euphoria 8.5%, feeling drunk 5.5%, hallucinations 5.1%, disorientation 1.7%, feeling abnormal 1.5%

29. Ezogabine (Potiga) • Phase 2 and 3 AE data (3 studies): • 300 to 1200 mg ezogabine: euphoric mood 0.5%, feeling drunk 0.9% • Placebo: ephoric mood 0%, feeling drunk 0% • Human abuse potential study: • 300, 600 and 900 mg doses of ezogabine • Euphoric mood: 18%, 21% and 33% vs. placebo 8% • Hallucination: 0%, 0%, 17% vs. placebo 0% • Somnolence: 18%, 15%, 67% vs. placebo 15% • Euphoria-type subjective responses to the 300 and 600 mg doses of ezogabine were statistically different from placebo, but statistically indistinguisable from alprazolam

30. Some needs and proposals • A prospective, targeted surveillance approach to collecting and evaluating adverse events potentially related to drug abuse is feasible today, especially in era of electronic CRFs • Guidance would benefit from “starter” list of AE terms to target • Include verbatim and preferred terms, at minimum • Sponsors could be supplement (with rationale) if needed • Guidance should suggest additional information to collect prospectively when a term “hits” • Information to provide clinical context, such as time after dose, what subject was doing, vital signs, etc.

31. Some needs and proposals (2) • A prospective, targeted surveillance approach… (continued) • Changes in investigator behavior may be needed, such as primary completion of eCRFs(vs. secondary, from paper worksheet) • Improved, standardized training of investigators re: recording of AEs across companies and trials • How? Who? • What “gold standard”? • Possible role for CPDD? • Bottom line: if it ain’t (too) broke, don’t abandon it prematurely (or: don’t throw the baby out with the bath water)

32. Some needs and proposals (3) • There MAY be value in developing new methods for prospectively collecting data relevant to abuse potential in clinical trials of healthy controls and patients, but will take time (10 years?) and resources • Need clear goal/objectives from start! • What problem needs to be solved? • What drug classes? • Priorities? • Approaches, form, methodology? • Validation? • Who? (believe NIDA/FDA/Academia/Industry collaborationessential)

33. Overview • General approach to evaluating drug safety • Goal of evaluating AEs from clinical trials as part of abuse potential evaluation • Some challenges to using adverse events to evaluate abuse potential • Learning from experience: • Suicidal ideation and behaviors • Learn from experience: Ezogabine (Potiga) • Some needs and proposals

34. Questions? Allenaj@Lilly.com

35. Backup Slides

36. FDA Draft Guidance on Assessment of Abuse Potential of Drugs http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf