1. Accutane FDA (Section Name - Saver’s Initials) 3/9/00 12:50 PM 1 Introduction Russell Ellison, MD Chief Medical Officer Vice President, Medical Affairs Roche Laboratories, Inc.

2. Accutane and Psychiatric Adverse Events February 1998 February 1998 –bolded warning in label based on spontaneous reports of psychiatric events with Accutane: ie: an unconfirmed “signal”

3. Accutane and Psychiatric Adverse Events February 1998 to June 2000: February 1998 to June 2000: –pharmacoepidemiological analysis of reports –clinical review of reports of suicides and related events –two retrospective epidemiologic cohorts [UKGPRD, Saskatchewan] –biological and clinical literature review

4. Accutane and Psychiatric Adverse Events This evidence does not support a causal association between Accutane and psychiatric events including suicide This evidence does not support a causal association between Accutane and psychiatric events including suicide Patients with acne, depending on age, gender, and prior history, may be at high risk for a concomitant psychiatric illness Patients with acne, depending on age, gender, and prior history, may be at high risk for a concomitant psychiatric illness

5. Agenda Introduction Russell Ellison, MD Introduction Russell Ellison, MD Chief Medical Officer, Vice President, Medical Affairs Roche Laboratories, Inc. Clinical Context for Evaluation of Psychiatric Events and Accutane Douglas Jacobs, MD Associate Clinical Professor of Psychiatry Harvard Medical School Clinical Context for Evaluation of Psychiatric Events and Accutane Douglas Jacobs, MD Associate Clinical Professor of Psychiatry Harvard Medical School Pharmacoepidemiological Evaluation of Spontaneous Reports Robert C. Nelson, PhD RCN Associates, Inc. Pharmacoepidemiological Evaluation of Spontaneous Reports Robert C. Nelson, PhD RCN Associates, Inc.

6. Agenda Epidemiological Studies and Biological Review John McLane, PhD Director/Medical Science and Safety Roche Laboratories, Inc. Epidemiological Studies and Biological Review John McLane, PhD Director/Medical Science and Safety Roche Laboratories, Inc. Risk Management Russell Ellison, MD Vice President/Medical Affairs Roche Laboratories, Inc. Risk Management Russell Ellison, MD Vice President/Medical Affairs Roche Laboratories, Inc.

7. Accutane FDA (Section Name - Saver’s Initials) 3/9/00 12:50 PM 7 Risk Management Options Russell Ellison, MD Chief Medical Officer Vice President, Medical Affairs Roche Laboratories, Inc.

8. Psychiatric Events Risk Management Issues The evidence does not support a causal association of psychiatric illness with Accutane. Specific information related to possible risk of events beyond known risk factors for disease is lacking. The evidence does not support a causal association of psychiatric illness with Accutane. Specific information related to possible risk of events beyond known risk factors for disease is lacking. Patients with severe acne, depending on age, gender, and prior history, may be at high risk for a concomitant psychiatric illness Patients with severe acne, depending on age, gender, and prior history, may be at high risk for a concomitant psychiatric illness

9. Psychiatric Events Risk Management Issues What information to convey, with what desired actions, to be taken by whom and in what circumstances? What information to convey, with what desired actions, to be taken by whom and in what circumstances? e.g.: CME e.g.: CME –Psychiatric disease as a concomitant illness: alert the prescriber to this phenomenon alert the prescriber to this phenomenon use the treatment venue as an opportunity for identifying possible problems use the treatment venue as an opportunity for identifying possible problems applicable to all high risk patients, include Accutane information applicable to all high risk patients, include Accutane information

10. Psychiatric Events Risk Management Issues What information to convey, with what desired actions, to be taken by whom and in what circumstances? What information to convey, with what desired actions, to be taken by whom and in what circumstances? e.g.: Labeling: e.g.: Labeling: –Professional: new Accutane data, symptoms, discontinuation, alert to comorbidity in all high risk patients –Patients: Accutane information, alert to symptoms, inform physician of previous history, alert to possibility of psychiatric illness irrespective of acne treatment

11. Psychiatric Events Risk Management Issues What information to convey, with what desired actions, to be taken by whom and in what circumstances? What information to convey, with what desired actions, to be taken by whom and in what circumstances? e.g.: Labeling: informed consent e.g.: Labeling: informed consent –relative strength of causal association compared to other serious adverse events –what to inform patients about, for consent to treatment without a strong statement of cause, or estimates of risk

12. Psychiatric Events Risk Management Issues What information to convey, with what desired actions, to be taken by whom and in what circumstances? What information to convey, with what desired actions, to be taken by whom and in what circumstances? e.g.: assessment before and during treatment e.g.: assessment before and during treatment –simple questionnaires (waiting room) available to identify the possibility of, psychiatric illness but not to confirm or rule out –for all high risk patients (part of dermatological assessment) –potential risk of conflict with time needed for pregnancy prevention in women...compliance?

13. Psychiatric Events Risk Management Issues Formal Studies: Formal Studies: Prospective clinical trial: Prospective clinical trial: – control group, hypothesis/sample size, blinding Open cohort studies Open cohort studies – matching cohorts unlikely – specificity of question, confidence in the answer – must be prospective

14. Psychiatric Events Risk Management Issues Retrospective epidemiologic cohort study: Retrospective epidemiologic cohort study: –available databases re: size, specific coding, population definitions In vitro / in vivo preclinical studies: In vitro / in vivo preclinical studies: – specific models for specific psychiatric illness vs general CNS effects

15. Conclusions The evidence does not support a causal association between Accutane and psychiatric illness The evidence does not support a causal association between Accutane and psychiatric illness Additional studies might somewhat clarify but not definitively resolve the issue Additional studies might somewhat clarify but not definitively resolve the issue Much has been learned about psychiatric disease in acne patients…there is an opportunity to enhance the overall medical impact of the management of all acne patients Much has been learned about psychiatric disease in acne patients…there is an opportunity to enhance the overall medical impact of the management of all acne patients