1. Long-term Efficacy for Psychiatric Drugs Frederick K. Goodwin, MD George Washington University Medical Center Frederick K. Goodwin, MD George Washington University Medical Center Psychopharmacologic Drugs Advisory Committee October 25 th, 2005 Psychopharmacologic Drugs Advisory Committee October 25 th, 2005

2. 2 What’s at stake: The Public Health implications uThe major psychiatric illnesses are highly prevalent, cause untold suffering, have substantial morbidity and mortality and impose substantial costs on society and on health care. uEven among the more successfully treated psychiatric illnesses, approximately one fourth of patients do not respond to existing medications. For major depression and bipolar disorder this translates into four or five million Americans. uThus the need for new and better agents, along with established new uses for existing agents, represents an urgent public health imperative. uPublic health agencies (such as FDA and NIMH), along with academic investigators, professional organizations and the pharmaceutical industry all share an ethical obligation to facilitate the timely availability of safe and effective new agents for the treatment of these devastating illnesses. uThis ethical obligation is especially compelling when potential new treatments involve novel mechanisms of action. uThe major psychiatric illnesses are highly prevalent, cause untold suffering, have substantial morbidity and mortality and impose substantial costs on society and on health care. uEven among the more successfully treated psychiatric illnesses, approximately one fourth of patients do not respond to existing medications. For major depression and bipolar disorder this translates into four or five million Americans. uThus the need for new and better agents, along with established new uses for existing agents, represents an urgent public health imperative. uPublic health agencies (such as FDA and NIMH), along with academic investigators, professional organizations and the pharmaceutical industry all share an ethical obligation to facilitate the timely availability of safe and effective new agents for the treatment of these devastating illnesses. uThis ethical obligation is especially compelling when potential new treatments involve novel mechanisms of action.

3. 3 Overview uBoth acute and long-term efficacy data is needed for psychiatric disorders that are recurrent or chronic, but these are very different indications and should not be made inter-dependent. –Some acute agents are not appropriate for long-term use –Some maintenance agents may not be effective acutely. uRequiring long-term efficacy data for an acute indication will reduce and/or delay the availability of new treatments –This requirement would double the cost of pivotal trials to register a new agent, representing a major disincentive for the development of new agents or new indications for existing agents uBeginning long-term efficacy studies before establishing acute efficacy and safety poses ethical/safety concerns uBoth acute and long-term efficacy data is needed for psychiatric disorders that are recurrent or chronic, but these are very different indications and should not be made inter-dependent. –Some acute agents are not appropriate for long-term use –Some maintenance agents may not be effective acutely. uRequiring long-term efficacy data for an acute indication will reduce and/or delay the availability of new treatments –This requirement would double the cost of pivotal trials to register a new agent, representing a major disincentive for the development of new agents or new indications for existing agents uBeginning long-term efficacy studies before establishing acute efficacy and safety poses ethical/safety concerns

4. 4 Overview (continued) uThe type, extent and timing of clinical studies required differs by indication, type of medication and the nature of existing data for the medication and class - hence regulatory guidelines should allow for such flexibility uStabilization time for discontinuation studies will vary by indication uThe way that long-term safety data is currently obtained (by open label extension of the acute trial) is closer to “real world” conditions and, in fact tends to overstate adverse events because of the absence of a placebo group uThe type, extent and timing of clinical studies required differs by indication, type of medication and the nature of existing data for the medication and class - hence regulatory guidelines should allow for such flexibility uStabilization time for discontinuation studies will vary by indication uThe way that long-term safety data is currently obtained (by open label extension of the acute trial) is closer to “real world” conditions and, in fact tends to overstate adverse events because of the absence of a placebo group

5. 5 Long-term Efficacy Data Should Not Be Required at Filing or Initial Approval uIndustry currently provides long-term safety data at the time of initial filing, per current regulatory (ICH-E1A) guideline 1 uAcute use can be valuable for patients, even if long-term efficacy has not been proven or has uncertain risk-benefit –Typical antipsychotics –bipolar mania (long-term use may trigger or exacerbate subsequent depressive episodes) –psychotic depression –Divalproex in mania 2,3,4 –Antidepressants in bipolar depression (long-term use may be associated with cycling) –Benzodiazepines in anxiety –Insomnia uIndustry currently provides long-term safety data at the time of initial filing, per current regulatory (ICH-E1A) guideline 1 uAcute use can be valuable for patients, even if long-term efficacy has not been proven or has uncertain risk-benefit –Typical antipsychotics –bipolar mania (long-term use may trigger or exacerbate subsequent depressive episodes) –psychotic depression –Divalproex in mania 2,3,4 –Antidepressants in bipolar depression (long-term use may be associated with cycling) –Benzodiazepines in anxiety –Insomnia 1 ICHE1A; 2 Pope HG et al. Arch Gen Psychiatry 1991;48:62-68; 3 Bowden CL et al. JAMA 1994;271:918-924; 4 Bowden CL et al. Arch Gen Psychiatry 2000;57:481-489

6. 6 Advantages of Sequential Approach to Acquisition of Long-Term Efficacy Data uAvoids the ethical and safety concerns raised by committing patients to a long-term trial before acute safety and efficacy have been established. uAvailability of drug after acute indication allows clinicians and researchers to develop and publish pilot information on long-term use to provide the basis (and the incentive) for large controlled trials uPatients have earlier access to new options for treatment uCompanies will be more likely to invest in novel agents (especially important for the millions of treatment resistant patients) if they can obtain an acute signal before committing to a long-term study uLong-term data for recently introduced compounds has been submitted in a timely manner following filing for the acute indication uAvoids the ethical and safety concerns raised by committing patients to a long-term trial before acute safety and efficacy have been established. uAvailability of drug after acute indication allows clinicians and researchers to develop and publish pilot information on long-term use to provide the basis (and the incentive) for large controlled trials uPatients have earlier access to new options for treatment uCompanies will be more likely to invest in novel agents (especially important for the millions of treatment resistant patients) if they can obtain an acute signal before committing to a long-term study uLong-term data for recently introduced compounds has been submitted in a timely manner following filing for the acute indication