# Presentation: 150922

## Timing and Duration of Relapse Prevention Trials in Psychiatric New Drug Development

- David Michelson, M.D.
- Executive Director, Neuroscience Medical Research
- Eli Lilly and Company

## Background

- The FDA has asked several questions, including particularly whether
- evidence of the long-term (maintenance) efficacy of new psychiatric drug treatments should be provided earlier than current practice
- 3-month lead-ins adequately assess efficacy during maintenance treatment
- Changes to current practice could provide more data at approval, but
- It is not established that current practice provides insufficient data
- How interpretable/valuable data from a longer/earlier study would be is unclear
- The changes being discussed would make the conduct of studies more difficult
- Large increases in sample size and issues around signal detection
- Time to study completion
- When studies are conducted during the development process
- Analysis of previous studies illustrates some of problems raised by such changes

## Attrition During Initial Treatment Predicted by Previous Relapse Prevention Studies at Lilly

| Indication
(Study Identifier) |  | OL Tx / Duration |  | Estimated Attrition at 12 weeks | Estimated attrition at 26 Weeks* |
| --- | --- | --- | --- | --- | --- |
| Depression
(HCEX) |  | Fluox 20 mg
12 weeks |  | 53% | 73% |
| Panic Disorder**
(HCHG) |  | Fluox 20 mg
10 weeks |  | 56% | 69% |
| ADHD
(LYAF) |  | Atmx 1.2-1.8 mg/kg 
12 weeks |  | 31% | 54% |
| Bipolar Mania
(HGHL) |  | Olanz 5-20 mg
12 weeks |  | 51% | 72% |

****  Attrition for 26 weeks are estimates derived by extrapolating from patient disposition or Kaplan-Meier ***
***curves during blinded treatment phase***
***** Acute phase was double-blind rather than open label***

## Attrition During Initial Treatment in Olanzapine Schizophrenia Studies

- Relapse prevention for olanzapine was assessed by
- switching patients stable on any antipsychotic to olanzapine,
- observing for 14 weeks
- randomizing to discontinuation or continued olanzapine
- Data are not directly comparable to data from long-term studies of the mood and anxiety disorders
- Patients not acutely ill at study outset
- Historical attrition rates in acute studies of olanzapine over ~12 weeks are approximately 50%
- Suggests that the discontinuation rates of approximately 50% at 3 months and 70% at 6 months seen in other disorders studied with standard designs also apply for schizophrenia

## Duration of Initial Treatment and Sample Size: Historical Data

|  Duration
Of
Treatment | Depression Relapse Rates  in Historical Data (HCEX) |  |  |  | ADHD Relapse Rates in Historical Data (LYAF) |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | Drug | Placebo | N needed at Study Entry |  | Drug | Placebo | N needed at Study Entry |
| 12 Weeks | 37% | 58% | 264 |  | 19% | 35% | 360 |
| 26 Weeks | 22% | 33% | 790 |  | n/a | n/a | n/a |
| 52 Weeks
 | n/a | n/a | n/a |  | 5% | 15% | 456 |

## Duration of Treatment Prior to Withdrawal: Other Considerations

- Treatment effect sizes in historical data do not appear to decrease markedly  with longer ‘run-ins’
- Longer treatment periods require signficantly larger samples
- Attrition prior to randomization rises with increasing time
- Event rates decrease with time (longer periods of stability appear to predict future stability)
- It is unknown whether longer stabilization time makes patients more stable or simply selects for patients with a more stable course of illness
- ‘Negative’ studies could only be interpreted in the presence of a positive control
- Would increase sample size and time to completion even more
- Increasing stringency around response criteria or restricting excursions would necessitate further increases in sample size

## Study Timing

- Relapse prevention studies take significantly longer to conduct than acute efficacy studies
- Requiring completion of such studies at NDA filing will delay approvals and patient access to novel treatments

## Time Required to Conduct Acute and Relapse Prevention Studies: Recent Data 

| Atomoxetine
Study Identifier |  | Study Description 1 | Time from First Patient Visit to Last Patient Visit  |
| --- | --- | --- | --- |
| LYAT 2
Pivotal acute efficacy |  | Two arm, 6-week acute placebo controlled study
N = 168 | 117 days (3.9 months) |
| LYAC 3
Pivotal acute efficacy |  | Four arm, 8–week, placebo-controlled dose response study
N = 297 | 242 days (8.1 months) |
| LYAF 4
Registration quality study to support labeling for long-term efficacy |  | Placebo-controlled withdrawal study with two randomizations (after 3 months and after 1 year)
N = 603  | 918 days (31.3 months) |

*1 ** *N = all patients with at least 1 post-baseline visit
*2 **Michelson et al. Am J Psychiatry 2002*
*3 **Michelson et al Pediatrics 2001*
*4 **Michelson et al J Am Acad Child Adol Psychiatry 2004*

## Requiring Completion of Relapse Prevention at NDA Filing: Concerns

- Optimal dosing may be poorly understood until late in phase III
- Potential for suboptimal/excessive dose in relapse prevention
- Relapse prevention studies involve extended acute open label treatment, and early in phase III
- can confound interpretation/attribution of adverse events
- Large numbers of patients will be exposed to drug for extended periods prior to a definitive demonstration of acute efficacy
- Relapse prevention studies started after the completion of pivotal trials in phase III will significantly delay in patient access to novel treatments

## What is the Risk of Chronically Inefficacious Drugs Being Approved and Used Under Current Practice? 

- Predictive value of 3 month lead-ins for longer efficacy
- Available data are limited, but the evidence we do have suggests that efficacy at 3 months predicts efficacy after longer periods
- Conversely, we are unaware of convincing data demonstrating a later loss of drug effect for any antidepressant or antipsychotic effective acutely and in continuation treatment after 3 months
- Predictive value of sub-acute data for longer efficacy
- The likelihood that a novel compound capable of inducing but not maintaining a symptom response chronically would fare well in 8-12 week acute, parallel design trials seems low
- Marked and early ‘therapeutic tachyphylaxis’ would make it very difficult to sustain superiority to placebo through the trial’s endpoint

## Conclusions

- Requiring longer relapse prevention studies and making them a condition of initial filing will delay patient access to new drugs without providing a clear offsetting benefit over current practice
- Access to novel drugs will be delayed, in some cases considerably
- The proposed changes could significantly increase barriers to approval, discouraging sponsors from undertaking some psychiatric drug development programs.
- The programs most affected may be drugs with highly novel and unprecedented mechanisms, which are most likely to provide breakthroughs for patients, but also have the highest likelihood of failure