Approximately 350 million people around the world live with major depressive disorder (MDD). While there are existing treatments, up to two-thirds of patients with MDD do not achieve remission following an initial adequate trial of antidepressant medications and nearly 70% experience residual symptoms with first line standard of care.1 There remains a critical need for more effective drugs that offer faster onset of action, higher rates of response, and sustained relief.
Both the FDA and EMA have developed clear guidance on clinical investigations involving drugs for the treatment of MDD. While these guidelines are similar, they are not harmonized. For developers seeking to globalize their innovations, it is essential to understand regulatory nuances in the paths to market in the US and EU.
In this blog, we explore the regulatory frameworks for antidepressant drugs in US and EU, highlighting recent changes proposed in EMA guidelines.
Regulatory framework in the US
FDA issued guidance on developing drugs for the treatment of MDD in June 2018. This guidance provides recommendations on multiple aspects of clinical development, including:2
Study design. The agency emphasizes the need for randomized, double-blind, placebo-controlled, parallel designs for short-term efficacy trials in MDD.
Since depression is typically a cyclical disease, FDA views maintenance studies as assessments of the ability of the investigational product to reduce the rate of recurrence of depression. Given that most recurrences are delayed, maintenance studies should generally be at least 6 months in duration. To inform labeling regarding maintenance treatment, FDA typically requests a post-marketing commitment to conduct a double-blind randomized withdrawal trial.
For fast-acting antidepressants, it is useful to assess whether the rapid effect persists for the episode treated. FDA is also interested in studies that explore whether treatment response can be maintained with a lower dose of the drug than is needed for short-term efficacy, and whether a lower dose may improve tolerability.
Study population criteria. The agency recommends that trials designed to assess the efficacy of antidepressant drugs should include patients with Diagnostic and Statistical Manual (DSM)-defined MDD and should reflect a range of severities.
Efficacy endpoints. To date, the primary endpoints FDA has accepted in phase 3 studies to support an MDD indication are:
- Hamilton Depression Rating Scale (HAM-D, typically the 17-item version)
- Montgomery-Asberg Depression Rating Scale (MADRS)
- Children’s Depression Rating Scale
While other endpoints may be acceptable, sponsors planning to use a novel primary endpoint in phase 3 trials should seek scientific advice before initiating studies.
Secondary endpoints usually assess other domains of symptom improvement relevant for labeling, such as Clinical Global Impression (CGI) and the Sheehan Disability Scale.
Statistical considerations. Due to the high placebo response and dropout rates commonly observed in MDD studies, FDA advises sponsors to consider these factors in sample size calculations to ensure sufficient power to detect a treatment effect.
Phase 3 or 4 (postmarketing) safety considerations. FDA highlights the importance of long-term safety data, especially for drugs intended for chronic use. While pregnant women are generally excluded from MDD studies, they remain a population that may require treatment. Thus, sponsors are advised to collect safety data both in women who are inadvertently exposed in pregnancy during clinical studies and in pregnant women who use these drugs after approval.
Considerations for special populations. To date, there is insufficient data to support extrapolation of adult efficacy data to support efficacy in pediatric populations. Consequently, FDA requires sponsors to conduct two independent, well-controlled clinical trials in pediatric patients, in addition to pharmacokinetic and safety studies in the relevant pediatric groups, even for antidepressant drugs that have already been approved for adults.
To improve generalizability, the agency also provides guidance on populations, such as geriatric patients and patients with hepatitis C, who should not be excluded from clinical trials.
Regulatory framework in the EU
Current guidance
Revision 2 of the EMA Guideline on clinical investigation of medicinal products in the treatment of depression describes short-term trials for evaluating acute effect and long-term trials for demonstrating either that the acute effect is maintained during an episode or that the drug prevents new episodes.
- Acute phase. For short-term, acute phase trials, the EMA expects randomized, double-blind, placebo controlled, parallel group studies comparing change in the primary endpoint. Inclusion of a well-accepted standard as an active control is strongly recommended. For pivotal studies, three-arm or multi-arm study designs are strongly recommended.
To be considered robust and clinically meaningful, the study must yield statistically significant results and incorporate analyses of response/remission to adequately assess clinical relevance. The guidance also confirms the need to monitor the degree of suicidal thoughts and behavior and their change with antidepressant therapy using validated instruments. - Continuation phase. Revision 2 states that it must be shown that initial response to treatment is maintained in at least one study. For authorization in the EU, a randomized withdrawal study should be conducted to demonstrate that the short-term effect continues throughout the index episode.
- Maintenance phase. Similar to FDA, the EMA views maintenance as prevention of the next episode of MDD or prevention of recurrence. In Revision 2, maintenance studies are not a mandatory part of the registration package. However, given the known unreliability of studies in MDD, the EMA requires at least 2 pivotal studies.
Revised draft guidance
EU guideline has been revised to reflect the latest advances and innovations in the field of research and development for MDD, including the emergence of new therapies and the need to foster more personalized treatments. In September 2023, the EMA released a draft Revision 3 of their Guideline on clinical investigation of medicinal products in the treatment of depression. This draft guideline reiterates the EMA’s position that, in addition to incorporating rates of response/remission to adequately assess clinical relevance, development of a medicinal product for the treatment of MDD requires demonstration that the initial response to treatment is maintained in at least one study following an adequate design.
Revision 3 proposes numerous changes, including:
- Recommendation for a relapse prevention study
- Removal of the requirement to include an active comparator
- Change in the definition of treatment-resistant depression (TRD)
- Addition of a requirement to conduct a specific, dedicated study to demonstrate cognitive aspects if seeking a separate claim for effect on cognitive function
- Updates to draw attention to potential safety concerns in special populations and antidepressants with new mechanisms of action
Summary
North America dominates the antidepressant drug market, and most developers first target approval in the US before seeking approval in other regions that may have different regulatory requirements. Developers seeking to expand outside of the US should proactively plan for that expansion through early engagement with regulators for feedback on proposed study designs. Developing a well thought out plan for both acute studies and maintenance studies, if needed, allows sponsors to better understand the timelines, cost, and resources associated with bringing an investigative antidepressant drug to market.
To learn more about designing and operationalizing maintenance studies in MDD, read our guide.
[1] European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of depression: Draft, September 2023. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-investigation-medicinal-products-treatment-depression-revision-3_en.pdf.
[2] US Food and Drug Administration. Major Depressive Disorder: Developing Drugs for Treatment, June 2018. Available at https://www.fda.gov/media/113988/download.