Clinical Researcher—June 2024 (Volume 38, Issue 3)
PRESCRIPTIONS FOR BUSINESS
Bradley D. Vince, DO; Sheldon H. Preskorn, MD
The most common pathway for developing a new molecular entity (NME) for approval by the U.S. Food and Drug Administration (FDA) is a well-defined process.
The first step is defining a substantive unmet medical need such as COVID-19 or a long-recognized condition like major depressive disorder (MDD). Approximately 30% to 35% of patients with MDD have a form that is not responsive to most currently available oral antidepressants.
The next step is for the biopharmaceutical sponsor to have reason to believe it has discovered a new treatment that may be a significant improvement over existing therapies.
The third step is to apply for patent approval, but in such a way that the filing is recognized by the government even though additional research must be conducted before the patent can be approved. This approach provides the sponsor with protection while the patent is being finalized and allows them additional time to work on the drug without burning through the patent exclusivity.
Preclinical studies must often be conducted before the new treatment can be given to human subjects. These preclinical studies may include in vitro (e.g., test tube) or animal research.
If these studies sufficiently demonstrate to the FDA that the investigational product can safely be given to study volunteers, then human testing can begin. It generally, but not always, involves three phases, aptly named Phases I, II, and III.
Phase by Phase
Phase I is usually conducted in healthy volunteers (i.e., they do not have the disease of interest). These studies help determine the pharmacokinetics or concentration of the drug in the body for the doses administered, as well as the safety of the drug in healthy volunteers. However, these studies do not always predict the safety of the drug in patients with the disease of interest. The reason is that participants with the medical condition may be more or less tolerant of the drug, so that different doses could be required.
Phase II trials are generally the initial studies that determine whether the drug has efficacy in the target illness. Everything from preclinical to Phase II studies is termed the “learning phase” of the drug development process.
Phase III trials are large-scale, multisite studies that either confirm what was learned in the early-phase work or demonstrate problems in translating the earlier findings regarding tolerability, safety, or efficacy. Depending on the degree of any issues discovered in Phase III, the drug may advance into regulatory review and possible approval for commercialization, more development work may be needed, or the drug’s development may be halted.
Each step in the above process costs more money and consumes patent life. Both may seriously impair the sponsor’s ability to continue developing the drug. This background is critical to understanding why establishing whether the investigational product is likely to have efficacy as early as possible is so important, as discussed in the rest of this article.
Aiming for Efficacy
There are multiple approaches to establishing a signal for earlier efficacy. Considering the sponsor’s need for volunteer study subjects, many clinical research sites have potential participants in their databases available with known inadequate response to current therapy. These sites can enroll such eligible patients quickly. Further, even a small number of enrolled subjects can test the efficacy of a mechanistically new treatment. The study design should minimize placebo response without compromising the detection of an efficacy signal.
One of the authors of this article conducted a study for an NMDA antagonist with only 15 subjects in each of the two arms of the study: the investigational treatment versus the placebo control.{1,2} This study provided a blueprint for the successful development of intranasal esketamine for patients with a form of MDD not responsive to biogenic amines (essentially all currently oral antidepressants).
The success of a new drug is ultimately judged by its ability to meet the predefined primary endpoint. In the context of clinical trials for depression treatments, early efficacy refers to evidence indicating that an investigational product shows promise in improving symptoms. This preliminary assessment of efficacy is crucial for gauging the potential effectiveness of the treatment before proceeding to the later stages of the drug development process.
Researchers use rating scales, like the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Depression-17, to assess how patients respond to the treatment. This endpoint is a specific, measurable outcome chosen by clinicians to determine the treatment’s antidepressant effectiveness. Clinical trials typically rely on the MADRS to obtain primary endpoint data in depression studies. The MADRS asks research participants questions about their mood, sleep, appetite, and concentration, providing a standardized assessment of core depression symptoms.
Rater variability, in which different clinicians administering the MADRS score the same depression symptoms differently, can significantly compromise the quality of collected data. To control this risk, psychiatric trial clinicians must first undergo extensive training to ensure consistent and reliable scoring of the various ratings scales among other raters at their own organization and at participating research sites.
Another approach is to use biomarkers as a surrogate for efficacy. For example, all serotonin transport (or re-uptake) inhibitors must inhibit this transporter by 70% to have an antidepressant response.{2} This biomarker has been successfully used to determine the dose needed in depression efficacy clinical trials.
Further Considerations
Beyond these examples, there are other biomarkers as well as other study designs. These can be used to test whether an investigational drug in early-phase trials will likely be able to show efficacy in the large-scale, multisite Phase III trials needed to obtain regulatory approval.
The neurobiology of underlying MDD has become better defined, resulting in the availability of more biomarkers as well as the potential for earlier efficacy signals. These studies require knowledge of the biology of MDD, the biomarkers that can be used as signals for efficacy, the optimal study design, and the availability of a study population that meets the protocol-specified inclusion and exclusion criteria.
Together with sponsors and sites, we can facilitate the successful development of new and effective treatments for MDD in a time- and cost-efficient way.
References
- Preskorn SH, Baker B, et al. 2008. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-mythyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28(6):631–7. PMID:19011431. https://pubmed.ncbi.nlm.nih.gov/19011431/
- Preskorn SH. 2012. The use of biomarkers in psychiatric research: how serotonin transporter occupancy explains the dose-response curves of SSRIs. J Psychiatric Practice 18(1):38–45. PMID:22261982. https://pubmed.ncbi.nlm.nih.gov/22261982/
Bradley D. Vince, DO, is CEO and Chief Medical Officer at Dr. Vince Clinical Research. With 25 years of experience in the clinical research industry, he has served as an investigator in more than 700 clinical trials and authored numerous scientific publications. He also has deep industry experience in government-funded studies, including acting as principal investigator for various NIH and FDA funded trials.
Sheldon H. Preskorn, MD, is Senior Vice President, Neuroscience, at Dr. Vince Clinical Research. He is an academic physician, psychiatrist, clinical researcher, neuropsychopharmacologist, and medical educator. His publications include more than 500 medical papers, books, and book chapters. Further, he has been cited in medical literature more than 18,000 times.
