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Regulatory Radar: New Draft FDA Guidance Modernizes Major Depressive Disorder (MDD) Drug Development
Major depressive disorder (MDD) is a chronic illness affecting approximately 19 million individuals in the U.S. and 300 million people worldwide. Since the late ’90s, depression has been on the rise especially in younger age groups. This rise has coincided with increased suicide rates, with depression estimated to be involved in more than two-thirds of approximately 40,000 suicides annually in the U.S.
The most widely used antidepressant treatments since their introduction in the 1990s have been drugs that alter certain neurotransmitters (e.g. serotonin, norepinephrine and dopamine). The majority affect serotonin and act as selective serotonin reuptake inhibitors (SSRIs) (e.g. Prozac, Zoloft, Paxil and Celexa), or act as serotonin and norepinephrine-reuptake inhibitors (SNRIs) (e.g. Cymbalta). These currently available drugs are all oral medications intended for chronic daily use and approved for indication of MDD, or as adjunctive-therapy to other MDD treatments or for treatment-resistant depression.
The effectiveness of these drugs however has shown wide variability with only 50 to 70 percent of people responding and only a small percentage (under 30 percent) reporting full remission. The responses observed differ from partial response to certain symptoms where the effect noted appears subjective from person to person and where one antidepressant is effective for one person but not for another.
In a long overdue update, the FDA issued a new guidance for the development of therapeutics for MDD in June 2018 that replaces the previous guidance issued in 1977.
This new guidance in particular addresses the emergence of a new class of rapid-action therapeutics where the existing classes of antidepressants on the market usually take at least four to six weeks to take effect.
To address the emergence of this new class of rapid-action antidepressants (e.g. ketamine analogues – see below), the guidance recommends the division of MDD treatment indications into two phases, each with specific regulatory considerations: short-term (e.g. for treatment of a depressive episode) and maintenance (e.g. for relapse prevention).
The guidance states that an earlier primary efficacy endpoint may be considered for products thought to be effective within hours or days. In addition, it recommends that the durability of the response be assessed after the initial response, e.g. through continued observation of drug-placebo differences over time to assess durability of the effect.
With regard to study design, the guidance states that a placebo group is necessary given the high response rate observed in placebo groups making it impossible to identify a consistent drug effect that could be used as a non-inferiority margin in comparative trials. The current standard for short-term efficacy trials in MDD is randomized, double-blind, placebo-controlled, parallel designs, where substantially earlier or larger effects could be demonstrated in an active control superiority trial.
For sponsors seeking a maintenance indication, studies of at least six months in duration are recommended based on the cyclic nature of depression and time to reoccurrence. Further, the agency will typically request a post marketing commitment to conduct a double-blind randomized withdrawal trial (e.g. to assess discontinuation syndrome). These studies usually include an open-label stabilization period followed by randomization to either continued treatment or to a placebo. In addition, long-term safety assessments should be incorporated in the design of maintenance studies.
FDA also encourages to include 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. For rapid-acting antidepressants, there is interest in whether the rapid effect does in fact persist for the episode treated.
The other recommendations cover extending inclusion criteria where in the past those with a history of suicidal ideation and behavior were excluded. The guidance recommends that the study populations reflect a range of severities of MDD and a demographically-broad population, and avoid unnecessary restriction, e.g. by excluding patients with concomitant illness and concomitant therapy (except those anticipated to cause drug-drug interactions).
Given the rise in children being prescribed antidepressants, the guidance states that at present data are insufficient to extrapolate adult efficacy data to efficacy in pediatrics, based on antidepressants showing efficacy in adults frequently lacking efficacy in pediatrics. The guidance recommends two independent, well controlled trials in pediatrics in addition to pharmacokinetic and safety in relevant pediatric age groups (ages 7 to 12 and ages 13- 17). A waiver for maintenance indication may be based on positive adult maintenance studies if short-term efficacy and long-term safety have been established in pediatrics.
The identification of pharmacokinetic and pharmacodynamic profiles is critical to all types of antidepressants where rapid-acting drugs under development may have different profiles. In general, sponsors should conduct pharmacodynamic studies, such as an in vivo receptor binding or biomarker study, for all antidepressants in order to identify ideal dosing ranges, as well as conduct a minimum of one dose-finding trial utilizing a fixed-dose design testing at least three doses.
To address nonclinical safety concerns, in additional to the typical animal toxicology studies necessary, the FDA recommends that for drugs with a new mechanism of action, specific nonclinical safety studies may be needed based on mechanism specific concerns. Further, general toxicology studies should include in-depth histopathological evaluation of at least seven slices of the brain with justification for use of alternate slices to predict drug sensitivity.
Taken together, the updated guidance outlining the two phases (short-term and maintenance) should aide sponsors developing new classes of antidepressants. One example is products targeting the N-methyl-d-aspartate (NMDA) receptor that may elicit rapid antidepressant activities. This includes a nasal spray formula of esketamine (the s-stereoisomer of ketamine) which is in the late stages of clinical development by J&J for treatment-resistant depression and Rapastinel, a tetrapeptide developed as an adjunct for treatment-resistant depression by Allergan that is entering Phase III trials. Both drugs have received breakthrough designation, with esketamine receiving two breakthrough designations for treatment of patients with MDD who are at imminent suicide risk and those with treatment-resistant depression.
It remains to be seen if the short-term indication and the new class of drugs in development will display a similar wide variance in efficacy as observed for the marketed antidepressants; this updated guidance calls for a wider inclusion of subjects which could make it harder to demonstrate a consistent effect. What is needed is a better understanding of the pathology behind MDD to guide inclusion criteria based on the drug’s mechanism of action.
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