For the vast majority of therapies, FDA requires a clear demonstration of safety and effectiveness in humans before marketing approval is granted. However, while an adequate demonstration of safety in humans is always expected, premarket efficacy evaluations are not always possible or appropriate. Such would be the case for drugs intended to treat individuals exposed to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. Indeed, acquiring such efficacy data would necessitate either deliberately exposing subjects to the toxic substance, which is clearly unethical, or doing field trials.
While field trials can be a great way (or the only way) to gather human efficacy data for these drugs, such trials are often not feasible since they would depend upon events that are by nature rather rare, such as a disease outbreak (e.g., the Ebola outbreak in West Africa), an act of war or terror (e.g., biological, chemical, or nuclear attack), or some other opportunistic exposure event (e.g., industrial chemical or radiological spill).
A Path Forward
To overcome these obstacles, FDA has developed an alternative pathway that utilizes appropriate animal models to demonstrate primary evidence of effectiveness for these types of therapies rather than requiring human efficacy studies for approval. This pathway is known as the “Animal Rule” (21 CFR 314.600 through 314.650 for drugs and 601.90 through 601.95 for biologics).
To qualify for approval under this rule, all four of the following criteria must be met:
- There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
- The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;
- The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and
- The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.
One thing to keep in mind, however, is that while human efficacy trials are not required for approval under the Animal Rule, this does not eliminate the need for post-marketing evaluation. According to 21 CFR 314.610 (drugs) and 21 CFR 601.91 (biologics), the Sponsor must conduct post-marketing studies, such as field studies, to verify and describe the product’s clinical benefit and to assess its safety when used as indicated when such studies are feasible (i.e., when an exigency arises) and ethical. Because of this, Sponsors are required to include a plan or approach to post-marketing study commitments in their marketing application (i.e., NDA or BLA).
Beyond the ability to use animal studies to demonstrate primary evidence of effectiveness for the marketing application, products developed under the Animal Rule may enjoy additional regulatory benefits. For example, protocols for these animal efficacy studies are eligible to receive a special protocol assessment (SPA) from FDA, which allows Sponsors to discuss critical study parameters with FDA upfront to ensure that they meet scientific and regulatory requirements prior to study initiation. As part of this, FDA will issue a formal letter that includes an assessment of the protocol, their agreement or non-agreement with the Sponsor’s proposal, and answers to additional questions from the Sponsor about the protocol design. While an SPA does not guarantee that the trial results will be adequate to support a marketing application, it is intended to improve the study design and put the Sponsor in the best possible position for success.
In addition to SPA eligibility, products developed under the Animal Rule may quality for other federal programs that carry with them a number of substantial benefits. For example, these products may be eligible for Fast Track designation and Priority Review (discussed in a previous post), which can expedite product development and marketing application review and potentially get these products to market more rapidly.
These products may also qualify for Orphan Product designation (discussed in a previous post), which provides among its many benefits an exemption from Prescription Drug User Fee Act (PDUFA) fees (currently over $2 million for standard NDAs and BLAs) and extended marketing exclusivity (7 years vs. 5 years for a non-orphan drug).
For products targeting a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance where human efficacy studies are not feasible or ethical, the Animal Rule provides a mechanism whereby marketing approval is possible using data from primary efficacy studies in animals rather than in humans. Development under the Animal Rule is a complex process, but offers a number of benefits that can expedite development and time to market for these products.