FDA Encourages Development of Rare Disease Drugs with Draft Guidance

On Monday, October 12^th, FDA issued a draft guidance regarding the role of Pre-IND Meetings in the development of drugs to treat rare diseases. The document, entitled "Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings," touches on four main issues to consider in the early phases of development and Pre-IND Meetings. These include:

• Pharmaceutical quality
• Nonclinical evaluation
• Clinical pharmacology
• Clinical development (including early phase study designs and statistical analysis plans)

Pharmaceutical Quality Considerations

During the Pre-IND Meeting for a rare disease drug development program, it is important that sponsors clearly summarize the type and amount of CMC information that will be included in their IND. Sponsors must also justify the appropriateness of the information in supporting the clinical trials being proposed. In addition to standard meeting background material, FDA recommends that sponsors "include additional detailed information to enable meaningful discussion of the specific questions posed to FDA." The draft guidance provides a list of various topics that may be appropriate based on the questions of interest. Some of these include a description of the:

• Drug substance
• Drug product
• Manufacturing processes for the drug substance and product
• Potency assay and its relationship to the mechanism of action – biologics only
• Testing strategy to characterize the drug
• Differences between the nonclinical batch(es) and the proposed clinical trial batch(es)
• Container closure systems used for long-term and in-use storage
• Proposed device delivery system and procedures
• Manufacturing facilities used to manufacture clinical lots and, if known, the proposed manufacturing facilities to be used for commercial manufacturing (if different)

Nonclinical Considerations

Nonclinical studies are used to determine whether it would be reasonably safe for the investigational drug to be tested in humans. As such, they must be completed before clinical trials can be started. The type(s) of studies required varies based on the investigational drug’s intended use, the proposed clinical trial population, and the proposed treatment regimen.

"In addition to providing the standard meeting package elements, sponsors should include the following information to support specific nonclinical questions posed to the FDA review division/office:

• The rationale for the proposed clinical indication, patient population, and clinical dosing plan.
• A description of and rationale for the proposed nonclinical plan to support the initial clinical development strategy, including the selection of appropriate animal models and appropriate species for toxicity evaluation.
• A nonclinical plan that supports the initiation of clinical studies by demonstrating the prospect of direct benefit in any planned pediatric age groups, as applicable. The plan should also include the selection of appropriate animal models and appropriate species for specific pediatric toxicity evaluation, as applicable.
• A summary (not full reports) of completed in vitro and in vivo pharmacology, proof of concept, and toxicology studies.
• A summary of relevant published information on the drug or related drugs, when available, and a summary of safety information for all components of the formulation.
• A description of how toxicities identified from nonclinical studies may be addressed in humans (e.g., modifying the exposure, clinical monitoring, stopping criteria), based on the drug’s toxicological profile and safety margins."

The draft guidance notes that "FDA may exercise flexibility in the types and amount of nonclinical data to accept to support drug development for serious and life-threatening diseases." Furthermore, during the Pre-IND Meeting, sponsors can ask the FDA about any additional nonclinical studies that may be necessary to support clinical trials as well as the timing of those studies during (as applicable).

Clinical Pharmacology Considerations

Clinical pharmacology studies serve as the link between nonclinical studies and the drug’s targeted population. These studies provide sponsors with critical information regarding a drug’s mechanism of action, pharmacokinetic and pharmacodynamic properties, potential for clinical benefit, safety profile, and dose- or exposure-response relationship.

Information from these studies can inform clinical trial design and provide supportive evidence of effectiveness. Sponsors should carefully plan and prepare for the clinical pharmacology aspects when developing a drug to treat a rare disease.

FDA recommends that sponsors "include the following information to address specific clinical pharmacology questions:"

• The drug’s known or suspected mechanism of action
• Summary of nonclinical/clinical study results regarding the drug’s pharmacokinetic and pharmacodynamic properties
• Justification of dose selection and patient selection strategy
• Detailed overview of all proposed studies
• Status of the bioanalytical method validation for all biomarkers
• Plans for conducting population pharmacokinetic, exposure-response modeling and simulation analyses, particularly for pediatric patients
• Plans for in vitro diagnostic development

Clinical Considerations

Developing drugs for rare diseases comes with many potential challenges, one of which is the small number of disease-affected individuals. Because of this limitation, it is critical for sponsors the maximize each patient’s contribution during clinical development.

"Although FDA has no specified minimum number of patients needed to establish drug safety and efficacy, the number of patients should be adequate to assess benefit and risk." While the Agency’s approval standards are the same for drugs treating rare and nonrare diseases, the broadest possible scientific judgement is used when applying the evidentiary standard in the case of rare diseases. As such, the Agency will consider the following:

1. Benefits and risks of the drug
2. Seriousness of the disease
3. If there is an unmet need

During the Pre-IND Meeting, sponsors should be prepared to discuss the following topics with the FDA:

• Description of the disease
• Description and rationale for the following: proposed clinical trial design(s), efficacy endpoints, biomarkers trial population, patient selection criteria, choice of control group, methods used to minimize bias, overview of statistical analysis plan, and statistical analysis methods
• Plans for evaluating the drug in other subgroups to determine whether trial results can be generalized to the broader disease population – only if trial population is a subgroup of the disease’s entire population
• Anticipated safety issues, plans for monitoring and mitigating such issues, and ways to augment the safety database if necessary
• Trial stopping rules and/or criteria for removing a patient from the study
• Plans for an independent data monitoring committee (DMC) to identify and respond to early safety issues
• Inclusion of patient perspectives in the drug development plan
• Extension study plans to evaluate longer term safety and durability of effect
• Considerations related to novel endpoints
• Plans for pediatric studies (as applicable)

Additional Considerations

On top of the four main areas discussed above, FDA’s draft guidance provides sponsors with a number of additional considerations. These considerations touch on a variety of topics, including:

• Expedited programs for serious conditions
• Companion diagnostics
• Orphan drug product incentives
• Pediatric studies
• Data standards and electronic submissions

Details on the Agency’s additional considerations are available in FDA’s full draft guidance. This draft guidance for comment purposes only and the Agency is asking interested individuals to submit written or electronic comments by December 17, 2018.

Are you developing a drug or biological product to treat a rare disease? Whether your product is indicated for a rare or nonrare disease, we can help you achieve successful interactions with the FDA, starting with the Pre-IND Meeting. To learn more about our services and how we can help get your product approved by the FDA, contact us today.