FDA Publishes Draft Guidance- Rare Diseases: Common Issues in Drug Development

January 31, 2019 Becky Hurt

Authored By: Brad Gillespie, Principal Consultant, PAREXEL® Consulting

The Orphan Drug Act defines a rare disease in two ways: (1) a pathology impacting less than 200,000 Americans or (2) a disease requiring a drug for treatment or prevention that is not expected to generate U.S. sales adequate to recover the cost of development1.

Although it is estimated that there are more than 7,000 orphan diseases, between the passage of the Orphan Drug Act (1983) and 2017, only 667 orphan drugs have been approved, with an acceleration of approvals between 2014 and 20172. While this shows progress, additional work remains.

FDA issued a draft guidance document in January 2019 intended to assist sponsors in the development of orphan drugs3 (orphans). While the need to fully document the safety and efficacy is the same as for all drugs, a variety of obstacles often complicate this process in the case of orphans. This guidance document is largely focused on strategies to facilitate the conduct of more efficient and ultimately more successful development programs. Key clinical considerations are discussed, below.

  • Efficacy: To obtain marketing authorization for a drug, it is required to generate substantial evidence that the drug will achieve its claimed effect in the target population.

Substantial evidence is generally obtained through the conduct of adequate and well controlled clinical trials designed to distinguish the effect of a candidate drug from other influential factors, including natural disease course and/or the placebo effect. In the case of clinical trials investigating drugs for rare disease, ethical considerations often complicate the use of a comparator group. One approach often employed is to use historical disease data in lieu of an active control. The absence of a well-defined control group, though, often handicaps the interpretation of resultant clinical data. In many cases, such failures can lead to an unsuccessful development strategy. Nonetheless, there are tools available to support superior clinical development programs for orphans:

  • Natural History Studies: A well-designed natural history study, initiated in the early stages of drug development, can create the foundations required for a successful orphan drug development program and if properly conducted, may serve as an external control group for future interventional trials.

  • Well-Defined Clinical Manifestations: Although some diseases lead to a variety of clinical outcomes, it is critical to identify those that may be of greater significance or are more responsive to pharmacological intervention. Generally, a focus on clinical manifestations that are closely linked to the pathology of disease and/or linked to the target drug’s mechanism of action are more likely to lead to clinical benefit.

  • Predictive Biomarkers: In some cases, biomarkers may be validated that are able to indicate the impact of a drug on an orphan disease’s pathophysiologic process. Such biomarkers can play an especially crucial role in establishing a drug’s proof of concept or dose ranging. Biomarkers may also be useful to support adaptive clinical study designs.

  • Safety: Obtaining FDA approval to market any drug requires the characterization of its safety profile in a reasonable number of patients, dosed over a reasonable duration of time.

FDA is usually able to view the descriptive term “reasonable” through the filter of orphans, and the challenges inherent to their development, to include a limited number of patients. This flexibility may be illustrated by the lack of regulations defining “evidence of safety.” Instead, FDA estimates the safety of each drug through analyses weighing the benefit of a drug against its potential risk of use. This approach allows the employment of scientific and regulatory judgement against the backdrop of the challenges of treating each disease.

Best practices require early and frequent discussions with regulatory bodies to discuss strategies to maximize the quantity and quality of safety data. Tactics to consider include:

  • Natural History Studies can facilitate the identification of disease-specific challenges to patient accrual and retention, as well as helping to distinguish drug-related adverse findings from disease manifestations.

  • Trial Eligibility is critical, balancing the efficient enrollment of patients against the need to properly represent the intended patient population. In some cases, enrichment strategies may be effective tools to decrease non-drug related variability and thus, better demonstrate a treatment effect.

  • Proper Dose Selection is crucial to demonstrate a drug’s potential efficacy (adequate dose) while minimizing patient discontinuations due to dose-related toxicities (excessive dose).

  • A Comparator Arm (no treatment, placebo or active control) should be selected based on ethical and practical considerations to optimize the interpretation of adverse events.

  • Auxiliary Safety Cohorts, including parallel safety arms (designed to enroll patients who may not meet all eligibility criteria for main study), expanded access and other sources of relevant data (for example trials using the same drug for other indications) can provide useful safety data to augment the pre-market safety database.

Frequent regulatory communication during the accrual of safety data may facilitate the submission of a complete marketing application and can help prevent approval delay.

  • Additional Considerations:

    • Expedited Pathways- Many orphan diseases are serious, life-threatening and represent unmet medical needs. As a result, orphan drugs are often eligible for consideration of FDA Expedited Approval programs.

    • Adaptive trials- The ability to increase a sample size or discontinue a dose arm that is not beneficial or has undesirable side effects are powerful tools that can increase the efficiency of clinical trials for orphan drugs.

In summary, publication of this guidance provides assurance that FDA is serious about supporting the development of drugs to counter rare diseases. In addition to describing useful strategies, a central theme of this document is illustrating the benefit of maintaining early and frequent communication with the Agency. PAREXEL is acutely aware of the challenges associated with orphan drugs. While the foundation of PAREXEL is broad and deep internal expertise in all phases of orphan drug development, it has also gained extensive Regulatory Affairs experience, through the representation of a variety of orphan drug clients in global regulatory interactions.

1 FDA.gov. How to apply for Orphan Product Designation (ucm364750.htm)

2 Miller & Lanthier (2018). Investigating the landscape of US orphan product approvals. Orphanet J Rare Dis. 2018; 13: 183.

3 FDA.gov. Guidance Compliance Regulatory Information (ucm629579.pdf)

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