Industry Seeks More Specifics on FDA's Flexibility With Orphan Drug Guidance

Regulatory NewsRegulatory News
| 04 November 2015 | By Michael Mezher 

Two industry associations and a rare disease patient advocacy group say they want the US Food and Drug Administration (FDA) to clarify its "regulatory flexibility" with orphan drug reviews.

Challenges in Orphan Drug Development

In August, FDA released a draft guidance intended to address the most common issues faced by drugmakers developing treatments for rare diseases.

The guidance notes that FDA's "regulations provide flexibility in applying regulatory standards" and that "this flexibility extends from early phases of development to design of adequate and well-controlled clinical studies required to demonstrate safety and effectiveness to support marketing approval."

FDA also acknowledges that "study approaches used in common diseases are not always feasible for rare diseases," due to small patient populations.


FDA has not yet released all the comments on the draft guidance, but Focus obtained comments from the National Organization for Rare Disorders (NORD), Pharmaceutical Research and Manufacturers of America (PhRMA) and Biotechnology Industry Organization (BIO).

While all three organizations expressed their support for the guidance, they each stressed the importance of FDA flexibility in evaluating orphan drugs, with PhRMA and BIO calling for the agency to be more specific on the use natural history studies, innovative trial designs and endpoint development.

In its comments, NORD requested FDA increase its efforts to develop additional guidance for specific rare diseases and emphasized the need for patient input in the drug development process.

Nonclinical Studies

While FDA says sponsors should typically conduct nonclinical studies to determine a drug's safety before human testing, the agency says "under limited circumstances, clinical studies can proceed in the absence of standard toxicology studies … for serious or life-threatening diseases."

In their comments, both PhRMA and BIO ask the agency to clarify under what circumstances the agency would waive nonclinical studies, with PhRMA urging FDA to consider four-week toxicity studies in animals to support Phase I and II studies, and three-month toxicity studies to support Phase III studies. BIO also requests that FDA include its perspective on "when carcinogenicity studies are warranted," before clinical testing.

On the other hand, NORD called on FDA to "remain vigilant" in requiring toxicology data, but urged the agency to "remain open to non-animal testing methods."

Natural History Studies

In its draft guidance, FDA tells sponsors that "a well-designed natural history study may help in designing an efficient drug development program."

However, both PhRMA and BIO expressed the need for more guidance from FDA on the use of natural history studies, with PhRMA saying, "It would be helpful if FDA could provide additional guidance and specific examples of how natural history data can be used not only in the design and analysis of clinical trials, but also for product review and approval."

FDA's draft guidance seems to discourage using these studies as historical comparators, saying they are "credible only when the observed effect is large in comparison to variability in the disease course." Both PhRMA and BIO call on FDA to give more specifics in this regard, with BIO pointing out that historical controls are "particularly important for studies in rare diseases for which the use of a placebo control group might be unethical, and/or no approved therapy exists."

NORD also cautioned that conducting natural history studies for specific treatments could be burdensome for patients.

Endpoint Identification

Both PhRMA and BIO call on FDA to give more specific guidance and examples of endpoint development and validation.

All three groups supported the inclusion of patient-focused factors in endpoint identification. In the guidance, FDA states that sponsors should consider "which aspects of the disease are meaningful to the patients and might also be affected by the drug's activity."

However, NORD felt that FDA did not go far enough to "encourage … industry to include patient perspectives at the initial stage of endpoint identification."

Trial Design and Demonstrating Effectiveness

In its guidance, FDA acknowledges that studying treatments for rare diseases is "challenging, and study approaches used in common diseases are not always feasible." However, the agency does not lay out specific examples of other approaches. Instead, the guidance encourages sponsors to engage in early and frequent communication with the agency to "identify clinical trial designs that are feasible … and that will have sufficient scientific rigor."

Both PhRMA and BIO again call for FDA to provide examples of how companies can demonstrate the safety and effectiveness of products to treat rare diseases. BIO requests FDA give a "more narrowly tailored" discussion on the "application of innovative statistics (e.g., Bayesian statistics)."

PhRMA cautions that unless FDA clarifies its flexibilities, "the sponsor perception will remain that the FDA is reluctant to accept innovative adaptive trial designs."

PhRHA also calls on the agency to include a discussion on how "existing expedited programs … specifically apply to drug development programs for rare and pediatric diseases."


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