The regulations developed by the FDA for implementing the Orphan Drug Act contain a number of features that are intended to maximize benefits to the orphan disease patient population, but which pose a number of competitive strategic issues for sponsors. These include the idea of product sameness, clinical superiority, and a need for speed in product development.
Sameness – In an effort to spur innovation, the Office of Orphan Products Development has chosen to determine the sameness of similar orphan products based on the portion of the drug substance molecule responsible for its pharmacological activity. Whereas modest structural modifications or formulation changes can cause drugs to be considered unique drugs in the eyes of the Office of New Drugs, the Office of Orphan Products Development focuses on differentiating orphan drugs based on the active moiety in the product. This feature of the regulations limits the use of orphan benefits for variations on a product that provide no distinguishable advantage for the patients. Thus, products requiring separate NDAs for approval but containing the same active moiety may be in competition for orphan product benefits. Once a product has been approved for marketing for a specific orphan indication, subsequent drugs with the same active moiety may be prevented from receiving orphan drug benefits or approval for the same indication (if the period of orphan exclusivity on the first-approved drug has not expired) unless they can be demonstrated to be clinically superior to the first-approved drug.
Clinical superiority – The need for demonstrating clinical superiority when drugs with the same active moiety are competing for the same orphan indication is a feature of the Orphan Drug Act designed to foster development of products that genuinely improve patient care. Once a product has received approval for an orphan indication, products with a similar active moiety would need to demonstrate superiority in one of the following ways in order to receive approval and orphan benefits for the same orphan indication: superior efficacy, superior safety, or a major improvement in patient care. In the latter case, the improvement in patient care must be accompanied by demonstration of no loss in efficacy or safety compared to the already approved drug. In the case where a drug has already been approved for an orphan indication, subsequent drugs with the same active moiety may be granted an orphan designation on the basis of a plausible hypothesis of clinical superiority. However, the recent proposed amendments to the Orphan Drug Act clarify that in order to obtain approval for the same indication and orphan benefits, clinical superiority to the approved drug needs to be demonstrated. While it is not yet clear whether this means head-to-head clinical trials, there is an added burden beyond merely showing efficacy and safety for the orphan disease. Thus, sponsors may find that after completing successful clinical trials when compared to placebo, orphan benefits may be denied unless superiority to the approved comparator is demonstrated.
Race for approval – A less widely recognized feature of the orphan drug approval process is the fact that multiple sponsors with products containing the same active moiety may simultaneously hold orphan designations for the same orphan indication. However, only the first drug approved for the orphan indication receives orphan benefits. This is considered to be beneficial to patients because the competition for the approval-contingent orphan benefits will spur the pace of orphan drug development. For sponsors, it adds a level of uncertainty to the orphan process. A sponsor may hold an orphan designation and make considerable progress toward an approval but the prior approval of a drug with the same active moiety for the same indication may block the availability of approval and orphan benefits that were being sought. The prohibition on orphan benefits for the second drug occurs irrespective of the order in which the two drugs obtained orphan designation status. This raises questions for sponsors regarding the timing of seeking an orphan designation since this information is made public. Sponsors need to balance whether it is more beneficial to have an orphan designation early in development in order to generate interest in a product with whether obtaining an orphan designation may signal to competitors with a product with the same active moiety that orphan benefits are available for the first to obtain approval.
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