Challenges and opportunities for Orphan Drug Designation

By Mo Heidaran
Vice President, Technical
Parexel International

By Steve Winitsky
Vice President, Technical
Parexel International

Rare diseases affect more than 30 million Americans. According to the FDA, a rare disease is defined as a disease or condition that has a prevalence of fewer than 200,000 affected individuals in the United States. An orphan product is a drug, biologic, device or medical food used for the prevention, diagnosis, or treatment of a rare disease.

The Orphan Drug Act enables the FDA to designate a drug or biologic agent as a therapy for a rare disease or condition. This Act, signed into law in 1983, promotes product development for rare conditions by providing incentives to developers of rare disease therapeutics.

If the prevalence in the United States is higher than 200,000 affected individuals, a product can still receive orphan designation for a particular rare disease indication. The sponsor, however, must demonstrate that the drug shows promise for the prevention, diagnosis, or treatment of a rare disease or condition, and that they would be unable to recoup the costs of clinical development.

The Orphan Drug Designation (ODD) process begins when an applicant submits an ODD request to the FDA. ODD applications are reviewed by the Office of Orphan Drug Products (OOPD), a centralized Office at the Agency that determines whether products qualify for ODD. The major criteria for designation are the size of the patient population (fewer than 200,000 affected individuals in the US) and adequate demonstration of the drug’s promise in prevention, diagnosis and/or treatment of a rare disease or condition. Evidence of the drug’s potential benefit can come from preclinical and/or clinical data. While an ODD application can be submitted to the Agency at any time during development, it is typically submitted prior to initial Investigational New Drug application.

Sponsors of drugs or biologic products intended to treat rare diseases have the opportunity to take advantage of three notable incentives provided by the Orphan Drug Act and the Food, Drug, and Cosmetic Act (the FD&C Act): PREA Orphan Exemption, financial incentives for orphan designated products, and the Rare Pediatric Disease Priority Review Voucher Program.

PREA Orphan Exemption

In 2003, the Pediatric Research Equity Act (PREA) was enacted, requiring certain marketing applications for new active ingredients, new indications, new dose forms, new dosing regimens, or new routes of administration to contain an assessment of safety and effectiveness for the proposed indications in all relevant pediatric subpopulations. The FD&C Act requires companies to assess the safety and effectiveness of certain products in pediatric patients but contains a statutory exception from the requirement to conduct pediatric studies under PREA for certain drugs with orphan designation. Under this exemption, PREA does not apply to any application for a drug for an indication for which orphan designation has been granted when the application would otherwise trigger PREA (i.e., because the application contains a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration).

Financial Incentives

There are several notable financial incentives available for sponsors of orphan designated products. These include a tax credit to cover 25 percent of clinical research costs, a waiver of the PDUFA marketing application fees, and eligibility for seven years of marketing exclusivity for the first orphan designated drug that’s approved for a given indication. Additionally, OOPD can issue grants to cover development costs.

Rare Pediatric Disease Priority Review Voucher Program

A sponsor that receives an approval for a drug or biologic under the Rare Pediatric Disease Priority Review Voucher Program can redeem the rare pediatric disease priority review voucher for priority review of a future marketing application for a different product, or they can sell the voucher to another sponsor. In a recent draft guidance, the FDA outlines the process for requesting such designations and vouchers, sponsor responsibilities upon approval of a rare pediatric disease product application, and the parameters for using and transferring a rare pediatric disease priority review voucher.

FDA’s interpretation of sameness:

Due to orphan drug exclusivity considerations, sponsors often ask whether it’s worthwhile to submit an ODD request when there’s already a closely related approved product that already received ODD for a given indication. The main consideration for this type of situation is whether the investigational product is sufficiently different from the approved orphan designated product. For cell and gene therapy products, this has not been a big issue, to date, given the small number of approved products. But, in light of the substantial expected increase in the number of future approvals for cell and gene therapies, FDA recently published a draft guidance titled, “Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations” that discusses the concept of sameness, as it applies to gene therapy products. If the indications and products are the same, to be awarded ODD, the second applicant is required to provide a plausible hypothesis of clinical superiority to the approved orphan designated. Under this scenario, when it comes time for approval, the second sponsor would be required to demonstrate clinical superiority over the marketed orphan product to receive FDA approval if the first product still has orphan exclusivity. However, if the two products are considered by FDA to be different, then the clinical superiority requirements are waived.

Below are three examples taken from the above-mentioned FDA guidance document:

“If two gene therapy products express different transgenes (e.g., transgenes that encode different enzymes for treatment of the same rare disease), and have or use different vectors, FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features.
• If two gene therapy products express different transgenes, FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features, regardless of whether they have or use the same vector.
• If two gene therapy products have or use vectors from a different viral class (e.g., gammaretrovirus vs. adeno-associated virus (AAV)), FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features, even if they express the same transgene (e.g., a transgene that encodes the same enzyme for treatment of the same rare disease). FDA intends to make the determination of whether two vectors from the same viral class (e.g., adeno-associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5)) are the same or different on a case-by-case basis.”

On the surface, the overall implications of this guidance document regarding the criteria for establishing sameness seems quite straightforward — i.e., for cell and gene therapy products, the indications for two products can be identical, but general changes in the drug product (i.e., different vectors, different transgenes, different modes of delivery, different cell types) can lead to FDA considering the two products to not be the same. Accordingly, a second company that is developing a biologic product would not be required to demonstrate superiority over an orphan designated biologic that’s already approved for a given indication. However, the guidance doesn’t contain sufficiently detailed information to be able to predict with certainty how FDA would consider the sameness issue for an individual gene therapy product, let alone for cell therapy products. It seems likely that FDA will further clarify sameness issues for cell and gene therapies over time, since there are clear implications for exclusivity, as two companies could potentially receive exclusivity for the same indication based on the products being considered as different entities.

Preparing Orphan Drug Designation applications

Sponsors who are developing rare diseases products must take careful steps in preparing their initial ODD application, since it can be challenging to change the narrative once FDA decides not to grant ODD. Consider engaging partners who have extensive experience with authoring ODD applications to take advantage of knowledge that they gained from prior interactions with OOPD/FDA. Experienced partners can also help to address concerns raised by FDA after initial review of an ODD application. With the right preparation, sponsors can best position themselves be awarded ODD. Keep in mind that reaping the full benefits of ODD can be a win-win for patients and the company, since an approved rare disease therapeutic that meets unmet needs for patients may have gone undeveloped without the financial feasibility afforded by ODD. 

 

References:

https://www.fda.gov/industry/developing-products-rare-diseases-conditions/designating-orphan-product-drugs-and-biological-products
https://www.fda.gov/files/about%20fda/published/Clarification-of-Orphan-Designation-of-Drugs-and–Biologics-for-Pediatric-Subpopulations-of-Common-Diseases.pdf
https://www.fda.gov/media/100571/download
https://www.fda.gov/news-events/fda-brief/fda-brief-fda-updates-draft-guidance-rare-pediatric-disease-priority-review-voucher-program
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/interpreting-sameness-gene-therapy-products-under-orphan-drug-regulations