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Orphan Exclusivity for ‘Same Drug’: What Has Changed Since FDARA 2017/ PDUFA VI?

Last month the US District Court for the District of Columbia ordered the FDA to grant Eagle Pharmaceuticals, Inc., 7-years of marketing exclusivity for Bendeka® (bendamustine). This was the second loss for the FDA regarding orphan exclusivity for the ‘same drug’ that is not clinically superior to the approved product, but it is likely among the last.

As part of the FDA Reauthorization Act of 2017 (FDARA), the statute was amended to prevent the apparent ‘loophole’ that allowed the same drug to get orphan exclusivity more than once without being clinically superior to the existing product. More on this later.

We took this opportunity to review the significant changes enacted by FDARA that are relevant for orphan products.


The current user fees system provides funds for the FDA’s review of medical products (human drugs and devices). The user fee programs for drugs, devices, generic drugs, and biosimilars require reauthorization by Congress every 5 years.

FDARA 2017 reauthorized the programs until 2022 and also included titles that amend some aspects of the law including orphan drugs. The changes for orphan programs are summarized below.

Some Orphan Cancer Drugs No Longer Exempt From PREA

The Pediatric Research Equity Act (PREA) requires NDAs for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment. PREA was enacted to compel Sponsors to conduct pediatric studies, which were often neglected historically. The assessment requires submission of a Pediatric Study Plan involving a commitment to conduct pediatric studies for the product, or a valid reason why the studies should be deferred or waived.

According to an FDA Briefing Document on ‘Relevant Molecular Targets in Pediatric Cancers: Applicability to Pediatric Therapeutic Investigations Required Under FDARA 2017,’ PREA has not been an effective mechanism to support the development of drugs for pediatric cancers.

The problem was that many pediatric cancer drugs were typically developed secondarily to products approved for adult indications, and were frequently exempt from PREA. This was because the approved indication might be rare in pediatric populations, or might be designated as orphan in all age groups.

The Briefing Document explains that the effect of FDARA on oncology products is to amend the requirement for a pediatric assessment under PREA from the basis of clinical indication to molecular mechanism of action.

In the past, all products designated as orphan were exempt from meeting the requirements of PREA. Title 5 of FDARA amends the Federal Food, Drug, and Cosmetics (FD&C) Act Section 505B (a)(3) such that a product being approved for an adult cancer that is directed against a molecular target that the Secretary of Health and Human Services (referred to as the Secretary from here on) determines is “substantially relevant to the growth or progression of a pediatric cancer” must comply with PREA.

As part of Title 5, the FDA and the National Cancer Institute were required to conduct a meeting to solicit feedback from physicians and researchers, patients, and other stakeholders to seek input for a guidance on determining the molecular targets considered to be substantially relevant to the growth or progression of pediatric cancers.

Two open public meetings have been held to date. The first meeting on 20 April 2018 was to review a candidate list of molecular targets. The second meeting on 20 June 2018 with the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee provided a final review of the list of targets and discussed processes for prioritization of targets and for international collaboration.

A summary of an earlier meeting on 20 February 2018 and sponsored by the Friends of Cancer Research has been published in the Pink Sheet, and reposted by KidsVCancer. The summary contains useful discussion on the FDA’s interpretations of the statute and plans for implementation.

According to the FDA’s presentation at the open public meeting, the candidate target list includes gene abnormalities, cell lineage markers, tumor microenvironment/immune molecules and an ‘other’ category. Waivers for products targeting molecules that are expected to cause serious developmental toxicity, such as vascular endothelial growth factor (VEGF), or for second and third in-class products are likely. Products targeting small study populations are likely to be assigned limited study requirements and/or innovative study designs.

An intentionally ‘fluid and inclusive’ list of relevant and non-relevant targets is to be published on the FDAs website within the next month and updated semi-annually. The Guidance is not due to be issued until August of 2019.

Pediatric Labeling Carve-outs Expanded to Orphan Exclusivity

Until now, sponsors of generic (ANDA) products but not 505(b)(2) NDAs could get their drug products approved prior to the expiration of patents and marketing exclusivity related to pediatric use. This is achieved via omitting the pediatric information from the labeling, known as a labeling ‘carve-out.’ A disclaimer regarding the omitted information is included in the labeling. The discrepancy between the pathways was likely an unintended oversight. The carve-out provision can now be applied to products approved via the 505(b)(2) pathway, as well as generics.

Further, the categories of such exclusivity that are eligible for such a carve-out has been expanded from pediatric only to also include orphan drugs, and qualified infectious disease products (FFDCA Section 505A(o)).

This means it is now possible to get some products approved via the 505(b)(2) or 505(j) (generic) pathways before pediatric orphan exclusivity for the reference/listed drug has expired.

Same Drug: Requirement for Clinical Superiority

Two decided and one pending court case later, FDARA returns us to the FDA’s interpretation of the statute for orphan drug regulations. The FDA interpreted the orphan drug statute as stated in the Code of Federal Regulations (CFR), including the condition described in 21CFR §316.34(c): “If a drug is otherwise the same drug as a previously approved drug for the same use or indication, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to demonstrate upon approval that the drug is clinically superior to the previously approved drug.” [Definitions of “clinically superior” and “same drug” are provided in 21CFR §316.3(b)(3) and 21CFR §316.3(b)(14), respectively.]

Essentially, the process involved the Sponsor presenting “a plausible hypothesis that its drug may be clinically superior to the first drug” at the time that orphan designation is requested. Then at the time of NDA review/approval, in accordance with 21CFR §316.34(c), the Sponsor must demonstrate the clinical superiority of its drug compared to the first drug in order to be eligible for 7 years of marketing exclusivity.

The problem was that although the FDA required proof that the drug was clinically superior at the time of approval, the statute didn’t say that. So Depomed, Inc., successfully sued the FDA in 2012 to receive exclusivity absent a demonstration of clinical superiority, followed by Eagle Pharmaceuticals, Inc., in 2018. One more suit from United Therapeutics Corporation is still pending.

The changes to FDARA Section 607(c)(1) amend Section 527 of the FFDCA to state that “If a sponsor of a drug that is designated under section 526 and is otherwise the same, as determined by the Secretary, as an already approved or licensed drug is seeking exclusive approval or exclusive licensure described in subsection (a) for the same rare disease or condition as the already approved drug, the Secretary shall require such sponsor, as a condition of such exclusive approval or licensure, to demonstrate that such drug is clinically superior to any already approved or licensed drug that is the same drug.”

This means a drug approved after 2017 will need to demonstrate clinical superiority over approved products that contain the same drug for the same indication at NDA approval to obtain the 7-years orphan drug exclusivity.

Clinically superior is defined in FDARA Section 607(c)(2) as “a significant therapeutic advantage over and above an already approved or licensed drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.

Publication of Clinical Superiority Cases

FDARA Section 607(e)(2) requires that the FDA publish clinical superiority findings from 2017 onward. The FDA has established such a page on its website and it currently lists only one such case (BLA 761060; Mylotarg (gemtuzumab ozogamicin).

In total, there are 4 other biologics and 11 drugs that have been found to be clinically superior to approved products prior to 2017.

Of these products, only one has been found to be superior on the basis of improved efficacy, and 8 on the basis of improved safety. The remaining 7 products were found to be superior based on a major contribution to patient care.

Contact us to discuss your unique orphan product. Premier Consulting’s regulatory and rare disease experts look forward to working with you.


Angela Drew, PhD
Product Ideation Consultant

William Stoltman, JD
Senior Director of Quality Assurance / Compliance