In most cases, the FDA grants orphan drugs a single seven-year exclusivity period for each designation covering a condition or disease. Once the seven years are up, drugmakers can apply for ANDA approval on generic versions of the drug - as long as they carve out any overlapping protected uses or indications from the drug label.
So, how do drugs like Merck, Sharp & Dohme’s Keytruda (pembrolizumab) get multiple, non-consecutive exclusivity periods for the same orphan indication?
Some call it a loophole, or “salami slicing.” Others agree the process is functioning exactly as Congress intended for the Orphan Drug Act. All opinions aside, a real opportunity exists that many pharmaceutical companies may not have appreciated.
When are Orphan Drugs Eligible for Multiple Exclusive Approvals?
In the October 19, 2011 Federal Register, the FDA issued a proposed rule to amend the Orphan Drug Regulations (21 CFR 316), proposing areas of improvement on orphan-drug designation and exclusivity.
In part, the proposed rule addressed the “eligibility for multiple orphan-drug exclusive approvals when a drug is designated for use in a rare disease or condition, but is then separately approved for different indication(s) or use(s) within that particular rare disease or condition;…”
According to the FDA, the language intends to convey the following:
- A drug obtains orphan-drug designation for a rare disease or condition,
- A drug obtains marketing approval (and orphan-drug exclusivity) for only select indications or uses within the rare disease or condition for which the drug was designated,
- If the sponsor subsequently obtains approval for additional (not previously approved) indications or uses of the drug within the same rare disease or condition for which the drug was designated, then
- The drug may be eligible for a new period of orphan- drug exclusivity for those new approved indications or uses without the need to re-seek designation—because these new (not previously approved) indications or uses would fall within the scope of the original designation (because the drug was designated for the rare disease or condition, not select indications or uses within that rare disease or condition).
The FDA goes on to reminds sponsors that, when it designates an orphan drug, it generally designates the drug for use by all persons with the rare disease or condition (or the orphan subset within a non-rare disease or condition) and expects that sponsors will seek marketing approval for all persons with the rare disease or condition (or the orphan subset).
But the FDA may, however, approve the drug for only select indications or uses within the rare disease or condition (or the orphan subset) because it can only approve a drug for the indications or uses for which there is adequate data and information in the marketing application to support approval.
How Orphan Exclusivity for Subsequent Indications Works
Regarding the scope of orphan-drug exclusive approval (21 CFR §316.31(b)), orphan-drug exclusive approval protects only the approved indication or use of a designated drug.
Orphan-drug exclusivity is limited to the indication(s) or use(s) for which the drug is approved for marketing, even if the orphan-drug designation for the drug is broader.
If such approval is limited to only particular indication(s) or uses(s) within the rare disease or condition for which the drug was designated, the FDA may later approve the drug for additional indication(s) or uses(s) within the rare disease or condition not protected by the exclusive approval.
If the sponsor who obtains approval for these new indication(s) or uses(s) has orphan-drug designation for the drug for the rare disease or condition, the FDA will recognize a new orphan-drug exclusive approval for these new (not previously approved) indication(s) or use(s) from the date of approval of the drug for such new indication(s) or use(s).
This application works well for the oncology arena, where drug companies develop cancer drugs to target a specific genomic mutation rather than a specific tissue type. The sponsor can pursue multiple orphan drug exclusivities, as long as the cancer type involving a specific area of the genome affects less than 200,000 patients.
For example, a drug may be designated for use in Stage IIB through IV malignant melanoma but approved for use only in patients with unresectable or metastatic melanoma, based on the data and information in the marketing application. As new data emerge, the FDA may approve the drug for additional indications or uses within the rare disease or condition for which the drug is designated (e.g., melanoma with involvement of lymph node(s) following complete resection).
The advantage to the sponsor in the above scenario is that, if the drug is later approved for additional indication(s) or use(s) within the rare disease or condition for which it is designated, the sponsor would not have to submit additional designation requests for the drug to cover these additional indication(s) or use(s)— because they would fall within the original designation.
Additional orphan-drug exclusivity may attach upon approval of these new (not previously approved) indications or uses that are within the scope of the original designation.
Why the FDA Granted Keytruda Multiple Exclusivity Periods
Consider Keytruda (pembrolizumab), an antibody delivered intravenously that targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes, thereby thwarting protection from the immune system.
First approved for medical use in 2014, Merck has exclusivity over Keytruda through:
- 03/14/2024 for Hodgkin lymphoma
- 09/22/2024 for gastric cancer, including gastroesophageal junction adenocarcinoma
- 06/13/2025 for primary mediastinal B cell lymphoma
- 11/09/2025 for hepatocellular carcinoma (HCC)
- 12/19/2025 for Merkel cell carcinoma
- 02/15/2026 for Stage IIB through IV malignant melanoma
One month ago, Keytruda received orphan drug approval for metastatic small cell lung cancer (SCLC) (exclusivity end date to be determined).
Regarding Stage IIB through IV malignant melanoma, Keytruda has orphan drug exclusivity for three separate indications:
- Indication #1: For the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. Expires 02/15/2026.
- Indication #2: Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Expires 09/04/2021.
- Indication #3: Treatment of patients with unresectable or metastatic melanoma. Expires 12/18/2022.
Some argue that allowing multiple orphan drug designations allows drug makers to take advantage of orphan drug status by getting exclusivity for separate components of the same disease.
While this is an understandable concern, remember that label carve outs by ANDA applicants and other such practices still limit obstacles to generic competition. Therefore, the availability of multiple orphan drug designations seems to provide the incentive that Congress intended to create with the Orphan Drug Act. The possibility for multiple exclusivity periods for a single Orphan indication creates an opportunity many drug companies should consider.