The US Orphan Drug Act (ODA) was passed into law in 1983, with the intention to incentivize the creation of therapies for rare diseases which would otherwise be too costly or inefficient to develop. Today, the orphan drug industry continues to grow thanks to the provision of the ODA providing lower research and development costs among other incentives . One such incentive of the ODA is providing market exclusivity for orphan drugs, which prevents the marketing approval of other therapies deemed the same as the exclusive drug or biologic for use in the same disease or condition. Products which have received Orphan Drug Designation (ODD) are awarded 7-years of exclusivity upon FDA marketing approval.
Orphan exclusivity is defined in the “Orphan Regulations” of 21 CFR 316.3(b)(12) as:
“[…] effective on the date of FDA approval as stated in the approval letter of a marketing application for a sponsor of a designated orphan drug, no approval will be given to a subsequent sponsor of the same drug for the same use or indication for 7 years, except as otherwise provided by law or in this part. A designated drug will receive orphan-drug exclusive approval only if the same drug has not already been approved for the same use or indication.” 
In short, a first-to-market orphan-designated therapy for an indication will automatically get orphan exclusivity upon marketing approval and will subsequently block any successive “same drug” therapies (second-to-market) from getting marketing approval for 7 years.
However, it is not impossible for a second-to-market therapy to overcome orphan exclusivity. According to 21 CFR 316.31(a), FDA specifies conditions in which a second-to-market therapy can still be approved:
“(1) Withdrawal of exclusive approval or revocation of orphan-drug designation by FDA under any provision of this part; or
(2) Withdrawal for any reason of the marketing application for the drug in question; or
(3) Consent by the holder of exclusive approval to permit another marketing application to gain approval; or
(4) Failure of the holder of exclusive approval to assure a sufficient quantity of the drug under section 527 of the act and §316.36.” 
While FDA may withdraw an approved marketing application with due cause, this is unlikely. Similarly, it is very rare for the sponsor of a first-to-market therapy to give consent for a second-to-market therapy to gain approval. The scenario of insufficient quantities of the first therapy is virtually unheard of, as review and approval of marketing applications (i.e., the second therapy’s application) usually takes far longer than the time required to produce sufficient quantities of the first therapy.
In addition, 21 CFR 316.34(c) directly addresses a second-to-market therapy’s ability to be approved based on clinical superiority:
“(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.” 
This method is most commonly used by sponsors of second-to-market therapies provided they demonstrate the clinical superiority of their product when compared to the first-to-market therapy. Clinical superiority is defined in 21 CFR 316.3(b)(3) as:
“(i) Greater effectiveness than an approved drug (as assessed by the effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials would be necessary; or
(ii) Greater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary; or
(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.” 
Thus, additional data or rationale supporting the hypothesis of clinical superiority must be included at the time of ODD application, with established evidence supporting the improved efficacy, safety, or major contribution to patient care provided by the second-to-market therapy upon application for marketing approval. If clinical superiority cannot be demonstrated, the marketing application for the second therapy will not be reviewed until the period of orphan exclusivity has lapsed. At that time, the second therapy may receive market approval as a non-orphan product.
If the first-to-market therapy is not approved for the entire orphan patient population with the rare disease, a subset of the population with an unmet need for treatment remains. If a second-to-market therapy then demonstrates sufficient safety and efficacy of the therapy, they may receive marketing approval and orphan exclusivity for treatment of this subset of the population, despite concurrent approval and orphan exclusivity of the first-to-market therapy.
A recent example of this strategy is the approval of Ruzurgi (amifampridine) by Jacobus Pharmaceuticals, indicated for the “treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age” . This approval was made during the ongoing orphan exclusivity period for the first-to-market drug Firdapse (amifampridine) by Catalyst Pharmaceuticals which is labeled for “the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults” . Firdapse was granted ODD for the treatment of LEMS on November 12, 2009, and approved for market on November 28, 2018, with marketing exclusivity lasting until 2025. Ruzurgi was granted ODD for the treatment LEMS on December 18, 1990, and granted marketing approval on May 6, 2019. Both products contain the same active ingredient, amifampridine, and are orphan indicated for LEMS, which would normally result in Ruzurgi being blocked from marketing approval by Firdapse. However, as Firdapse is labeled for the treatment of adults, Jacobus was able to get marketing approval for Ruzurgi for the treatment of “patients 6 to less than 17 years of age” [3, 4]. These represent two non-overlapping subsets of the LEMS patient population and allow FDA to grant marketing approval for Ruzurgi for a separate subset of LEMS with an unmet need. Further, in their tentative approval letter to Jakobus, FDA stated:
“The Orphan Drug provisions of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 360aa-360dd, provide for a grant of seven years of market exclusivity to which a period of pediatric exclusivity may attach. Orphan drug exclusivity blocks approval of any other application for the same drug for the same indication. Due to the orphan exclusivity granted to Catalyst Pharmaceuticals, Inc., for Firdapse, your application for Ruzurgi may not be finally approved for marketing under Section 505 of the Act until the period has expired.” 
FDA is clarifying Jacobus will only have orphan exclusivity for the pediatric subset of LEMS, but can apply to expand their label to include the adult population after 2025 when Catalyst’s exclusivity expires. This also implies the converse is true, and Catalyst cannot market Firdapse for pediatric patients until the pediatric exclusivity period for Ruzurgi has elapsed . Regardless, Ruzurgi is now an approved therapy and may be used off-label in adults with LEMS where applicable. FDA is aware of this, clarifying the “off-label” use of approved drugs:
“Unapproved use of an approved drug is often called “off-label” use. This term can mean that the drug is:
· Used for a disease or medical condition that it is not approved to treat, such as when a chemotherapy is approved to treat one type of cancer, but healthcare providers use it to treat a different type of cancer.
· Given in a different way, such as when a drug is approved as a capsule, but it is given instead in an oral solution.
· Given in a different dose, such as when a drug is approved at a dose of one tablet every day, but a patient is told by their healthcare provider to take two tablets every day.” 
Orphan drug exclusivity provides an important benefit for therapies with ODD, effectively limiting competition in the marketplace from generics for seven years following approval. However, as drug development in the orphan space is growing, newer, more improved formulations or doses of currently marketed products are being prepared for approval. As previously mentioned, the most common approach to overcoming orphan exclusivity is to prove clinical superiority of the second-to-market therapy to the currently approved first-to-market product. However, the recent approvals of Fidapse and Ruzurgi, with marketing approval for non-overlapping subsets of the LEMS population, exemplifies another approach which abides by the orphan drug regulations. These methods require a careful understanding of the ODA and FDA regulations on marketing approval and orphan exclusivity to prevent blockage or rejection of their marketing applications. As such, case studies such as this can aid companies in understanding the nuances and FDA interpretations of regulations governing drug development.
1. Herder, M., What Is the Purpose of the Orphan Drug Act? PLoS medicine, 2017. 14(1):
2. FDA. CFR §316. e-CFR 2019; Available from: https://www.ecfr.gov/cgi-bin/text-idx?SID=c146218bf040a3dae0111597a0316d54&mc=true&node=pt21.5.316&rgn=div5.
3. FDA. Label: Ruzurgi. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209321s000lbl.pdf.
4. FDA. Label: Firdapse. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208078s000lbl.pdf.
5. FDA. Tentative Approval Letter: Ruzurgi. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/209321Orig2s000_TAltr.pdf.
6. FDA. Understanding Unapproved Use of Approved Drugs “Off Label”. 2018; Available from: https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label.
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