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FDA Firsts and Updates: Competitive Generics, Complex Generics, SiRNA approval, and Closing the Orphan Loophole

We decided to mention some noteworthy firsts from the FDA during August 2018 and a change in the FDA’s policy on obtaining orphan incentives via pediatric-subpopulation designation.

Competitive Generic Therapy Designation

The FDA granted Competitive Generic Therapy (CGT) designation for the first time for Potassium Chloride oral solution (ANDA 211067; Apotex, Inc; approved 8 August 2018). This change was made possible by the FDA Reauthorization Act of 2017 (FDARA), which amended the statute to allow the designation for drugs lacking competition, defined as one or fewer generics listed in the Orange Book (FDARA Section 803).

CGT-designated drugs receive priority and ‘enhanced’ review, and are eligible for 180 days of marketing exclusivity if they are the first CGT-designated product and are marketed within 75 days of approval.(FDARA Section 808) However, as noted in a blog by Hyman, Phelps, and McNamara, there is nothing to stop the FDA approving another generic after approval of, but prior to the commercial launch of a CGT-designated product.

Interestingly, another generic potassium chloride oral solution product was approved before the Apotex product (ANDA 210041; Amneal Pharmaceuticals, LLC; approved 19 July 2018). As the approval documents for both products are not yet available, we can only speculate that Amneal was not granted Competitive Generic Therapy Designation because it didn’t request it. So while the exclusivity that Apotek is likely to get will not block Amneal from marketing its product, Amneal could have blocked Apotex’ product if it had obtained CGT designation.

It is worth being familiar with the statute.

First siRNA Product Approved

The FDA’s Center for Drug Evaluation and Research (CDER) recently approved the first small interfering RNA (siRNA) product. The new drug, called patisiran (Onpattro) was approved on 10 August 2018 to treat polyneuropathy caused by a rare and frequently fatal disease called hereditary transthyretin-mediated amyloidosis (hATTR). The product is a double-stranded siRNA formulated as a lipid complex for delivery to liver cells (hepatocytes).

SiRNAs are nucleic acids designed to bind to a specific RNA sequence within a cell and degrade the RNA. This alters or prevents the production of a protein within the cell. This technology is particularly useful in rare genetic diseases caused by the production of mutant proteins. In the case of hATTR, siRNAs reduce the amount of the unstable mutant transthyretin protein that is produced, and subsequently prevent accumulation of the misfolded degradation proteins.

In the clinical efficacy study conducted for the approval of Onpattro, significant improvements were seen via the Neuropathy Impairment scale, Norfolk Quality of Life-Diabetic Neuropathy scale, modified body mass index and gait speed (10-meter walk test) over an 18-month period.

This significant result in a new class of drugs is exciting from a scientific point of view and life-saving for patients with hATTR.

First (Complex) Generic Version of Epipen Approved

Amidst global shortages of Mylan’s epinephrine autoinjector EpiPen, the FDA has just approved the first generic product based on EpiPen.

As we have previously blogged (here and here), approval of complex generics, including drug-device combination products, can be challenging. Teva Pharmaceuticals found this out when it received a complete Response Letter for the epinephrine ANDA submission in 2016. In November 2017, the FDA issued a new Guidance for Industry: Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA to facilitate the approval process for complex generics.

Several other epinephrine autoinjectors have been approved via the 505(b)(2) pathway but are not substitutable for EpiPen. Mylan has launched its own generic version of EpiPen at half the cost. The commercial launch date and price or Teva’s product have not yet been revealed.

Closing the Orphan Loophole

The Orphan Drug Act covers pediatric subpopulations in cases where the disease is (i) rare (prevalence of less than 200,000 people in the US), (ii) a valid orphan subset of the disease is rare, or (iii) if the disease in the pediatric subpopulation is a different disease to that in adults.

Until now, the FDA also granted orphan designation (referred to as pediatric-subpopulation designation) for drugs indicated for common diseases or conditions that are not rare overall but that have a prevalence of less than 200,000 in the pediatric population. This practice began prior to the enactment of legislation designed to incentivize studies in pediatric populations.

However, as we have blogged in the past, one of the benefits of orphan designation is the exemption from complying with the Pediatric Research Equity Act (PREA).

So a loophole was inadvertently created whereby sponsors of products designed for use in both adult and pediatric populations could obtain pediatric-subpopulation (orphan) designation and were thus exempt from conducting pediatric studies, thus avoiding the very studies that PREA was enacted to mandate.

According to the July 2018 Guidance for Industry: Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases, the “FDA does not expect to grant any additional pediatric-subpopulation designation (i.e., designation for rare pediatric subpopulations of common diseases). Pediatric subpopulation designation is no longer necessary to stimulate the study of drugs in pediatric populations now that various programs, such as PREA and BPCA, have proven to be effective in achieving those ends.”

Orphan designation can still be granted for pediatric indications as provided by the Orphan Drug Act as listed above. Further, drugs that have already been granted pediatric-subpopulation designation will not be affected.

In summary, it has been a month of exciting scientific and regulatory firsts at the FDA. Contact us to discuss your development program and the impacts of the changing scientific and regulatory environment.


Angela Drew, PhD
Product Ideation Consultant