Generic Industry Wants More Guidance On Demonstrating Equivalence Of Drug-Device Combinations

The generic drug industry would like more guidance from FDA on its criteria for determining whether a proposed generic of a drug-device combination product is therapeutically equivalent or substitutable with its reference.

The industry also wants some clarity on other areas as well, such as what information should be submitted in generic drug applications and what information should be maintained at the manufacturing site and available during inspections for combination products. Cory Wohlback, senior director of regulatory affairs for Teva Pharmaceutical Industries Ltd., presented the generic industry’s viewpoints May 23 at a meeting of the Association for Accessible Medicines in Bethesda, Md.

Wohlback said that there is no clear-cut answer to the question of how “similar is similar enough” in existing law, regulations or guidance, and whether FDA would allow slight differences between a reference-listed drug (RLD) combination product and a generic provided that these differences do not confuse patients.

US FDA officials have recently indicated an openness to some differences in delivery devices that would make it easier for generic combination products to reach the market, but acknowledged the difficulties of balancing product variations with safety concerns. (Also see "Generic Combination Products May Be Permitted Delivery Device Variations" - Pink Sheet, 4 Jun, 2017.)

FDA Commissioner Scott Gottlieb said that making it easier to register complex generics, including combination drugs, as well as biosimilar drugs, is a high priority. In his inaugural remarks to FDA staff, the new commissioner identified rising drug costs among the pending challenges for the agency. Gottlieb said that while FDA cannot directly deal with the issue, it can work to promote competition. (Also see "Gottlieb Places Drug Pricing Out Front In First Speech To US FDA Staff" - Pink Sheet, 16 May, 2017.)

Whether the agency's interest in the issue will translate into concrete actions remains unclear, especially since it just issued draft guidance on human factor studies for generics, but Wohlback's presentation offered a detailed list of what FDA could clarify if the agency were able to.

Defining The Problem

The recent controversy over Mylan NV’s EpiPen, an epinephrine autoinjector used in allergy emergencies, highlights some of the challenges in developing generic drug-device combination products. Mylan CEO Heather Bresch has come under fire for hiking EpiPen's price 500% since 2009.

Teva's ANDA for an EpiPen generic received a complete response letter in February 2016. The firm said that FDA identified “major deficiencies” in the application, and told investors to expect a significant delay at least until 2017. (Also see "Mylan’s EpiPen Exclusivity Saved Again As Teva Reports CRL" - Pink Sheet, 1 Mar, 2016.) The agency's concerns may center on a plastic cap. Mylan argued in a January 2015 citizen’s petition that Teva’s proposed two-cap version of the drug requires patients to take an extra step and may be confusing and could potentially cause patients to deliver lethal doses.

Mylan has also been on the receiving end of problems with combination ANDAs. Its generic version of GlaxoSmithKline PLC's asthma blockbuster AdvairDiskus (fluticasone/salmeterol) won't be coming to market until at least next year after FDA raised questions about data for the substitute device that Mylan's product uses. (Also see "Advair Generic: Mylan Takes Issue With US FDA's 'Major' Concerns" - Pink Sheet, 10 May, 2017.)

Wohlback seems to want to nip these problems in the bud – or at least in the initial stage of application review. FDA’s guidance on refuse-to-receive (RTR) standards issued in December 2016 does not address similarity for combination products, Wohlback said, arguing that “a more precise definition of similarity is needed than currently listed in the RTR guidance and that more clear-cut and additional clarity regarding which changes from the RLD are permitted.”

The RTR guidance states that “any device used to deliver the drug should be similar enough to that used with/for the RLD so as to ensure, at a minimum, safe and proper administration of the product without the need for retraining by a health care professional and to ensure that its performance characteristics, operating principles, and critical design attributes will result in a product that will perform the same as the RLD under the conditions of use described in the labeling. In addition, the patient instructions in the labeling, as it concerns use of the device, should meet the labeling requirements for ANDAs.”

Likewise, FDA’s Jan. 13 draft guidance on human factors studies is too general to be useful, Wohlback said. The guidance, "Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA," includes standards for determining whether a proposed generic of a novel drug-device combination is therapeutically equivalent or substitutable with its reference. (Also see "ANDAs For Drug/Device Combos Face High Bar At US FDA; Epipen, Advair May Benefit" - Pink Sheet, 17 Jan, 2017.).

Wohlback also said that the law under Section 505(j)(2)(A)(v) of the Food, Drug and Cosmetic Act on labeling as well as the regulations under 21 CFR 314.94(a)(8)(iv) on labeling also do not adequately address determining similarity for combination products.

Seeking The Solution

Wohlback gave three examples of where more clarity is needed:

• Prefilled syringes. Wohlback said that it is unclear whether different capping systems of prefilled syringes used in generics are similar enough. “If the RLD has a twist and pull to remove the cap while the proposed product is a pull cap, are they similar enough? These are some of the questions we’re asking. It would be helpful to have additional guidance such as a question-and-answer or decision tree to determine this early on. Hopefully we can have guidance on this sometime in 2017.”
• Drug product filled in a cartridge and assembled in an auto injector. Wohlback said that it is unclear whether minor changes to the text or the graphics on the instructions for use can occur “so long as the device is not substantially more complex to use” and whether generic versions can have different instructions of use, and whether the content of the instructions can change as long as the graphics are unchanged.
• Metered dose nasal sprays. Wohlback said that it also is unclear whether generic metered nasal sprays are similar if the proposed product “produces slightly different data that appears to show not equivalence but rather superiority to the RLD.” Also, if the results show that the proposed product was equivalent to the RLD yet the RLD subsequently underwent design changes that impact the more recent in vitro bioequivalence test results, are they similar enough if the differences are not clinically meaningful and or noticeable by the patients?

Wohlback said that the industry also other concerns related to combination drugs, including the following:

• There needs to be additional clarification regarding expectation of information that is required to be submitted and maintained versus available during inspection and the design history file;
• There needs to be additional information on how to report an NDA/ANDA post-approval change for device components of a combination product that is covered by various routes in a 510(k) submission and premarket approval applications;
• FDA needs to issue more drug-product-specific BE guidances that detail essential performance requirements to be tested, as well as sample sizes and analysis plans; and
• There needs to be clarification regarding sample sizes for human factor studies.

From the editors of the Gold Sheet