At the US Food and Drug Administration’s (FDA) Generic Drug Science Day, FDA Commissioner Scott Gottlieb outlined the steps the agency is taking to improve the generic-drug review process, including work to finalize draft guidance on complex generic drugs.

“I’ve been especially focused on areas in our regulatory portfolio where the law allows for vigorous competition from generic medicines, and access to more affordable drugs that it enables,” said Gottlieb in an agency statement. “But in these cases, for different reasons, that expected competition isn’t materializing.”

Gottlieb said the agency has bucketed the focus of its attention into three areas. The first area is addressing ways branded-drug makers may block generic-drug makers from amassing the physical doses of the branded drugs needed for bioequivalence studies that are needed to win FDA approval.

The second area relates to the general throughput of the agency’s approval process, including ways to create more competition among generic drugs. Gottlieb addressed ways to improve the timeliness of the generic-drug review process, in particular for generic drugs with limited competition, often low-volume drugs that would potentially be more subject to higher prices due to limited competition. To address that, the agency recently published a list of off-patent, off-exclusivity branded drugs without approved generics. “By proactively listing these drugs, and making clear that we’ll expedite approval of any application for one of these medicines, we’ll be helping to reduce the financial incentive to play games with these drugs,” said Gottlieb.

The third area addressed by Gottlieb is improving the process for developing generic copies of complex drugs. Complex generic drugs are broadly defined as generic drugs where it is especially hard to establish therapeutic equivalence and also difficult to get through the FDA’s abbreviated new drug application (ANDA) pathway. These drugs often involve a complex formulation or complex active ingredient.

“FDA’s ANDA pathway, under Hatch-Waxman, was developed at a time when most drugs were simple small molecules,” said Gottlieb. “They were easy to characterize and evaluate through bioequivalence studies. “In most cases, the activity of a drug correlated directly with how quickly it got into the bloodstream, and how long it stayed in the blood so it could have its intended effect on its site of action. In contrast, complex drugs are often hard to formulate or difficult to measure through the blood. There’s often no simple path to approval. The hurdle to approval can also be higher when the drug is delivered through a complex device like a metered dose inhaler, or an auto-injector. These drugs also fall into the broader category of complex generics.”

In these cases, Gottlieb said that the branded-drug maker may still hold intellectual property on certain features of the device. “In such a circumstance, the drug can be an old medicine, but the device can be hard to copy since new patents protect its key features,” he said. “A generic competitor may propose differences to the device in an effort to avoid infringing such patents.  However, this may raise complicated scientific and regulatory questions as to whether the generic product will have the same clinical effect and safety profile–and thus be substitutable for–the branded drug product.”      

To address that, he said the agency has taken steps to provide industry with greater guidance on the types of information and analyses generic sponsors that want to copy a branded product, such as an auto-injector or a metered-dose inhaler, should submit to the FDA to support approval of such products, even when the generic versions have some design differences relative to the branded drug they are copying; and how those design differences might correlate with different instructions for use of the two products.

Gottlieb said the FDA is working to finalize draft guidance that it issued in January 2017 to provide parameters to generic applicants in addressing these issues. The guidance lays out how generic applicants should consider when design differences between a generic version of a branded drug could impact the clinical effect or safety profile of the generic product, and thus, the substitutability of the generic medicine. The final guidance will clarify new policies related to these situation, including putting forth a principle that allows a generic product to have certain labeling differences from the branded product if such labeling changes stem from permitted design differences.  

“In other words, under this guidance, as long as the generic applicant is able to demonstrate with data, where appropriate, that differences in the design of the generic product do not affect the clinical effect or safety profile when the generic is substituted for the branded product, the generic product can be approved as a competitor to the branded drug where all other requirements for generic approval are met,” said Gottlieb in the agency statement. The Commissioner says the agency is separately working on policy issues to resolve obstacles that block or delay approval of generic drug-device combination products. “For example, we’re working to develop guidance for industry with the aim of clarifying ‘sameness’ requirements for ANDAs,” he said. “We believe that guidance in this area may be particularly helpful for complex generics, including drug-device combination products.”

He added that there a lot of other complex drugs that lack generic competition even though they don’t have intellectual property blocking generic entrants but rather that scientific principles for proving sameness have not been firmly established.

“Going forward, we’ve committed to put out guidance laying out how a generic firm would copy a particular complex drug at least two years in advance of the first potential generic entrant,” he said. “This will make it easier for generic firms to plan how they can copy complex drugs. But we also need to continue to improve the science for demonstrating sameness in these settings.”

Source: FDA