Reducing the Hurdles for Complex Generic Drug Development

Posted on October 2, 2017 by FDA Voice

By: Scott Gottlieb, M.D.

Earlier this year, I announced our Drug Competition Action Plan to advance new policies aimed at bringing more competition to the drug market. My goal was to improve access consumers have to the medicines that they need. I consider access to medicine a matter of public health. If consumers are priced out of the drugs they need, that’s a public health concern that FDA should address, within the scope of its mandate and authorities.

While FDA doesn’t control drug pricing, our policies do affect competition in the market. This is the nexus of our current efforts on drug pricing.

Our plan has a number of different domains. Among them is a compilation of efforts to improve the efficiency of the generic drug approval process; and another is a group of policies aimed at closing loopholes that allow branded drug companies to game our rules in ways that forestall the generic competition that Congress intended. One important group of policies is aimed at making it easier to bring generic competition to a category of branded drugs known as complex drugs. Today we’re announcing a major new set of policies to advance these goals.

Complex drugs comprise high cost medicines like metered dose inhalers used to treat asthma, as well as some costly injectable drugs. These medicines generally have at least one feature that makes them harder to “genericize” under our traditional approaches. As a consequence, these drugs can face less competition. In some cases, costly, branded drugs that are complex drugs have lost their exclusivity, but are subject to no generic competition.

The new policies we’re announcing today are aimed at ensuring that we provide as much scientific and regulatory clarity as possible with respect to complex generic drugs. This focus is critical because, first and foremost, these drug products provide important therapies to patients. They are also becoming increasingly significant to the economic health of the generic drug industry. Being able to “genericize” a complex drug can be a high-value opportunity for a generic drug maker that helps underwrite the costs of other generic applications. In other words, because brand-name versions of complex drug products are often higher-priced than many other brand name drugs, any steps we can take to encourage the development of generic competitors to complex drugs will have an outsized impact on access, and prices.

When considering the scope of complex drugs, people often first think of drug products where the active ingredient itself is complex. Glatiramer acetate injection, a drug used in the treatment of multiple sclerosis, is a good example. However, the terms “complex drug product” and “complex generic drug” are used to refer to a much larger and diverse group of drug products. In addition to drug products with complex active ingredients, or sites of action, complex drug products also include complex drug-device combination products.

Together, this diverse collection of drug products has one or more elements that are more complex than an average drug product. This complexity, in turn, means that the scientific and regulatory pathways for approval of generic versions of these drug products are not as well traveled by generic drug developers. In some cases, use of another established regulatory pathway may be appropriate to streamline development.

We’re undertaking a number of efforts to ensure that the pathways for approval for generic versions of complex drug products are as efficient as possible, including a number of new steps that I’m announcing today and others that we’ll be working on in the coming months.

We know that our regulatory requirements impact both the direct and indirect costs of drug development. These include costs associated with the time it takes to develop a drug and gain its regulatory approval, as well as those associated with the research and development of experimental products that ultimately do not make it to market.

Manufacturers of complex generic drugs face a number of challenges in developing their products and demonstrating that their products meet the approval requirements for generic drug applications (abbreviated new drug applications or ANDAs), including establishing that they are bioequivalent to and have the same active ingredient as the brand-name drug.

Bioequivalence for complex generic drugs can be challenging with complex drug products that can’t be easily measured in the blood, or when the drug’s therapeutic effect is delivered locally to a particular organ, rather than systemically, through the bloodstream. In other instances, showing active ingredient sameness can be challenging when the drug product contains an active mixture of components and not a single active molecule.

These challenges – and resulting regulatory uncertainties – may deter generic manufacturers from beginning development. It can mean these ANDAs undergo more review cycles than other generic drugs. These hurdles, in turn, may result in limited competition and higher prices.

We recognize these problems and are taking a number of new steps to support the development of high quality ANDAs for complex generic drugs.

First, FDA is issuing a draft guidance to assist ANDA applicants and prospective ANDA applicants in creating and submitting pre-ANDA meeting requests, including meeting package materials, so FDA can give better advice to sponsors looking to develop complex generic drugs.

The guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review cycle meetings with FDA. These meetings will allow for enhanced communication between generic drug applicants and FDA early in the generic drug development process, allowing for more efficient generic drug development, review, and approval pathways. We’ve found from analyzing our new drug program, that early and better meetings between FDA and sponsors can improve development timelines. We want to bring these same types of opportunities to developers of complex generics.

Second, we’re issuing a draft guidance to help applicants determine when submission of ANDAs for certain complex products, known as peptides, would be appropriate. Peptides are compounds made up of 40 or fewer amino acids, the building blocks of proteins. There are a number of branded medicines that are peptides, where exclusivity has lapsed, but these drugs face little or no competition. This new guidance applies to ANDAs for certain specific synthetic peptides, namely, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, that reference brand-name versions of these peptides manufactured using recombinant DNA technology.

This guidance represents how advances in regulatory science — when coupled with careful policy considerations — can enable generic drug development that was previously infeasible.

In this case, advances in technology for peptide synthesis and characterization allow an ANDA applicant for one of these products to demonstrate that its product meets the “sameness” requirements for generic drug approval. The recommendations in the new guidance will help ensure that the risk of an immune response from the generic due to differences in impurities will not differ from that of the reference drug.

We’re doing all of this without sacrificing the scientific rigor of the process one bit. A central aspect of our approach, and our efforts to spur innovation and generic competition, is focused on adopting more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review.

We’ll soon release other important policies aimed at spurring competition to complex drugs. But we know that better guidance isn’t the only answer. Some drugs lack generic competition because they cannot be measured through traditional in vivo bioequivalence methods and there’s no efficient and convincing bioequivalence test method available.

In these instances, an applicant needs to conduct more extensive clinical endpoint testing to show bioequivalence of a generic drug to a brand-name drug. This can be burdensome and discourage generic product development. A further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs.

Over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible. To help with this task, we’re holding a series of important scientific workshops, beginning today, that will identify opportunities for complex generic drug development, discuss quantitative modeling approaches and principles and aid product-specific guidance development. The workshops will also help in the development of new analytical tools that will help overcome the unique development and regulatory challenges for demonstrating active ingredient sameness in complex products. We intend for these efforts to speed product development, reduce development costs, and improve access to these products.

Our announcements today are part of a broader effort by the administration to address the high and rising cost of drugs and in the coming months, we’ll advance other policies aimed at enabling generic competition to complex drugs. Some of these will be product specific guidance documents; others will deal with more crosscutting aspects of our process. And we’ll advance more new policies to help bring more competition to other aspects of the drug market. We’re just getting started. Drug access is a matter of public health concern. We know that enabling more generic competition, where Congress intended, helps reduce prices, enable more access, and improve public health.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA