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Speech

Event Title
Remarks to the FDA/DIA 2018 Complex Generic Drug-Device Combination Products Workshop
October 09-10, 2018

Speech by
Anna Abram
Leadership Role
Deputy Commissioner for Policy, Legislation, and International Affairs - Food and Drug Administration

Remarks by Anna Abram
Deputy Commissioner for Policy, Planning, Legislation and Analysis
Food and Drug Administration
FDA/DIA 2018 Complex Generic Drug-Device Combination Products Workshop
Silver Spring, MD

(Remarks as prepared for delivery)

Good morning.  I’m delighted to be with you today for this very important workshop.  As the Deputy Commissioner for Policy, Planning, Legislation, and Analysis at the U.S Food and Drug Administration (FDA), I’m excited to have the opportunity to share some of the critical work FDA is doing with complex generic drug-device combination products as we work to fulfill our mission to protect and promote the public health, and I’m pleased to bring you warm regards from our Commissioner, Dr. Scott Gottlieb.

I want to welcome my colleagues from FDA and the members of DIA who are here today, as well as the many other stakeholders from across the globe who are engaged in important work in this field, from the researchers and scientists involved in development of complex generic drug-device combination products, to the policy analysts and regulatory and medical scientists, to the academics, biopharmaceutical consultants, clinicians, and many others. 

When FDA talks about protecting and promoting public health in the context of product development, we often talk about addressing the full continuum of the development and use of new products. This comprehensive approach spans the entire life cycle of the product, from pre-market development to clinical trials to post-market safety surveillance, and for some products to generic competition. It includes providing sufficient guidance and helping to develop the tools that product developers need. Across this entire continuum, the FDA works to ensure that products are safe and effective for their intended use. And it’s an approach that remains important today amid such rapid biomedical discovery.

We are at a remarkable inflection point in medicine and science, a time in which patients battling deadly diseases may see advances that can alter the trajectory of their lives.  These advances are providing new ways to address human disease at a faster pace than ever before, but they also challenge FDA to modernize its approach to evaluating innovations. Or more simply stated, to keep up.  This has meant, in many cases, creating new approaches that are better suited to the efficient evaluation of these advances without compromising FDA’s science-based standards.

Each of you are participants in a process designed to support the development and evaluation of an essential category of medical products that play a critical role in meeting the needs of patients, including many with life-threatening conditions.

Over the next two days you’ll engage in substantive discussions about a variety of drug-device combination products.  You’ll seek to tackle some of the significant challenges developers face as a result of each product’s unique features, as well as the complicated scientific and regulatory issues involved in bringing these products to market.

You face many challenges: the complex nature of the drug constituent and its interaction with the device constituent; identifying the most accurate, sensitive, and reproducible way to demonstrate bioequivalence; and the complexity of the manufacturing process itself, to name just a few.

Each of these obstacles can have a significant and negative impact on the ability to “genericize” these products.  That impediment, in turn, means that many of these drugs face less competition than other products, and therefore can be more expensive and less accessible to the patients who need them.

At this meeting, you’ll hear from speakers from the FDA, from industry, and others on many of these scientific and regulatory challenges and some of the means we are working on to address them. And, through your discussions, you’ll be enhancing collaboration and communication among the relevant stakeholders.

The high price of prescription drugs has certainly been one of the most controversial issues confronting the biopharmaceutical industry in recent years. Drug pricing is a major concern for the public and for the Administration. The fact is, new medical innovations will not benefit patients and consumers if people cannot afford to access these innovations. To the extent that the FDA can ensure that our regulatory requirements are streamlined, predictable, and science-based, we can help reduce the time, uncertainty, and cost of drug development for branded drugs as well as generic and biosimilar alternatives.

At the same time, we are working to help prevent certain practices across the drug supply chain that can push the cost of effective treatments out of the reach of patients and prevent the public from realizing the full benefits of innovation. And by helping lower the direct costs of drug product development, as well as the time and risk embedded in these important endeavors, we also reduce the cost of the capital needed to underwrite new discovery, which in turn can translate to lower costs and greater opportunities for patients to afford and get the treatments they need.

Generic drugs represent 90 percent of all prescriptions dispensed in the United States. Generic drugs with their large market penetration and a cost that is typically 75 to 90 percent less than their brand name competitors have had a profound dollars and cents effect on patients and the U.S. health care system.  Use of generics has resulted in savings of more than $1 trillion over a decade and $265 billion in 2017 alone.  But competition from complex generics, including complex generic drug-device combination products, is lagging behind.

And yet, being able to “genericize” a complex drug can be a high-value opportunity for a generic drug developer. These higher value generic business opportunities can help underwrite the costs of other generic applications at a time when we believe the generic industry is facing new economic pressures from rising costs, supply chain consolidation, increased competition and declining reimbursement on many competitive generic medicines. Moreover, 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 for complex drugs may have an outsized impact on access, and drug spending.

As many of you know, last year the Commissioner introduced the three-pronged Drug Competition Action Plan (also called DCAP), that addresses some of the issues that make it difficult for sponsors to bring generic copies of novel drugs to market after all of the legal barriers to approval, such as patents and statutory exclusivities, have lapsed or otherwise been addressed.

The goal of DCAP was to further encourage competition and help bring greater efficiency and transparency to the generic drug approval process.  There are three major components of DCAP, and I’m pleased to say that we’ve made significant progress on each one:

First, is further streamlining the generic drug review process to increase efficiency and effectiveness with the ultimate goal of more approvals. To accomplish this we’re making both internal and external changes - issuing an internal policy guide on good Abbreviated New Drug Application assessment practices designed to improve the quality and consistency of assessments and issuing a draft guidance that describes common deficiencies that we continue to see in generic drug applications that result in a low percentage of first cycle approvals. We have also implemented a new pathway authorized under the FDA Reauthorization Act of 2017, or FDARA, for competitive generic therapies, which are drugs with inadequate generic competition. This pathway is intended to incentivize and expedite the development and review of these products.

The second component of our plan is reducing the so-called “gaming” that frustrates and delays generic drug approvals and extends brand monopolies beyond what Congress intended with the Hatch-Waxman Amendments of 1984; This includes tactics that are used to prevent generic developers from obtaining the samples of the branded drug product that are typically needed to conduct required testing to demonstrate, among other things, that a generic medicine is bioequivalent to its brand reference drug;

The third component of the DCAP is central to today’s meeting, supporting the development and enhanced review of complex generic drug products to make it easier for companies to bring generic competition to this important category of branded drugs.

To understand the challenges posed by complex generics, we need to go back to the pathway developed in 1984 under the Hatch-Waxman Amendments. This legislation put into place the framework for generic drug review at a time when most drugs were simpler small molecules requiring simple manufacturing processes. They were generally easy to characterize and evaluate through traditional methods, including traditional bioequivalence studies. In most cases, a drug’s activity correlated directly with how quickly it got into the blood, and how long the drug stayed in the blood, so it could have its intended effect on the intended site of action.

In contrast, complex drugs involve cases where the drug is often harder to formulate and manufacture because it has a complex formulation or complex active ingredient. In other cases, the drug acts locally on the tissue rather than through the concentration in the blood. This includes inhaled drugs that act directly on the lungs, a topical patch that acts directly on the skin, or an eye drop that acts on the surface of the eye. The therapeutic effect of these types of drugs does not necessarily correlate with the amount in the blood and can be more difficult to measure through the blood. They can raise other issues that make the traditional, and often simpler, metrics generally used to evaluate generic drugs difficult to employ. There’s often no easy way to make the demonstrations necessary for generic approval.

We’ve taken a number of steps under GDUFA II to proactively address these scientific and regulatory challenges that may impact the development of these combination products, from development to approval.

As you know, a great challenge in developing a complex generic drug-device combination product is identifying the most accurate, sensitive, efficient, and reproducible method for demonstrating bioequivalence between a proposed generic combination product and its Reference Listed Drug (or RLD).  The goal is to identify new ways to demonstrate bioequivalence.

We are making significant progress in the development and validation of novel methods to more effectively assess quality and bioequivalence for generic combination products, and ultimately provide ways for more complex generics to enter the market.

We’ve also been working to provide industry with greater guidance on the types of information and analyses FDA recommends generic drug developers submit to FDA when developing a generic drug with an auto-injector or a metered dose inhaler.  This is true even when the generic versions have some design differences relative to the branded drug-device combination product they’re copying.

Our goal is to help clarify how generic applicants evaluate whether design differences between a generic version and a branded drug-device combination product could impact the clinical effect or safety profile of the generic product, and thus the substitutability of the generic medicine.

Under GDUFA, our research is enabling us to provide more product-specific guidances to generic drug developers in advance of ANDA submissions to offer them clearer understanding of FDA’s expectations when developing generic versions of complex combination products.

Indeed, under GDUFA II, we’re advancing new product-specific guidance (PSG) to aid the generic industry seeking to develop generic versions of complex products and more efficiently allocate their resources so they can prepare better, more complete submissions. To date, the Office of Generic Drugs has published a total of about 1600 product specific guidances. Of this number, 102 New and 51 Revised were published in 2018 as of September 30, 2018.

To this end, I’m delighted to announce today the release of two draft guidances and 25 individual product-specific guidances related to generic transdermal delivery systems or TDS.  These guidances reflect scientific advances in the field, many of which are a direct result of the GDUFA regulatory science program.  Specifically, they will help:

• streamline and harmonize the regulatory standards for all proposed generic TDS products;

• recommend statistical analyses that are more powerful so that high quality TDS products can more efficiently demonstrate that they are well-adhering and that they have a low irritation potential;

• clarify that the Agency will consider alternative approaches like the use of alternative grading scales or the elimination of comparative clinical studies to evaluate the sensitization potential of certain TDS products; and

• greatly improve clarity on numerous aspects of study design, conduct, and data analysis that provide transparency about FDA’s review standards and expectations.

In short, these TDS guidances will advance more efficient and effective generic development for these complex drug-device combination products, and ultimately, enhance patient access to high-quality generic TDS products.

Another important area in which we’ve made great strides under GDUFA II is providing earlier and more extensive engagement for the generic drug industry when developing complex drug-device products in pre-ANDA meetings.

This kind of early and consistent communication can help address uncertainties and provide early answers to product development questions.  This, in turn, can help companies make decisions that are more predictable, efficient, and cost effective. It also advances the opportunity for discussion of new or alternative development strategies for complex generic drug-device combination products.

We’ve also made progress on our inter-center consult process, which you’ll hear about in more detail from some of the other FDA speakers.  This program is designed to strengthen coordination, ensure consistency, enhance clarity, and provide transparency with the Agency and stakeholders, as we work to modernize the combination products review program.

With new technologies emerging across many fields, we must work to eliminate the challenges associated with review of drug-device combination products assigned to an individual medical product center.  By enhancing collaboration and coordination between and among FDA’s medical product centers we can promote a more efficient and productive assessment of applications covering combination products, including generic drug-device combination products.

I’m pleased to report that our efforts in all these areas to facilitate greater competition for complex combination products are bearing fruit.

As most of you know, in August we approved a significant complex generic, the first generic for Epipen, the most widely prescribed epinephrine auto-injector in the U.S. This approval makes possible a potentially lower-cost option for patients, including many children, who live with the threat of an anaphylactic episode and who must have access to an emergency dose of epinephrine at all times. And by providing an FDA-approved alternative, it will also help protect against potential drug shortages.

We anticipate that this meeting will provide a robust discussion of current and new ideas for developing novel methods and standards to assess complex generic drug-device combination products.

 As we continue to advance our efforts to enhance competition for these products, we look forward to building on the collaboration and ongoing dialogue with industry, academia, and other stakeholders who share these important interests.

Our goal of fostering greater access to safe, effective, and affordable generic medicines is a key part of our broader public health mission.  And we look forward to working with you to achieve that goal.

Thank you.