From a Clinical Perspective

A conversation with Rob Lionberger, Ph.D.

Caricature of Robert Lionberger, Ph.D.
What is the Generic Drug User Fee Amendments (GDUFA) of 2012 regulatory science program?

The Generic Drug User Fee Amendments of 2012 provided FDA with funding via user fee funds from the generic drugs industry to supplement the costs of reviewing generic drug applications and inspecting facilities. We spend a portion of the funding on grants and contracts for research on generic drugs. We solicit input from the public and industry yearly and choose research priorities that answer questions that are currently blocking the development of generic prescription drugs.

The results of these studies should help generic drugs get to market -- by providing industry with evidence-based FDA guidance for developing new generic products, improving FDA’s review process for generic drug applications, and helping FDA ensure patients receive high-quality generic drugs.

The five generic drug regulatory science priorities for fiscal year 2014 are:

What prompted the establishment of this program?

Currently, there are scientific challenges that limit development of generic drugs. FDA, Congress, and industry all felt that this type of research should be an important part of the generic drug program at FDA. Although OGD has had a regulatory science program for years, with limited staffing and financial support, GDUFA now provides the sort of sustained funding commitment this type of effort requires. We can have a consistent effort across a longer time frame, allowing us to explore different approaches to regulatory science and improving our tools and methods for responsibly overseeing the generic drug industry.

Is this a new effort?

FDA has always tracked how drugs -- brand-name and generic -- perform once they receive FDA approval. But in terms of the scale, and the involvement of the public and industry (through GDUFA), the regulatory science program really is a new program. It’s a bigger effort than we’ve ever had before, and we’re incredibly excited.

How do you think the GDUFA regulatory science research program will impact perceptions about generic drugs?

Even with findings that prove generic products are as effective as brand-name drugs, consumer and health care provider skepticism that generics are as safe or effective as their brand-name counterparts persist. With generics, patients may be less likely to take their drugs or could experience the opposite of the placebo effect – meaning they might feel as though their drugs are less effective.   

Another thing our research program can do is assure people that when there are complaints, such as the generic product not working like the brand name product, we investigate them thoroughly. We continually look at generics, whether they’re in the application process or in market, and apply this information to our review processes.

I also think our research activities will help develop newer and better tools to evaluate products and companies will know what they have to do to develop equivalent products. A stronger scientific foundation for the generic drug program will build confidence that FDA is ensuring generic drugs have the same high quality as the brand-name product.

For generics, have you seen an increase in consumer confidence in the last few years?

I don't know that we have been able to translate our results to the public as well as we could. That’s a challenge for us in terms of communication. Consumer information is an area where we can improve.

What we can do from a regulatory science standpoint is build a foundation as strong as possible so that we can to establish equivalence between brand-name and generic drug products. Some of the best universities in pharmaceutical science and related fields are involved in this research program. In addition to our expertise, we are drawing on top-level collaborators from around the world. I think the American public expects us to make approval decisions based on the best available science. In the long term, that's what will impact how people think about generic drugs and provide the confidence that is needed.

What do you see as the greatest benefits of the GDUFA regulatory science program?

This program will allow us to develop the newer and better tools for the initial evaluation of generic drug products before they are FDA-approved and to evaluate the continued quality of approved generic products. And also allow us to find new bioequivalence methods for categories of products where there's currently limited development and production of generic drugs -- ultimately allowing more companies to compete in the generic space.

I think this research will help assure product quality, and create newer better tools for assessing product performance and relating it to generic substitution for the brand-name drug product. 

When we have more confidence in the basis for our regulatory decisions, we can make our decisions more efficiently. We can make them faster. We can make them better.   

Therapeutic equivalence of evaluation and standards

What is therapeutic equivalence?

Therapeutic equivalence means that generic products can be freely substituted for the brand-name product and for each other -- thus giving the patient the assurance of safety and effectiveness.

What enhancements do you want to see in how you evaluate therapeutic equivalence?

We should be moving away from a one-size-fits-all generic standards approach to a product-specific approach. It really needs to be focused -- having the right type of product quality and bioequivalence standards that ensure substitutability for a product's particular clinical use. 

Post-market evaluation of generic drugs

Doesn’t FDA already evaluate drugs after they go on the market?

Other parts of FDA’s Center for Drug Evaluation and Research look at unexpected adverse events (any side effects not noted on the drug’s label) that were not seen in the original clinical studies. The research we are supporting is focused on therapeutic equivalence (ensuring generic prescription drugs are chemically identical to and have the same efficacy and safety when given in the same doses as their brand-name counterparts) and successful generic drug substitution.

The new feedback we’ll get from the FY2014 regulatory science program looks at what happens when a patient is switched from the brand-name drug to the generic or from one generic to another generic.

Why aren’t these types of post-market evaluation studies performed by generic drug manufacturers and submitted to FDA?

Drug manufacturers are required to report to us when they receive adverse event reports about their products (FDA also receives adverse event reports from health care providers and consumers.) In fact, those reports become part of the information used to track potential public health issues and determine if further actions and analyses are necessary. But there could be 20 different generic manufacturers producing generic drug products that are all able to be substituted for a single brand-name drug product. Patients often do not know which generic manufacturer made the product they are taking. If FDA suspects an issue with a generic, sometimes it can be a challenge to identify which manufacturer should investigate the problem.

What type of information from this program would surprise you?

Generic products we approve are shown to be therapeutically equivalent substitutes for the brand-name product, so any type of finding that shows approved products aren't substitutable would be very surprising. Any type of non-equivalence is taken very seriously, and we would work to protect the public from any potential harm. We would work with the manufacturer to correct the problem and would provide consumers and health care with information they need to make health care decisions about the medications they use.

What drug types will have research priority this year?

This year we are focusing on anti-epileptic drugs, immunosuppressant drugs, bupropion, ADHD drugs, and cardiovascular drugs.

Equivalence of complex products

What’s a complex product and how does it differ from other drugs?

Complex products can mean that the molecule size is larger than typically seen in more traditional generic drug products. It could mean that there is structural complexity of the drug molecule or drug substance or finished dosage form. Or it can have to do with the drug delivery mechanism, such as drug-device combinations such as inhalers.

Complex products often meet otherwise unmet medical needs. For example, they include transdermal systems that delivery continuously across the skin or liposomes that target drug delivery to cancer tumors. Many new medical technologies are considered more complex dosage forms.

How does FDA address approving complex products?

The more information we can provide in these cases, the better. It's very important to us that generics are available for all types of brand-name drug products. But it is also always important to FDA that a generic product, complex or otherwise, is truly bioequivalent to the brand-name product. There should not be a product that is too complicated to have a generic. We have a really strong commitment to that principle.

However complicated the reference drug product is, we should figure out the generic approval pathway. It may be a very difficult pathway, but we are committed to making sure that an approval pathway is available in for every drug product.
How do you think this research will help guide future product development?

There will likely be more in vitro tests available that sponsors can use to develop generics faster, because they may not need to conduct certain clinical or human studies. Also more applicants will likely enter the complex product space and thus increase the public’s access to generic medicines.

For example, there was a drug shortage for the anti-cancer drug Doxil. Thankfully, we had invested in regulatory science for this type of drug product several years prior and were able to use the results from that research to inform the appropriate development and evaluation of this drug to ensure a generic product became available more quickly and was able to mitigate the drug shortage. 

Equivalence of locally acting products

What are locally acting products?

Locally acting products are applied directly to the skin or mucous membranes (the soft, moist areas just inside the openings to the body), for example, nasal passages. 

Is there a lack of efficient bioequivalent methods for locally acting drugs?

Yes, because the science is challenging and each product may have a different delivery method. It is very difficult to determine an appropriate way to demonstrate bioequivalence for products that you apply to the skin or directly to the eye, or inhale. For example, many Americans use inhalation therapy for asthma. None of these inhaled products are available as a generic at this time. So that’s an obvious gap in access to more affordable generic drug products.

To check the bioequivalence of tablets and capsules taken by mouth, we typically measure the concentration of drugs in the blood after taking the product. Using the same study for an inhalation product presents different challenges. You have to answer questions about the product and the device. Did the drug land in the right place in the lung? Can patients use the generic device just as effectively as the brand-name device?

What type of advancements would you like to see in this area?

Industry clearly recognizes the need. Last year we issued draft guidance for a dry powder inhalation drug. We received a huge amount of positive feedback from industry. Hopefully, our guidance will help industry to develop generic drugs for this product and then submit more applications in these types of products.

Computational and analytical tools

What is meant by computational and analytical tools?

I think of this as the infrastructure that supports our efforts. For example, we can integrate generic and brand-name drug data into better decision-making tools using mathematical and computational models. These models allow us to extrapolate our experiences to other situations. For example, if we use a model of how drugs are absorbed, we can begin to predict how changes in particle size impact a particular drug.

There are commercially-available tools that claim to be able to do this. FDA will be able to evaluate those tools using our models. It’s leveraging one set of the computation models to make better, more efficient decisions about product quality, and predictive decisions based on analysis of product capability. In addition, there are new characterization methods that allow us to look at products in ways that we previously couldn't. For the complex products, we may need new analytical methods. For post-marketing surveillance, we may need new ways to analyze data on approved products.


Dr. Lionberger is the director, Office of Research and Standards, which includes the Division of Therapeutic Performance and the Division of Quantitative Methods and Modeling, Office of Generic Drugs, in the Center for Drug Evaluation and Research


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