John R. Peters, M.D., Deputy Director of the Office of Generic Drugs and Acting Director of its Clinical Safety and Surveillance Staff, discusses the significance of size, shape, and other physical attributes of generic tablets and capsules on patient adherence and safety.
Benefits of generic drugs
Generic drugs approved by FDA have the same high quality, strength, purity, and stability as their brand name counterparts. Generics provide safe and effective alternatives to brand name drugs at lower costs through an abbreviated approval pathway introduced in the 1980s. This abbreviated new drug application (ANDA) process eliminates repetition of the very expensive clinical safety and efficacy studies as well as pre-clinical animal studies, allowing manufacturers to bring a generic copy to market at a significantly reduced cost. The affordability of generic drugs has led to a sharp increase in their use; about 86 percent of all prescriptions in the United States are now filled by a generic drug product.
Comparing generic and brand name drug products
In order for there to be generic drugs, there must first be an approved innovator or brand name drug to copy, we call this the reference listed drug (RLD). All RLD products are approved by FDA on the basis of safety and effectiveness demonstrated by extensive pre-clinical and clinical studies. Generic drug manufacturers use the RLD to guide the development of their products. According to the Hatch-Waxman Amendments, a generic drug must not show any “significant difference” from the RLD. This way, FDA can rely on the finding of safety and effectiveness of the RLD as evidence that the generic version will also be safe and effective.
The concepts of what exactly constitutes a “significant difference” and how to demonstrate that a generic drug is equivalent to the brand name drug have been evolving since the 1960s. Initially it was believed that if the brand name drug and a drug copy were pharmaceutically equivalent, meaning they had the same active pharmaceutical ingredient in the same strength and in the same dose form, then the drug copy could be considered to be as safe and effective as the RLD. Later, it was found that pharmaceutical equivalence alone does not ensure that a drug copy (i.e., the generic drug) works the same way biologically, leading to potential differences in bioavailability due to the formulation of the drug. This resulted in the requirement that generics must be both pharmaceutically equivalent and bioequivalent.
For bioequivalence, the drug must show equivalent bioavailability as demonstrated by statistically similar plasma concentration curves. This shows that the drug will be delivered to the correct site of action at the same concentration for both generic and RLD products. Therefore, if a drug product is found to be both pharmaceutically equivalent and bioequivalent to the RLD, it is classified as a generic drug.
In recent years, another group of significant factors that affect generic drug performance have come to light – physical characteristics of drug products. We’ve found that these characteristics are important to patient acceptance of generic drugs and also to both compliance with treatment programs and safety. We are now considering physical characteristics alongside pharmaceutical equivalence and bioequivalence when we review certain new generic drug applications.
Impact of physical characteristics of generic drugs on patients
Several years ago, the Office of Generic Drugs began to notice that many ANDAs were being submitted to FDA with tablets and capsules that were much larger than the reference product. Staff in the office became concerned that a larger pill would affect a patient’s ability to take medication because it was well-documented in the medical literature that increased pill size can cause swallowing issues.
Upon extensive review of the medical and scientific literature, as well as the agency’s experience with drug applications submitted for oral tablets and capsules, significant concerns about changes in pill or tablet size, shape, color, and other physical characteristics surfaced. Research has shown that changes in the physical characteristics of drugs can impact patient compliance with treatment regiments and also cause medication errors. In fact, it is even possible for a patient’s response to a drug product to vary based on changes in the physical attributes of the drug, referred to as the placebo or nocebo effects.
When the appearance, particularly the color and shape, of a generic drug is different from the RLD, it becomes increasingly difficult for patients and health care professionals to correctly identify medications. The risk of error is especially high with elderly patients who take multiple medications each day and are used to sorting their medications by shape, color, and size.
It became clear to us that differences in the appearance of a generic drug from the brand name drug or other generic products for the same indication can negatively affect acceptance and use of generic drugs by both patients and health care professionals. That’s when we decided to develop a guidance document for industry on this topic. This guidance is a way of respecting and addressing patient perceptions of “significance difference,” what we think of as “Patient-Focused equivalence.”
Guidance from FDA on physical attributes of generic tablets and capsules
This year, FDA issued a final guidance for industry to explain our current thinking on size, shape, and other physical attributes of generic tablets and capsules. The recommendations in the guidance are meant to assist generic drug manufacturers in drug development and assure manufacturers that they are on the right track with their application. In a nutshell, we’re recommending that applicants design and develop generic drugs with a similar size and shape to the RLD.
The guidance is conservative; it does not restrict industry, but does provide some parameters from both a manufacturing and clinical safety standpoint. Within the guidance, FDA also gives industry the opportunity to vary from our recommendations. If they do, we simply request that they provide us with a justification so that we can review it in the context of our information on the reference product. This allows us the opportunity to help them develop the best product possible.
This guidance does not apply to generic drugs currently on the market. It is not necessary to go back to every product that has been on the market without any reported problems and change it for cosmetic reasons. However, we do conduct rigorous surveillance work. If a safety issue is reported about a marketed generic drug, we will investigate the issue, and if it is found to be related to the physical characteristics of the product, we may require changes.
Going forward – implementation of FDA’s recommendations in the guidance
The key to implementing this guidance actually comes during the filing process. Applicants should include all of the necessary information when they submit an application, including justification if their product is outside of the new guidelines for physical attributes. As long as the applicants have provided us with all the information, the application should not encounter additional “speedbumps” during review.
Our goal is to improve patient compliance with treatment regimens, reduce the occurrence of medication errors, and increase patient safety by encouraging the development of generic tablets and capsules that have physical characteristics similar to the brand name drug product. We aim to ensure generic drug quality and safety by confirming that these drug products are pharmaceutically equivalent, bioequivalent, and have similar physical attributes to their brand name counterparts.
The next step will be to evaluate the response from the medical and patient communities going forward. If generic products that are closer in appearance to the brand name drug products are better accepted within these groups, we may be able to identify other characteristics upon which we should provide further guidance.
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