As generic drugs assume a larger role in medical treatment, now accounting for more than 70% of prescribed medicines in the United States, regulators and manufacturers are looking more closely at the role of product appearance and physical characteristics in assuring the safe and appropriate use of medicines. There are concerns that interchangeable drugs with different sizes, colors, and shapes could lead to medication errors or reduce consumer acceptance of a prescribed treatment. In recent years, FDA has shown greater interest in how physical attributes of medicines reflect a manufacturer’s ability to reliably produce quality products that meet patient needs and expectations. FDA has addressed issues of “sameness” between reference-listed drugs and generic copies in guidance documents on such subjects as tablet scoring, ease of tablet splitting, ability to “sprinkle” capsule particles evenly to ease administration, and how various coatings may affect patient satisfaction with a tablet or capsule.
Generic drugs have to be bioequivalent and pharmaceutically equivalent (i.e., containing the same active ingredient, same strength, same dosage form and same route of administration of the brand drug) to qualify as therapeutically equivalent under the Hatch-Waxman Act. But the law does not require generic drugs and brands to have the same appearance. In fact, brand-name manufacturers frequently invoke trademark law to protect a product’s unique physical attributes. But compelling generic drugs to assume different appearances raises concerns among regulatory and public health officials that such differences could compromise patient safety and appropriate drug utilization, and possibly block effective and economic generics from coming to market.
Size and shape
Draft guidance from FDA discusses how differences in size, shape, and other features of drug tablets and capsules could affect proper use of medicines. This advisory on “Size, Shape and Physical Attributes of Generic Tablets and Capsules” does not alter current standards, but calls on manufacturers to consider whether physical changes in size or shape of a product present risks to patients and public health (1).
Differences in tablet or capsule size or shape could lead to difficulties in swallowing the drug, which could undermine compliance with prescribed treatment, FDA says. Oval and round tablets and capsules appear easier to swallow than flat tablets, and certain coatings on pills also can ease administration, as can the weight of a tablet or capsule. The agency notes that swallowing problems may affect a broad number of patients, and not just those with specific throat conditions, and that dosing difficulties could prompt patients to skip or discontinue treatment.
FDA advises manufacturers to consider the range of factors that can minimize swallowing difficulties in developing the quality target product profile (QTPP) for a generic drug. Generic-drug tablets and capsules should be of similar size and shape to the reference product, and tablet coating, weight, surface area, and disintegration time should be examined.
This guidance arises from a Regulatory Science Plan for examining 13 topics likely to facilitate the development and approval of generics, which was established under the Generic Drug User Fee Act (GDUFA) of 2012. An item on the plan’s list is to evaluate drug product physical attributes as one way to facilitate patient use and perception of quality in generic drugs. The Plan calls for FDA to advise manufacturers on how to control these attributes and to compare them to reference products through laboratory and human studies on characteristics such as tablet size, shape, coating, score configuration, taste masking, color, or odor perception from residual solvents.
The guidance on drug size and shape “reflects and the current environment where all products are being held to a higher standard,” observes attorney Phil Katz of Hogan Lovells. FDA is not saying that generic-drug makers have to match all the characteristics of the innovator product to gain approval, Katz explains, but offers advice on how to identify characteristics that could have an effect on product quality, safety, and adherence.
This guidance is in line with several earlier FDA documents addressing drug appearance and formulation. A March 2013 guidance on tablet scoring advises manufacturers of both brand and generic drugs on data and criteria to include in applications to support approval of such products. FDA discusses appropriate nomenclature and labeling for such products, as well as stability and dissolution testing, and notes that scoring should be the same for generics and brands to ensure that split tablets are safe and effective.
FDA also addressed the need for consistency in the size and characteristics of beads in capsules for drugs and biologics in a February 2012 guidance. The aim is to ensure that generic and brand products will work as intended and that bioavailability and bioequivalence remain constant when beads are sprinkled on soft foods or swallowed without chewing. The guidance recommends a target bead size, with no more than 10% variation, and notes that generic-drug makers may need to conduct sprinkle studies analyzing the bioequivalence of a modified-release drug product administered in this way.
FDA’s push for sameness between generics and brands, however, opens the door to broader legal entanglements. Policies that encourage generic drugs to “look and feel the same as the RLD product,” says attorney Kurt Karst of Hyman, Phelps & McNamara, raise the likelihood that “a generic will run smack dab into intellectual property protections on the brand-name drug, such as patents and trademarks.” In fact, Karst suggests in his FDA law blog, that tight FDA restrictions on physical attribute differences may actually encourage some brand manufacturers to seek patents with sufficiently broad claims to capture physical attribute variations (2).
The ability of pharmaceutical companies to ensure that brand products maintain unique appearances has long been a subject of legal debate. FDA requires generic drugs to be interchangeable in clinical effects, but allows products to look different. Thus brand manufacturers often adopt certain color patterns and identifiable shapes that can be protected under “trade dress” legal policy, originally designed to prevent illegal copying and counterfeiting. Trade dress protection does not apply to features affecting a product’s function, but can ward off outright imitation, explain Harvard Medical School professors Jeremy Green and Aaron Kesselheim (3). And there have been charges that brands have added scoring to tablets largely to delay generic entry.
Green and Kesselheim argue that growing use of generic drugs warrants changes in policy to make it easier for generic drugs to appear the same as brands. Research on placebo effect, they note, suggests that drug appearance has a noticeable effect on patients, particularly those with psychological disorders. And patients with multiple medical conditions frequently rely on drug color and shape to distinguish one medicine from another. Because drug physical attributes are not part of the new drug approval process under current regulations, the authors urge incorporating these factors into new drug applications to establish a clear process for generic manufacturers to formulate products with similar appearances (3).
1. FDA, Guidance for Industry, Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules, Draft Guidance (Silver Spring, Md., December 2013).
2. K. Karst, “A Hard Pill to Swallow? In Transit for a Couple of Years, FDA Finally Coughs Up Draft Guidance on Physical Attributes of Generic Tablets and Capsules,” www.FDAlawblog.net (Dec. 15, 2013).
3. J. Green and A. Kesselheim, New England Journal of Medicine, 365, 83-89 (July 7, 2011).