Generic Drugs Come of Age

Since the enactment of the Hatch-Waxman Act 25 years ago, the generic-drug industry in the US has grown exponentially. The landmark Drug Price Competition and Patent Term Restoration Act of 1984 generated more than 1000 applications for new generic drugs in its first year, boosting generic-drug use initially to 22% and to nearly 30% by 1989. Sales have tripled in the past decade, from $15 billion in 1999 to nearly $50 billion today. Generic drugs now account for 70% of prescriptions in the US, as health plans, payers, and pharmacy-benefit managers (PBMs) promote these inexpensive medications as a bioequivalent way to reduce healthcare costs and facilitate patient access to important treatments. Industry analysts anticipate further growth as brand-name products with about $60 billion in sales lose patent protection over the next two years.

Jill Wechsler

One aim of the 1984 legislation was to maintain a balance between encouraging generic-product development and maintaining incentives for innovation. This goal has been tested over the years by efforts on both sides to game the system. Generic-drug makers have aggressively challenged drug patents before scheduled expiration,

and brand-name manufacturers have delayed the market entry of generic drugs through 30-month stays, citizen petitions, and deals to "authorize" generic products that are less threatening to the brand.

Ensuring quality

Such intense market competition has generated disputes about the quality and safety of generic products. Officials at the US Food and Drug Administration maintain that the agency's test procedures and standards ensure that an approved generic drug will yield the same clinical results and safety profile as the reference product. Such assurance, though, requires clear documentation that generic drugs are made according to good manufacturing practices (GMPs) and in compliance with regulatory requirements.

Holding a majority of the market, generic-drug makers have to assume more responsibility for informing doctors and patients about how to use drugs safely, commented FDA's Deputy Commissioner Joshua Sharfstein at the annual meeting of the Generic Pharmaceutical Association (GPhA) in September 2009. He noted that overdoses of acetaminophen, for example, can cause liver damage and urged greater industry collaboration on important public-health issues.

At GPhA's fall technical conference in October 2009, Helen Winkle, director of the Office of Pharmaceutical Science (OPS) in FDA's Center for Drug Evaluation and Research (CDER), described efforts to ensure safety throughout the drug product life cycle that involve more collaboration between CDER offices that approve new drugs and those that regulate generic drugs. She anticipates that more information about how generic drugs will be involved in CDER's Safety First initiative will be included in an upcoming guidance.

The emphasis on safety should help the generic-drug industry deal with questions about product quality and general skepticism about the equivalence of generic drugs. Gary Buehler, director of OPS's Office of Generic Drugs (OGD), pointed to publications and television programs featuring individual patients who claimed extreme adverse reactions to generic therapies. Recent FDA approval of generic versions of new epilepsy treatments has generated complaints from neurologists about poor patient response and serious adverse events related to these new products.

In addition, a wave of product recalls and FDA warnings about lax generic-drug manufacturing practices have tarnished the industry's image and aggravated public concerns. FDA compliance officials are looking hard at drug companies in the US and abroad, Winkle noted, including generic-drug makers who fail to respond quickly and completely to Warning Letters or to plant-inspection citations.

Last year, FDA banned the importation of Ranbaxy (Gurgaon, India) products from two plants in India and subsequently halted the review of new applications until the company addressed charges of data-falsification at its Paonta Sahib, India, facility. FDA hit KV Pharmaceuticals (St. Louis) with a consent decree in March 2009 after years of inadequate responses to inspection reports and letters citing GMP violations.

Another consent decree requires Caraco Pharmaceutical Laboratories (Detroit) to submit a remedial plan and conduct audits of its Michigan facility following a high-profile product seizure. FDA also recalled some 50 drug products produced at Actavis's (Haf-narfjordur, Iceland) New Jersey plant and blocked the importation of drugs made by Apotex (Toronto) when the firm failed to address batch failures and GMP deficiencies at its Ontario plant.

Manufacturers have a responsibility to be vigilant in monitoring manufacturing processes and supply chains, particularly those for active ingredients and excipients, Winkle emphasized.

At the GPhA meeting, CDER compliance officer David Jaworski highlighted the importance of securing contractors and suppliers with a high commitment to quality. Contractor agreements, he noted, should allow for periodic audits, describe clear procedures for handling changes, and provide full information on deviations, changes, out-of-specification results, investigations, and adverse events.

As the demand for affordable generic drugs grows, it's important for the public to have confidence in these treatments, Buehler noted. "Many Americans are waiting for our products," he said, "but we want them to be the products they are waiting for."

Support for science

One way to address quality and safety concerns, said Winkle, is for "the ge-nerics industry step up to the plate" and support efforts to "strengthen the science underpinning FDA regulatory decisions." FDA researchers are examining the effects of excipients on bioavailability and new sequential designs for bioequivalence (BE) studies that may require fewer subjects to test highly variable drugs. Even with added resources, though, CDER is limited in its ability to support research projects, Winkle noted. FDA's Critical Path Initiative seeks industry collaboration on several research projects such as studies to support the development of generic products using metered-dose inhalers, topical drugs, and other challenging dosage forms.

Other parties are weighing in with further examinations of these issues. The National Institute on Neurological Disorders and Stroke at the National Institutes of Health aims to address the controversial question of whether new generic anticonvulsants may pose safety problems for some patients by studying the pharmacokinetic results of patients who have reported problems with generic drugs. The goal is to determine whether any measurable difference exists between responses to brand and generic products.

Payers and PBMs also are examining generic-drug quality and efficacy to support prescribing decisions when new generic drugs come to market. In anticipation of generic versions of the sanofi aventis (Paris) and Bristol-Myers Squibb (New York) anticlotting drug Plavix (clopidogrel) in two years, Medco has launched a large observational study comparing deaths and

heart problems of patients prescribed Plavix with those experienced by patients using Eli Lilly (Indianapolis) and Daiichi Sankyo's (Tokyo) Effient (prasugrel). Through pharmacogenetic assessments, the study will identify patients who can metabolize Plavix normally who would fare well with a generic drug, and the smaller group who should be allowed to stay with the expensive brand prasugrel.

The results of such research can help the public understand the meaning of BE and confidence intervals. One way for sponsors to address anecdotal claims about varying responses to generic products, Buehler suggested, is to add another reference arm to BE studies to examine more conclusively whether differences appear between multiple lots of the reference product.

Review pile-up

Although some manufacturers support such analysis, they are more focused on how FDA can improve the generic-drug approval process. Generic-drug makers complain that it still takes almost two years, on average, to gain approval of an abbreviated new drug application (ANDA), and that backlogs in pending applications continue to rise. OGD receives more than 800 ANDAs per year (up from about 350 in 2002) and approves about 600; the result is more than 1600 pending applications. Congress stipulated that OGD receive an extra $10 million in its 2010 budget, but the office needs another 100 staffers to clear the backlog and perform all its functions as required, Buehler acknowledged. An obvious solution is to establish a user-fee program for generics, but so far negotiations have failed to establish a viable fee system. Last year, the Obama administration proposed a $36-million fee program for generics, which was more than double previous levels, but industry opposed the plan and Congress dropped it.

Sharfstein emphasized at the GPhA meeting that reducing the backlog of generic-drug applications was a top priority for FDA's leadership, but that a user-fee program was needed to achieve this goal. At that meeting, both Sen. Orrin Hatch (R-UT) and Rep. Henry Waxman (D-CA) agreed on the need for increased funding for OGD and for generic-drug user fees. The funding would expedite the review process for generics, said Hatch, and speed consumer access to medicines. Waxman noted that a user-fee program should come with "real accountability" on the length of review processes and on transparency on regulatory decisions.

Industry leaders say they're willing to reopen negotiations in what they now regard as a congenial environment at FDA. The agency's progress in responding to citizen petitions within a new six-month timeframe and in dealing with 30-month stays is encouraging manufacturers to map out performance metrics that could form the basis of a fee program. "But we want some value for what we're paying," said Bill Marth, president of Teva North America. This could include specified consultations on the development of complex dosage forms and timely plant inspections, as well as quicker application approvals.

At the October 2009 GPhA meeting, Buehler reported on various initiatives to make OGD more responsive and more efficient than before. The microbiology review team has been expanded, and a new team structure for the BE review staff has improved its performance. Added funds may support another chemistry-review division in the coming year, Buehler said. Almost all ANDAs are adopting FDA's Question-based-Review (QbR) system, and a QbR for microbiology is in the works. CDER's 21st-century review process, which focuses on improving application reviews for new drugs, may help generic-drug applicants by freeing up new drug reviewers for consultations on complex generic products.

A key issue for OGD staff is inconsistent quality in ANDAs. Manufactures frequently present different data in different sections of an application and fail to fully justify in-process parameters and proposed product specifications. Complete and coordinated applications would help OGD review and assess ANDAs in the first review cycle and save time and money on all sides.

Battle over biosimilars

More research on the quality and safety of generic drugs should support the future development of generic versions of large molecules, an important goal of the generic-drug industry. New legislation is expected to establish a pathway for FDA to approve follow-on or similar versions of biological therapies. The regulatory framework for follow-on biologics is not expected to be the same as that established under Hatch-Waxman for conventional drugs, but the debate continues over how much clinical research should be required to document similarity between an innovator and a follow-on product, and over how much exclusivity brand manufacturers should be granted to stimulate new research and development.

Healthcare-reform legislation moving through Congress proposes 12 years of market exclusivity for innovative therapies, a term championed by pharmaceutical and biotechnology companies, but hotly opposed by generic-drug firms as likely to block biosimilar development. A long exclusivity period, said Marth, "will result in few, if any, generic biologics and less, rather than more, innovation." Teva would be involved in this market, he predicted, but as an innovator firm.

Almost as contentious as the exclusivity issue is what kind of framework will be established for resolving patent disputes. Proposals differ for requiring the disclosure of patent information, for challenging patent terms, and for communicating pending challenges to the involved parties. Generic-drug makers won a small victory by gaining Senate approval of an amendment to assign the same Medicare billing code to brand and follow-on products, an approach that would encourage the use of biosimilars. But this policy has much less of an impact on research and development decisions than the data-exclusivity term does.

Carve-outs and settlements

While seeking political support for follow-on biologics, generic-drug manufacturers also have gone on the defense to oppose policies designed to reduce generic-drug use. One threat comes from state "carve-out" laws, policies that limit the ability of pharmacists to substitute a generic product for a brand prescription. Such approaches reflect fears that certain drugs raise safety and substitutability concerns and require special attention by prescribers and additional protections for patients.

Generic-drug makers also oppose efforts by brand-name manufacturers to market authorized generic products just before patent expiration to delay generic competition during the 180-day exclusivity period. The looming wave of patent expirations is prompting the development of more branded generics by pharmaceutical companies. These drugs are produced either by the original manufacturer or under contract by a generics maker. Major pharmaceutical manufacturers are purchasing generics firms around the world to become more prominent in generic-drug marketing.

Interestingly enough, both innovators and generic-drug companies want the flexibility to settle patent disputes through agreements involving pharmaceutical payments to generic-drug firms to delay market entry until an agreed-on future time. The Federal Trade Commission (FTC) and other critics have labeled these pay-for-delay deals as anticompetitive, but manufacturers on both sides claim that such arrangements can avoid lengthy patent battles and end up accelerating consumer access to generic products. FTC has gone to court to block several delay settlements, and Congressional leaders seek to impose curbs on such deals.

Going global

One benefit of the generic-drug industry's growth has been expanded access to high-quality, low-cost medicines around the world. Federal government efforts to ramp up the distribution of treatments for HIV and AIDS in Africa and other developing areas initially faced a dilemma. The most effective brand-name combination AIDS therapies were expensive and would quickly eat up program funds, but policymakers considered it unethical to purchase less effective old-line generics or products that might be counterfeit or adulterated.

The solution was to establish an FDA program that grants tentative approval to generic versions of patented AIDS therapies for distribution overseas. During the past five years, consequently, FDA has approved more than 100 generic drugs for the President's Emergency Program for AIDS Relief (PEPFAR), including 71 generic versions of antiretrovirals that are marketed in the US and not yet eligible for generic competition because of patents and exclusivity. Permitting PEPFAR to access these less costly, high-quality products saves the program $150 million per year, commented FDA Commissioner Margaret Hamburg, and thus increases the amount of quality products PEPFAR can make available to treat people around the world.

The policy also demonstrates that there is "no double standard for the US and the rest of the world," commented OGD director Buehler. "It is something that the generic industry should be proud of."

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com