Generic Drugs for Everyone

At a time when healthcare costs are escalating and millions of Americans are uninsured, generic drugs have emerged as the answer to the nation's healthcare woes. Low-cost prescription drugs can ease patient access to medicines, reduce insurance outlays, curb Medicare and Medicaid spending, and improve the overall quality of care.

Jill Wechsler

The clamor for generic drugs puts added pressure on the US Food and Drug Administration to bring new generic drugs to market as fast as they can be developed, produced, and evaluated. This task will remain a challenge as more blockbuster brand-name products lose patent protection, thus generating more applications and other documents for the agency to consider.

FDA is doing all it can to streamline its generic-drug review process. The agency's lack of resources makes the task difficult, however, as do established policies that often delay when a new generic product can come to market. The debate continues about whether generic versions of biotechnology therapies can be safe and effective and less costly than their more complex reference products.

FDA officials would like to collect user fees from generic drug makers to expand the agency's resources devoted to this area. Industry, however, wants to link fees to clear improvements in the review process and reduced barriers to market. Future legislation to facilitate approval of "biosimilars" may provide a vehicle for a generic-drug user fee program as well as other changes in current policies governing generic-drug development and approval.

Taking initiative

A main challenge for generics makers is to move applications as fast as possible through a complex review process for abbreviated new drug applications (ANDAs). FDA's Office of Generic Drugs (GPhA) has launched several new initiatives during the last few years to accelerate reviews and reduce application backlogs. The initiatives have facilitated the approval of some important new generic therapies in recent months, including generic versions of extended release pro-ducts, inhalation solutions, and a leading topical product. FDA also has provided expedited reviews for important generic versions of AIDS treatments, which qualifies the products for purchase by the President's Emergency Plan for AIDS Relief, which provides drugs to Africa and developing nations.

Yet the steady rise in new ANDAs coming in the door makes it hard to raise FDA's productivity. OGD received 877 ANDAs in fiscal year 2007 (ended Sept. 30, 2007), a new high in submissions. Even though the office set another record when it approved more than 600 ANDAs, another 200 or so applications were added to an unending backlog. More than 1300 ANDAs currently await approval, a process that takes 16 to 17 months. At the current rate of submissions, the agency finds it difficult "to keep up with everything," said Helen Winkle, director of the Office of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER), at an October conference sponsored by the Generic Pharmaceutical Association (GPhA).

In addition to ANDAs, each newly approved generic drug generates multiple chemistry, manufacturing, and controls (CMC) supplements. CDER receives about 4000 CMC supplements each year for brand and generic drugs and biotechnology therapies. The volume has inspired an initiative to reduce the number of supplements that must be submitted in advance to the agency. FDA hopes to issue guidance in early 2008 that identifies a lengthy list of low-risk postmarketing changes that may be filed in annual reports instead of as supplements. Winkle anticipates that this initiative will reduce the supplements that FDA must review by 60%.

OGD also must deal with a massive amount of regulatory correspondence—more than 1300 documents this year, reported OGD Director Gary Buehler at the GPhA meeting. About three-fourths of the letters seek information on bioequivalence data requirements. OGD's Division of Bioequivalence takes 16 months on average to answer the letters individually.

Plus, a growing number of citizen petitions raises both legal and scientific issues. FDA receives 20 to 25 petitions each year. Most require 8 to 10 months to review, although some take years, Winkle noted. Responding to petitions is a highly variable process that may involve CDER's Office of New Drugs, FDA lawyers, regulatory officials, and OGD. As a result, more than 60 petitions are pending.

The recently enacted FDA Amendments Act (FDAAA) includes a provision designed to prevent citizen petitions from delaying generic approvals, but it's unclear what the impact of the measure will be. The bill calls for FDA to resolve the issues raised in a citizen's petition within six months. During this process, GPhA may continue to review and approve ANDAs affected by the petition, instead of waiting for full resolution of the issues, as has been the practice. But OGD will need added resources to meet these new requirements, and it's not clear where the funds will come from.

Buehler also pointed out that reviews take longer when ANDAs lack necessary information. Of almost 900 ANDAs filed last year, the agency rejected 96, most often because of the manufacturer's failure to provide full bioequivalence data, dissolution data, or information about inactive ingredients. Insufficient applications also frequently have omissions regarding the source of active ingredients and other suppliers and lack complete drug master file data.

Seeking solutions

In September, FDA Commissioner Andrew von Eschenbach unveiled what was billed as a new initiative to improve the ANDA review process. The Generic Initiative for Value and Efficiency (GIVE) program aims to increase OGD's productivity by consolidating activities, hiring more staff, improving communication with industry, and encouraging electronic submissions. A main provision is to expedite reviews of first generic products that do not have to overcome blocking patents or exclusivity protections to reach the market. But manufacturers complained that the plan offered nothing new. The GIVE program fails to address the serious legislative and regulatory issues that block consumer access to generics, said GPhA President Kathleen Jaeger. "Another initiative in name only simply will not get the job done."

In Washington This Month

Many of the GIVE proposals already were on OGD's agenda. The office is posting individual bioequivalence recommendations on the FDA website and plans to issue a draft guidance on the issue in coming months. A database of recommended dissolution methods also has 450 entries, primarily for immediate-release products.

More ANDAs are being approved after only one review cycle, Buehler pointed out. OGD has begun simultaneous assessment of multiple applications for the same product and is moving more high-priority products up the review queue. But these strategies provide only minor assistance in addressing OGD's difficulties in keeping up with a mushrooming volume of work.

Asking questions

A leading OGD initiative for establishing a more efficient and science-based submission and review approach is its Question-based Review (QbR) system, which was fully implemented this year. The QbR method provides manufacturers with a series of questions about pharmaceutical development, drug-product components, manufacturing-process development, and container-closure methods that collectively provide important information for the quality section of the Common Technical Document (CTD). To answer the questions, the sponsor taps its pharmaceutical development reports to describe how the drug product was designed to have certain attributes and how critical manufacturing steps relate to product quality.

In the area of drug-product stability, for example, a QbR assessment seeks an understanding of stability design, how formulation variables affect stability, and how to assess stability in future drug batches. QbR encourages sponsors to provide tables, process-flow diagrams, and other graphics that can help OGD reviewers. The information from product development reports also can explain a sponsor's choice of formulations, especially for less conventional dosage forms.

After months of fine-tuning, the QbR program appears to be gaining traction among manufacturers. OGD has received about 500 applications in the QbR format this year, and most new ANDAs now follow this approach. The review and approval of 15 QbR applications so far has taken 10 months each on average. Buehler hopes that QbR will cut review time by about 20%, but evaluating full product development information may initially take more time. Manufacturers and FDA reviewers are still getting used to the new approach, and many applications contain incomplete or superfluous information. If successful, though, FDA may consider establishing a similar process for innovator drugs.

OPS is also implementing a Quality Management System for all CMC review processes, said Winkle. And the agency hopes to identify ways to streamline its Drug Master File system. An increase in electronic submissions would contribute a great deal to streamlining OGD's review process, but generics firms have been slow to adopt the necessary computer systems. FDA is encouraging companies to provide bioequivalence data electronically in summary tables based on CTD guidelines. This process can facilitate a streamlined administrative review of well-known and well-studied products.

A major disruption in OGD's work will occur early next year when about 900 agency staffers move to FDA's new White Oak, Maryland, campus. The move will bring all OGD employees to the same location, which will improve communications within OGD and with other CDER operations. But the shift will slow down OGD's regular work temporarily and require patience on all sides, Winkle noted.

Seeking support

With more applications and other documents coming in the door, OGD ultimately will need more staffers to handle the volume efficiently. The FDA budget has provided additional funds for OGD in recent years, but those increases barely keep up with the rising work load. To reduce ANDA approval times significantly, generic-drug manufacturers may have to pay user fees. FDA officials have been negotiating such a program with industry for several months, but the talks have been inconclusive. Manufacturers want to establish a set of performance measures for the ANDA review process and obtain a clear commitment of resources from FDA. Most important for industry is to curb regulatory and legal barriers to market access for generics. This goal would involve the reform of the citizen's petition process, curbs on authorized generics, and limits on late labeling changes by brand-name firms.

Without clear performance measures and timeframes for generic drugs to actually reach the market, said Jaeger, "it's just throwing money down a hole." FDA believes that added resources will enable it to resolve issues raised in citizen petitions more quickly, but is reluctant to set specific review timeframes. The steady growth in applications and other tasks for OGD makes it difficult for FDA to commit to reviewing, for example, 90% of the applications within certain timeframes, Winkle points out.

Approving FOBs

A generic-drug user-fee program could be established as part of legislation to authorize approval of follow-on biologics (FOBs). Generic-drug manufacturers pushed hard to include FOB provisions in FDAAA based on legislation approved in June by the Senate Health Committee, but the provisions were dropped in the end. In early September, Rep. Henry Waxman (D-CA) told a GPhA meeting that chances of adding generics biologics legislation to FDAAA were "extremely slim." And Rep. Frank Pallone (D-NJ), who chairs the House Energy and Commerce Health subcommittee, said that the House would not just "take the Senate bill" but would hold hearings on FOBs later in the year. Now Democrats may wait until after the 2008 presidential elections to tackle the issue.

FOB advocates concede that gaining consensus on biosimilar legislation will take time because of the considerable debate about what kind of exclusivity to grant innovator biologics. The Senate bill provides protection for 12 years, a period designed to encourage continued research and development investment by biotechnology companies. This term is less than the 14 years demanded by the Biotechnology Industry Organization, but much more than generics makers consider reasonable. Waxman told GPhA that he wants to see hard data supporting any exclusivity period, and that the brand industry "can't just make up these numbers."

Another contentious issue is interchangeability. Innovators maintain that "similar" does not mean "the same" and that a biosimilar should not be considered interchangeable or have the same generic name as the innovator, as is the case for conventional generic drugs.

Meanwhile, the biogenerics bandwagon is picking up steam. The European Union has approved new biosimilar versions of epoetin, and additional biosimilar applications are pending. Generics makers, as well as small biotechnology companies, maintain that analytical advances make characterization of FOBs more precise, but are willing to accept FDA case-by-case review of FOB applications. Even if biosimilars cost only 25% less than innovators, manufacturers predict significant cost savings for patients.

Promoting innovation

Officials at the US Food and Drug Administration are urging drug manufacturers to support initiatives to improve the science behind generic-drug development. Proposals are outlined in a list of "Critical Path Opportunities for Generic Drugs" issued in May 2007. Research projects that could establish new tools for assessing drug absorption and release and provide alternative methods for determining equivalence would benefit the development of generic versions of conventional drugs, as well as of nonoral dosage forms.

For locally acting drugs such as nasal sprays, inhalation drugs, topical treatments, and certain gastrointestinal drugs, FDA describes opportunities to use new imaging and pulmonary testing methods to assess bioequivalency. Better methods for characterizing complex drug substances and products may support a streamlined approach to developing generic versions of biologics.

FDA also would like generic-drug makers to become more involved in efforts to improve the science underlying quality by design (QbD) approaches for drug development and manufacturing. Janet Woodcock, FDA's deputy commissioner and chief medical officer, has been promoting QbD for innovator drugs for several years as key to modernizing regulatory oversight of drug manufacturing and testing. Now she and her colleagues want to explicitly extend this initiative to generic-drug production. Quality issues are equally important for generics, Woodcock said, noting that generics now constitute the majority of prescription-drug consumption. And, more efficient production methods are particularly important in a highly competitive industry that experiences tight profit margins, she told generics makers at a September Generic Pharmaceutical Association conference.

A QbD approach, moreover, can help ease FDA's regulatory burden and support a more efficient review system, Woodcock pointed out. The Office of Generic Drugs's question-based review system provides a framework to enable FDA to assess critical formulation and manufacturing process variables and set regulatory specifications relevant to product quality. Such information can help FDA determine the level of risk relative to product design and use and eventually enable generic-drug makers to be more flexible in making postapproval changes without having to file a supplement.

More efficient methods for ensuring drug quality also promise to maintain the safety of generic drugs, pointed out Helen Winkle, director of the Office of Pharmaceutical Science at the Center for Drug Evaluation and Research. Drug safety is a top priority for FDA, and it's "just as important for generic drugs as it is for innovators," she commented. Provisions in recently enacted FDA legislation and in the reauthorized user-fee program for prescription drugs will lead to upgrades in the agency's adverse-event reporting systems, expanded access to health-safety databases, and a new tracking system for managing postmarket drug-safety issues—all likely to increase postmarket scrutiny of prescription drugs overall.

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