The Push for Generic Drugs Accelerates

It seems that everyone wants access to more generic drugs more quickly. Officials heading government health programs, insurers, and pharmacy benefit managers are promoting generic drugs as a safe and effective way to improve patient care while controlling drug expenditures. Consumers eye generics as a way to cope with higher copays for brand-name drugs. Wal-Mart made headlines in October by announcing a set $4 price for many generic products. And, Medicare drug plans are trying to attract seniors by covering generic drugs through the program's confusing "donut hole."

Jill Wechsler

These and other developments are expanding demand for high-quality generic drugs, for additional dosage forms, and for expensive biotechnology therapies (see sidebar, "Generics outpace growth in drug sales"). Members of Congress have introduced legislation laying out a pathway for bringing lower-cost biopharmaceuticals to market. Democratic gains on Capitol Hill now set the stage for the issue to gain more momentum in Congress in the coming year.

At the same time, the push for more generic drugs has complicated the US Food and Drug Administration's challenge of keeping up with a soaring volume of abbreviated new drug applications (ANDAs) and improving policies and programs. The US Department of Health and Human Services Inspector General is investigating the causes of long approval queues and growing backlogs. FDA is looking for more-efficient regulatory approaches as well as expanded resources.

Generics outpace growth in drug sales

The only rain on this progeneric parade comes from the innovator pharmaceutical industry. Brand-name manufacturers continue to defend patents and to implement strategies to protect markets for lucrative products. Some of these activities draw criticism from healthcare providers and patient advocates, but failure in the generic–innovator patent battles carries severe consequences, as seen in the "Plavix" (clopidogrel) debacle at Bristol-Myers Squibb in recent months. At the same time, pharmaceutical companies are moving more visibly into generic-drug production to reap some of the rewards of this market shift.

Manufacturing issues key

While economic forces drive the clamor for generic versions of biologics and other drugs, more efficient and technically advanced analytical and production systems underlie the ability of manufacturers to produce follow-on versions of complex medicines. Demonstrating the comparability of large molecules, inhalants, and topicals requires an understanding of molecular structure, dosage forms, heterogeneity profiles, impurities, and degradation patterns. If companies must repeat much of the innovator's preclinical and clinical testing, they will end up with highly expensive follow-on biopharmaceuticals, many priced just 25% below the innovator products.

Nevertheless, the prospect of any cost savings has been fueling efforts to establish a pathway for developing follow-on versions of biopharmaceuticals. Because the quality of therapies produced from living cell cultures is variable, even politicians recognize that it may not be possible to develop identical or therapeutically equivalent biotechnology generics. But, many manufacturers and policy makers believe that some kind of abbreviated research and development process could yield more affordable biotechnology treatments.

FDA has held meetings about the scientific and technical issues related to developing follow-on protein products, the agency's preferred term, but the legal and political infighting has delayed a long-promised white paper about the relevant regulatory issues. A key point of contention is whether generics firms would have to conduct a full battery of clinical trials to document that a follow-on product has an efficacy and immunogenicity profile similar to that of a reference product. Biotechnology and pharmaceutical companies insist that another manufacturer cannot access proprietary clinical or manufacturing data about biologics and that new legislation is needed to clarify FDA's regulatory authority in this area.

In Washington This Month

The Hatch–Waxman Act of 1984 established a legal process for developing generic versions of conventional drugs regulated by the Food, Drug, and Cosmetic Act, but does not apply to proteins and other biologics that fall under the Public Health Service Act. Although new legislation is needed to address that issue, generic-drug advocates believe that Hatch–Waxman should apply to biologics such as insulin and human growth hormone that are regulated as drugs. FDA has drafted guidances for developing generic versions of these products, but has not released them, despite demands from members of Congress, state governors, and generics manufacturers to do so. In response to a call from several governors for FDA to "help states reduce the burden of excessive pharmaceutical costs," the agency said in April 2006 that it was holding off on product-specific guidances for biogenerics to draft broad requirements for approving all follow-on biologics.

Action on Omnitrope

While efforts to clarify FDA regulatory policy have been on hold, the agency was compelled to consider approval of a follow-on version of the human growth hormone "Omnitrope" from Novartis's generics unit Sandoz. FDA approved this first biotechnology therapy made by another manufacturer last May, but this was almost three years after Sandoz submitted its application and only when a federal court ruled that the agency must stop stalling and act on the submission.

Sandoz adopted the 505(b)(2) application route, which permits a manufacturer to tap publicly available data about a reference product instead of duplicating all preclinical and clinical studies. FDA explained that it approved the application because Omnitrope is a well-characterized product with a well-known primary structure and mechanism of action and publicly available bioassays and biomarkers. The agency determined that it was sufficient for Sandoz to document the safety and effectiveness of its own system for the cell expression, fermentation, isolation, and purification of the active ingredient, instead of demonstrating that Omnitrope has the same active ingredient as its reference drug (Pfizer's "Genotropin"), as is required for conventional ANDAs.

Moreover, Sandoz conducted several clinical trials to demonstrate a similar safety and efficacy profile plus a sufficiently low level of immunogenicity. Even though the scope and duration of these studies represents a modified clinical program, the trials avoided reliance on innovators' proprietary data. FDA thus rejected petitions opposing the approval from Pfizer, Genentech, and the Biotechnology Industry Organization.

At the same time, the agency did not rate Omnitrope as equivalent to Genotropin. And, FDA emphasized that this approval does not establish a pathway for other biotechnology products to come to market, including other proteins regulated as drugs.

Proposing legislation

In explaining its action on Omnitrope, FDA reiterated its request for new legislation to clarify its legal authority to approve follow-on versions of any biotechnology therapies. Just before Congress recessed in October, three leading Democratic legislators offered a proposal to move the debate forward. Rep. Henry Waxman of California and Sens. Charles Schumer and Hillary Rodham Clinton of New York introduced the "Access to Life-Saving Medicine Act" (HR 6257) that describes an approach for approving copies of biopharmaceuticals. Although the legislators acknowledge that more complicated scientific issues are involved in demonstrating that a generic version of a biotechnology drug is the same as the branded product, they assert that the Omnitrope approval shows that such action is "scientifically feasible."

The bill authorizes FDA to approve abbreviated applications for biological products that are "comparable" with previously approved (reference) biologics. FDA will determine on a case-by-case basis which clinical and preclinical studies are necessary to establish comparability, and all applicants for follow-on biologics would pay user fees.

A summary of the bill emphasizes the importance of technical and scientific expertise for documenting comparability. The manufacturer must show that its product shares the "principal molecular structural features" and has the same mechanism of action (if known), route of administration, dosage form, and strength. Manufacturing controls must be established to ensure product identity, strength, quality, and purity.

The legislation also encourages manufacturers to conduct additional testing to demonstrate that a drug is interchangeable with the reference product, instead of just being comparable. Interchangeable products would produce the "same clinical result(s)" as reference products, a claim that would require clinical testing because there is no simple bioequivalence study for biologics as there is for conventional drugs. Because interchangeable products would be "significantly more costly and difficult to produce than comparable products," the bill offers manufacturers tax credits to cover the extra studies, plus six months exclusivity for the first applicant that establishes interchangeability. The policy becomes a little murky, though, because it permits FDA to approve a subsequent comparable biotechnology product while the initial exclusivity period is in effect for the interchangeable drug.

The bill also aims to prevent innovator firms from maneuvering to extend patents and block new follow-on products from market. It prohibits brand-name firms from producing authorized generics during the exclusivity period and imposes curbs on "frivolous" citizens' petitions. And, the measure seeks to resolve patent disputes early on by establishing a new patent listing and notification procedure that requires the manufacturer of a reference product to disclose all valid related patents so that generics firms know which patents to challenge.

A call for user fees

Because follow-on biologics would be more difficult and time-consuming for FDA to assess and approve, the bill establishes user fees for follow-on biologics applications to boost agency resources. This move may set a precedent for the generic-drug industry, which is the only drug-industry segment that does not ante up to file applications or support FDA oversight of marketed products. The issue has been discussed for years, and the current squeeze on FDA resources has put generic drug user fees on the table as part of the debate on the renewal of the Prescription Drug User Fee program in the coming year.

Officials at the Generics Pharmaceutical Association (GPhA) point out that long delays in bringing new generics to market sometimes occur even after FDA approves an application, making it unfair to require generics makers to pay a fee and wait months to resolve patent disputes before being able to sell their products. But, FDA has been pushing for more fees unofficially and emphasizes that its Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER) needs more staff to deal with its mounting workload in a timely manner.

In fact, the number of ANDAs has been growing steadily as important blockbuster drugs lose patent protection. In fiscal year 2006, which ended on Sept. 30, OGD approved a record 510 ANDAs, passing the 500 mark for the first time. The list includes several first-generic products such as pravastatin ("Pravachol"), sertraline ("Zoloft"), simvastatin ("Zocor"), clopidogrel ("Plavix"), and fluticasone ("Flonase" nasal spray).

Despite the boost in approvals, OGD's backlog swelled to more than 1500 pending applications because the total number of submissions rose to almost 800 this past year. "If you approve 500 applications but get 800 submissions, the backlog number is going to go up," lamented OGD Director Gary Buehler at the GPhA fall meeting in October. OGD's 200 staffers are struggling to reduce application review times. About 70% of ANDAs were assessed in less than 14 months, but difficult submissions boosted the median approval time to 16.6 months.

In addition to dealing with applications, OGD had to process more than 1700 letters last year (up from about 500 in 2000) that sought information on generic-drug testing, development, and regulatory issues. Citizens' petitions, lawsuits, and queries from manufacturers all add to OGD's workload.

Streamlining efforts

In response, FDA is trying to make OGD processes more efficient and productive. A new policy will permit the agency to modify its "first-in, first-reviewed" rule to quickly approve certain applications for products that address public-health needs. CDER Director Steven Galson announced at the GPhA conference that FDA would expedite the approval of applications for a first generic version of a drug, provided no patent or exclusivity issues arise. The six-month review policy also applies to certain AIDS therapies and to products that meet public-health emergencies and drug shortages. The program is expected to affect only a handful of drugs each year, but represents a visible effort to make the OGD approval system more flexible.

Buehler already has instituted joint reviews for multiple applications for the same drug, instead of repeating the process for each ANDA separately. Another key initiative is to encourage electronic submissions of ANDAs based on the format of the Common Technical Document (CTD). The office received 26 electronic CTD submissions through the end of August 2006 and is encouraging more. OGD also seeks to improve operations with several new measures.

One plan suggests implementing the Question-Based Review (QbR) program. FDA approved the first QbR application in September after an eight-month, one-cycle review. OGD's call for all ANDAs to follow the CTD format as of Jan. 1, 2007 should help expand the QbR approach.

Another tactic entails finalizing the Individual Product Bioequivalence Guidance. This long-anticipated listing of bioequivalence data for more than 300 drugs promises to reduce queries from manufacturers. Last year, OGD established a public Dissolution Methods Database with recommended dissolution methods to help streamline product development and review.

In addition, OGD hopes to reduce the application queues. To speed up reviews of clear and complete applications, OGD's Division of Bioequivalence is using an abbreviated review process for assessing bioequivalence data for uncomplicated, immediate-release products. Separately, chemistry review teams are shifting around applications to prevent any one group from being overloaded. And, noticeable delays in microbiology reviews are prompting efforts to develop a more efficient review template.

Finally, OGD hopes to achieve more first-cycle reviews. Increased use of telephone communications late in the review process can inform an applicant of minor problems that can be remedied easily. This year, OGD approved 63 applications in one cycle, compared with only three in 2004.

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