In the Field

GENERICS

FDA Aims to Approve Record Number of Generics

The US Food and Drug Administration launched a new program on Oct. 4 to increase the number and variety of generic drugs available to the public, beginning in fiscal year 2008. The Generic Initiative for Value and Efficiency (GIVE) will use existing resources to help the agency "modernize and streamline the generic drug approval process," according to FDA.

WARNING LETTER

"To keep pace with the increasing number of generic drug applications, FDA will implement some changes to the generic drug approval process," said Gary Buehler, director of FDA's Office of Generic Drugs (OGD), in an agency release. "The GIVE plan outlines ways to maximize the use of our resources so that FDA can review and approve even more high-quality generic drugs during the upcoming fiscal year than it did in 2007."

More than 600 generic drugs, which cost 30–80% less than brand-name drugs, were approved by FDA in fiscal year 2007. This number represented a 33% increase over fiscal year 2006. Although generic drugs undergo FDA review before approval, generic drugmakers are not required to repeat the extensive clinical trials that have already been used to develop the original drug, Buehler pointed out. "But they must scientifically demonstrate that their product is bioequivalent" or performs in the same manner as the brand-name product. Generic manufacturers must also demonstrate that the generic version delivers the same amount of its active ingredient over the same amount of time, and uses the same administration route as the brand-name drug.

Under the GIVE initiative, FDA intends to increase the number of applications it reviews and facilitate the review of applications to make more generic drugs available to the public more quickly. These efforts should cut down on the backlog (approximately 1300) of abbreviated new drug applications (ANDAs) within OGD. As a review-oriented program, FDA says that GIVE will focus on:

• Mobilizing staff efforts to increase review productivity

• Optimizing the capacity and capability of all assets within OGD and leveraging resources from other FDA components wherever possible

• Using every avenue possible to recruit, hire, and train reviewers for critical need areas

• Using new application review procedures to increase the number of low-cost-generic products available to consumers.

Specific GIVE improvements in the OGD review process, according to FDA information, will include:

• Revising the review order for certain applications. First generic products, for which there are no blocking patents or exclusivity protections on the reference listed drug, are identified at the time of submission for expedited review.

• Using a new review process for the chemistry, manufacturing, and controls information in the ANDA called "Question-based Review." The process is based on the Quality Overall Summary and other components of the common technical document and uses the principles of quality by design.

• Completing team reviews in the Divisions of Chemistry of multiple applications for the same drug product, including early review of drug master files to ensure timely resolution of any issues

• Encouraging sponsors to submit bioequivalence data in summary table format to enable a more rapid review of data

• Concluding the review of changes being effected (CBE) supplements with an approval, if appropriate, at the same time it is determined the proposed change qualifies as a CBE supplement

• Capitalizing on the capabilities of regulatory project managers in the divisions of chemistry and bioequivalence, including acting on administrative supplements and responding to requests for information

• Developing mechanisms to leverage the power of the Internet to provide dissolution and bioequivalence information, quality overall summary templates, bioequivalence data table formats, and microbiology review templates to the industry to ensure submission of full documentation of the quality of the products

• Increasing direct communication with individual sponsors and industry as a whole through communication about application-specific matters and providing training to the industry in meetings and webcasts.

OGD expects that GIVE will have positive results in the near term by providing for greater efficiency in document handling, storage, and retrieval, among other improvements.

-Angie Drakulich

USER FEES

Bush Signs Bill Reauthorizing PDUFA

President Bush signed the FDA Amendments Act (FDAAA) into law on Sept. 27, thereby reauthorizing the Prescription Drug User Fee Act (PDUFA). The act, H.R. 3580, will increase the agency's drug-safety authority, provide needed resources, and spur innovation.

Company note

FDA's Deputy Commissioner for Policy Randall Lutter said FDAAA allows the agency to collect at least $392 million in user fees per year. The new amount is $87 million more than the previous level and effectively triples the user fees for postmarketing safety surveillance. Lutter observed that PDUFA user fees make up nearly a quarter of FDA's total budget.

Reauthorizing PDUFA ensures "that our centers have the additional resources that are needed to conduct the very complex and comprehensive reviews of new drugs," Commissioner Andrew von Eschenbach said. He added that FDAAA provides continuity for many of FDA's important programs and "eliminates the possibility of significant, potentially very damaging, reduction" in the agency's workforce.

The law also establishes the Reagan–Udall Foundation, a nonprofit organization that will assist FDA by modernizing product development and stimulating innovation, according to Deputy Commissioner and Chief Medical Officer Janet Woodcock. The foundation will identify unmet research needs and form partnerships with scientists.

FDAAA calls on FDA to set up an electronic surveillance system to track adverse events. It also requires companies to submit postmarketing clinical-trial results to a database. Woodcock added that the legislation increases FDA's responsibility to protect children's health by extending the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act, which gives drugmakers an incentive to perform pediatric studies by granting six months of exclusivity.

See for more details on the FDA Amendments Act, in this issue.

-Erik Greb

INGREDIENTS

European Fine Chemicals Group Issues Position Paper on Excipients

The European Fine Chemicals Group (EFCG, Brussels) issued a position paper on excipients used in pharmaceutical manufacturing at CPhI Worldwide, held in Milan Oct. 2–4. Arnulf Heubner, chairman of EFCG's pharma business committee and director of pharma and food raw materials at Merck KGaA (Darmstadt, Germany) outlined the group's position as it seeks to improve the quality and regulatory aspects for excipients used in pharmaceutical products in Europe through the adoption of certain key proposals.

"By far the largest volume and weight of any medicine consists of a range of excipients, the manufacture of which varies, is covered by limited regulation and lacks legal enforceability," said Heubner. "I am, therefore, concerned that by allowing this situation to prevail we could be putting the health of European citizens at risk."

The EFCG outlined that with the implementation of the EU Directive 2001/83/EC (amended by Directive 2004/27/EC) into national law, it is now mandatory that all active pharmaceutical ingredients (APIs), and the yet-to-be-defined list of "Certain Excipients" used in pharmaceutical manufacturing, must be produced in compliance with current good manufacturing practice.

EFCG says its position paper builds on this expectation and proposes the following:

• That all "Common Excipients," by far the largest grouping, conform to the United States Pharmacopeia's General Chapter <1078>, including certified requirements by the International Organization for Standardization.

• That all "Specific Excipients" (which include "Certain Excipients") and "Novel Excipients," a much smaller defined group, are covered by EC Directive 2001/83 (amended by Directive 2004/27/EC), and that all these requirements are certified and effectively enforced.

"Specific Excipients" are pharmaceutically inactive substances that are associated with an increased risk potential, and therefore require an elevated degree of safety management, according to the EFCG position paper. The EFCG is proposing additional requirements and further classification, for example, for biologically derived excipients, sterile excipients, or excipients with a known track record of toxic contamination.

"Novel Excipients" are all "new chemical entities" excipients with "novel use" named in the European Medicines Agency's draft Guideline on Excipients in the Dossier for Application for Marketing Authorization of a Medicinal Product and all "Novel Biological Excipients," according to the draft position paper by the International Pharmaceutical Council Europe on Excipient Master File Systems in Europe.

"EFCG believes that the consequences of the full implementation of their proposals not only supports the need to better protect the health of EU citizens, but it also would bring into law what is already the accepted practice for a wide range of reputable suppliers in the Far East, North America, and Europe," according to an EFCG press release. "As such, it should have an insignificant effect on product prices."

-Patricia Van Arnum

REGULATION

Proposed Legislation Calls for Import User Fee

US House Representative John D. Dingell (D-MI), chairman of the Committee on Energy and Commerce, along with Reps. Frank Pallone (D-MI), chairman of the Subcommittee on Health, and Bart Stupak (D-MI), chairman of the Subcommittee on Oversight and Investigations, introduced legislation on Sept. 20 that would create a user fee on imported drug and food shipments.

"Increasing reports of contaminated imports have made it clear that the FDA does not have the resources and authority it needs to ensure the safety of our food and drug supply," said Dingel in a prepared statement. "This puts every American consumer at risk."

The Energy and Commerce Committee is conducting an investigation into the safety of the nation's drug and food supply, particularly the ability of the US Food and Drug Administration to adequately conduct inspections and perform laboratory analysis. The legislation, H.R. 3610, the "Food and Drug Import Safety Act of 2007," would specifically create a user fee on imported drug and food shipments. Funds generated by the fee would be used to hire additional personnel to perform inspections to increase analysis of drug and food imports. Funds would also be used to test import samples and research new testing techniques.

The legislation would also prevent the Secretary of Health and Human Services from closing or consolidating any of the current 13 FDA field laboratories and grant the agency new authority to:

• Issue mandatory recalls

• Require country-of-origin labeling for drugs, medical devices, and food

• Halt imports of certain products until a foreign facility can demonstrate that significant steps have been taken to rectify an identified problem

• Increase civil monetary penalties for manufacturers or importers that violate the Federal Food, Drug and Cosmetic Act.

Alan Goldhammer, deputy vice-president of regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), testified on the proposed legislation in late September. "While PhRMA believes that the United States drug distribution system is the safest in the world ... some steps ... will further secure the pharmaceutical supply chain." For example: increasing requirements for repackagers; strengthening federal requirements for wholesalers–distributors; and increasing criminal penalties for counterfeiting activities.

Patricia Van Arnum

GENERICS

Ranbaxy First to Offer Tablet and Suspension Forms

Ranbaxy (Haryana, India) received full market approval from the US Food and Drug Admnistration on Oct. 2 for its anti-infective agent clarithromycin oral suspension, USP (125 mg/5 mL and 250 mg/5 mL). The approval makes the company the first to win generic approval for the oral suspension form and the tablet form.

Company note

FDA's Office of Generic Drugs determined that Ranbaxy's formulation was bioequivalent and offers the same therapeutic effect as that of the reference listed drug, "Biaxin" granules of Abbott Laboratories. Total annual market sales for clarithromycin were $99.7 million, with suspension sales totaling $25.3 million.

-Maribel Rios

TRAINING FACILITY

New Center in North Carolina

North Carolina State University opened an 86,000-ft² biotechnology training and education center on Sept. 18 to teach manufacturing sciences in a real-time environment. Commercial-grade equipment is being used for the first time in a pilot-scale training facility to train students in microbial fermentation and cell-structure biotechnologies for the development of protein-based therapeutic drugs and commercial products. The facility, called the Biomanufacturing Training and Education Center, employs ABB's "Industrial IT System 800xA Extended Automation" technology, instrumentation, analyzers, and variable speed drives to achieve continuous validation and control of the bioreactors for real-time release under strictly maintained and regulated conditions.

-Alexis Brekke

ACQUISITION

Bristol-Myers Squibb To Buy Adnexus Therapeutics for $430 Million

Reflecting a strategic interest to strengthen its position in biologics, Bristol-Myers Squibb (BMS) agreed to acquire the biopharmaceutical company Adnexus Therapeutics (Waltham, MA) for $430 million on Sept. 24. "Bringing Adnexus into the Bristol-Myers Squibb family builds upon a successful and productive collaboration between the two companies in oncology and is an important step in accelerating the strategic transformation of our pharmaceutical business to a biopharma business model," said Jim Cornelius, chief executive officer at BMS, in a company release.

Company note

"Biologics are one cornerstone of our growth strategy. This investment in biologics discovery complements our continued investment in a growing biologics pipeline and portfolio, and will benefit from our expanding biologics manufacturing capabilities, both at our existing site in Syracuse, New York, and our future large-scale bulk biologics facility in Devens, Massachusetts."

Adnexus is a developer of a proprietary class of biologics called "Adnectins," which are derived from fibronectin, an extracellular protein that is naturally abundant in human serum. Fibronectin binds to other proteins using protein structures called targeting domains. An Adnectin consists of a backbone of the natural amino-acid sequence of a certain domain of human fibronectin and one to three targeting loops redirected to enable an Adnectin to specifically recognize a therapeutic target of interest, according to the company. The Adnectins are generated using the company's "Profusion" proprietary protein-engineering system. According to Adnexus, although Adnectins and antibodies have targeting domains with three-dimensional shapes that resemble each other, the amino-acid sequences of each protein class are distinctly different.

Under the deal, BMS will pay $430 million in cash for Adnexus,with the net purchase price of $415 million after deducting Adnexus' net-cash balance at closing. In addition, there is an earn-out structure that could result in BMS paying an additional amount of approximately $75 million, in three increments of approximately $25 million each, in the event certain development and regulatory milestones are achieved. The closing of the transaction is subject to customary regulatory approvals. Upon closing of the deal, Adnexus Therapeutics will become a BMS subsidiary and will remain located in Waltham, Massachusetts.

-Patricia Van Arnum