November 2005

REGULATION

FDA Proposes New CMC "Regulatory Agreement"

Moheb Nasr, PhD, director of the newly created Office of New Drug Quality Assessment at the US Food and Drug Administration (Rockville, MD, www.fda.gov), has proposed creating a "regulatory agreement" between FDA and sponsors to govern the chemistry, manufacturing, and controls (CMC) sections of new drug applications (NDAs).

Representatives of industry and FDA discussed the proposal at the Oct. 5–7 AAPS Workshop on Pharmaceutical Quality Assessment in North Bethesda, Maryland, as part of a broad examination of FDA's planned overhaul of the way it reviews CMC submissions and regulates manufacturing quality.

The new agreement could provide a structure for the regulatory flexibility that FDA has said will be possible for manufacturers who demonstrate a thorough scientific understanding of their manufacturing processes. As proposed, the agreement would include binding CMC elements such as critical process parameters or critical quality attributes, and would define the boundaries of a "design space" within which manufacturers could implement changes with limited or no filing of manufacturing supplements.

During three breakout sessions held to discuss the proposal, workshop participants generally voiced support for a regulatory agreement because it could help all parties—industry sponsors, reviewers, and inspectors—focus on the most important aspects of a CMC application. "In the current system, the entire NDA functions like a regulatory agreement," noted one industry participant. Participants raised concerns, however, about the legal implications of the term agreement and whether the agreement would end up being an additional requirement or a burden on industry. Some also commented that for an agreement to be useful, it must be agency-wide; in other words, inspectors must have the same understanding as reviewers about the meaning and application of the agreement.

During the two-and-a-half-day workshop, attended by 600 people (about two-thirds of whom were from industry and the other third from FDA), participants met in a series of repeated breakout sessions to discuss key concepts underlying Nasr's proposed "new paradigm" for CMC review. Key topics included the definition and use of design space, the use of pharmaceutical development information in CMC submissions, the handling of postmarketing changes, the use of a comprehensive quality overall summary (QOS) as part of CMC submissions, and whether the QOS could or should be a key tool for the review of the submission, or simply an executive summary.

Yukio Hiyama, PhD, of Japan's National Institute of Health Sciences, said Japan relies on a QOS as the primary review document. "We review the submission in half a day," he said.

Throughout the meeting, the consensus was that implementing these concepts would be challenging and would require a critical transition period. Helen Winkle, director of the Office of Pharmaceutical Science, noted that in the transition, there would be early adopters, companies that would stay in the current paradigm, and those taking the middle ground by only implementing moderate changes. "The middle group will be the hardest to manage," she said. Winkle noted that the journey to change will require "moving into unfamiliar ground for everyone."

–Laura Bush

FDA

Tumult at FDA: Crawford Leaves, von Eschenbach Arrives

US Food and Drug Administration (Rockville, MD, www.fda.gov) Commissioner Lester M. Crawford resigned abruptly on Sept. 23, after only two months in the top spot, generating considerable uncertainty about the future leadership of the agency. The White House immediately named Andrew C. von Eschenbach, MD, director of the National Cancer Institute (NCI, www.cancer.gov) at the National Institutes of Health (NIH), as acting FDA commissioner. Von Eschenbach initially said he would continue as NCI director while taking the helm of FDA.

In the face of sharp criticism, however, von Eschenbach agreed to hand over active NCI leadership. He issued a memo on Sept. 30, just a week after assuming his FDA position, stating that John Niederhuber, a newly appointed NCI deputy director, would take over day-to-day management of the Institute. Von Eschenbach also said that he would not participate in the approval of new drug applications or other FDA matters that involve NCI research.

Senate Finance Committee Chairman Charles Grassley (R-IA) called for an FDA commissioner "who can be totally dedicated to the job." Sen. Edward Kennedy (D-MA) noted the "immense challenge" in managing either FDA or NCI and that was "unfair to the nation" for one person to attempt to run both.

Von Eschenbach officially remains director of NCI, a position he wants to retain because HHS secretary Mike Leavitt has indicated that the acting commissioner will not be named to take the reins at FDA permanently. But, he has moved his office to the FDA Parklawn building and said in his memo to FDA personnel that he is "now devoting my energies to the work of FDA in protecting and advancing the health of the American people."

Von Eschenbach has little familiarity with the many complex and critical issues that face FDA, but he may be a reasonable choice to head the agency. He is well known among cancer researchers. He was an executive at the M.D. Anderson Cancer Center (Houston, TX, www.mdanderson.org) before coming to NCI in 2002. His Texas connections are a plus for the Bush administration, and he has passed through the Senate confirmation process in moving to NCI. James Greenwood, president of the Biotechnology Industry Organization (Washington, DC, www.bio.gov), applauded the administration's speedy appointment of someone with "unique insights into the critical need to advance new treatments for patients with life-threatening illnesses." Cancer patient groups offer similar praise, but some parties consider him more interested in making headlines than bringing about real change: at NCI he set a goal of making cancer a manageable disease by 2015, which has been termed optimistic at best, and unrealistic by many observers.

At FDA, von Eschenbach must deal with many of the issues that plagued Crawford and delayed his confirmation by the Senate last spring. Because Crawford had served as acting or deputy commissioner during the past five years, he could not escape responsibility for the drug safety issues surrounding the "Vioxx" (Merck & Co., Whitehouse Station, NJ, www.merck.com) debacle, last year's flu vaccine shortage, or the agency's delay in approving broader access to the emergency contraceptive pill, "Plan B" (Barr Labs, Pomona, NY, www.barrlabs.com). The legislators finally approved him for the top job in July, but not unanimously.

A veterinarian and food safety expert—and not a medical doctor—Crawford had difficulty articulating the risks as well as the benefits of prescription drugs and advocating for continued speedy approval of new medicines. He lost support within the agency for some unpopular personnel decisions and for continuing to delay the approval of Barr's application to switch "Plan B" to over-the-counter status, even after pledging to make a decision on the issue by Sept. 1. A senior FDA official resigned over Crawford's refusal to follow the scientific evidence supporting the Barr application, reflecting escalating discontent throughout the agency's rank and file.

The New York Times reported that Crawford family members attributed his resignation to an unintentional omission on the financial disclosure forms he submitted as part of the confirmation process earlier this year.

Although administration officials hinted of personal financial problems as the immediate cause of Crawford's departure, the White House appeared content to let him go. Conflict-of-interest charges would only further undermine Crawford's ability to lead FDA at a time when the agency requires a leader with strong medical and scientific credentials who can restore public trust in the troubled agency that has long been regarded as the gold standard in the pharmaceutical regulatory world.

It may take months for the White House to appoint and the Senate to confirm a permanent FDA commissioner. In the meantime, controversial issues such as regulating follow-on biologics and strengthening drug safety oversight may remain in limbo, along with efforts to address the many scientific issues that stymie new drug development.

–Jill Wechsler

WARNING LETTER

CEPH International

On Sept. 13, the US Food and Drug Administration's San Juan (PR) District office sent a warning letter to CEPH International Corp. (Caguas, PR), acquired by Patheon (Mississauga, ON, Canada, www.patheon.com) in 2004 in its purchase of Mova Corporation. The letter, posted on FDA's Web site on Sept. 27, cites the facility for failing to control and correct out-of-specification fill weights for certain versions of the "Omnicef OP" oral suspensions it manufactures under contract.

A Sept. 27 Patheon press release said, "As indicated in the Warning Letter, the affected product is powder for oral suspension, Omnicef OP 250 mg/5mL and 125 mg/5mL. The issues identified in the Warning Letter affect all manufacturing lines for the powder for oral suspension product. The capsule product is not affected.

"Patheon and CEPH are working diligently with their client to resolve the issues identified by the FDA in the Warning Letter. CEPH has decided to voluntarily suspend production of the powder product while it resolves these matters. Patheon and CEPH are committed to working expeditiously to resolve these issues so as to avoid interruption of supply of the product for the client."

The company reports that "CEPH, with the assistance of experts from Patheon, its client, and external consultants, worked diligently to analyze the issues raised by the FDA and to develop an enhanced process-improvement program to address the FDA's concerns. CEPH is currently implementing process improvements consistent with the program outlined in the response letter to the FDA.

The initiation of the program follows a positive reply from FDA to the companies' Oct. 6 response letter, which outlined the corrective action plan.

According to a company announcement, CEPH expected to begin manufacturing qualification and validation batches of the Omnicef oral powder for suspension in October. The company plans to perform qualification and validation testing of these batches in early November and, subject to satisfactory test results, will release these batches to its client. Moreover, in November, CEPH hopes to be in a position to notify FDA that production has been reinitiated and that it will be prepared for an FDA reinspection to verify the implementation of the corrective actions.

–Douglas McCormick and Maribel Rios

FDA

CDER Creates Office of New Drug Quality Assessment

US Food and Drug Administration Center for Drug Evaluation and Research (Rockville, MD, CDER, www.fda.gov/cder) Director Stephen K. Galson announced on Oct. 4 the official establishment of the Office of New Drug Quality Assessment (ONDQA), effective Nov. 1. The new office is being formed from the Office of New Drug Chemistry (ONDC), part of the CDER's Office of Pharmaceutical Science.

"ONDQA is being created to facilitate the implementation of a modern, risk-based 'pharmaceutical quality assessment system' (PQAS) to replace the current CMC review system in ONDC," the announcement said. Moheb Nasr (currently director of ONDC) will head the new ONDQA, which will evaluate the chemistry, manufacturing, and controls (CMC) sections of investigational new drug (IND), new drug application (NDA), and supplemental NDAs.

"ONDQA is a science-based organization designed to be more efficient, effective, and flexible in managing CMC issues and workload," Galson said, and it is designed to put into action the principles of agency's Sept. 2005 report, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach.

As Pharmaceutical Technology's October issue reports (see "FDA Lowers Barriers to Process Improvement" by Laura Bush), the new office is part of a reorganization that will separate premarket reviews (to be handled by ONDQA) from postmarket CMC supplements (now reviewed by 19 chemistry teams in 15 clinical divisions, which will be consolidated into a single office).

–Douglas McCormick

FDA Approves Lots of Flu Vaccine

FDA has approved three lots of Chiron's (Emeryville, CA, www.chiron.com) flu vaccine "Fluvirin." FDA officials maintain that lot approval does not mean the vaccines are ready for sale. Chiron CEO Howard Pien said on Oct. 18 that the company would produce fewer than 18 million doses for the 2005–2006 flu season; far lower than the estimated 18 to 26 million doses orignally estimated.

LEGISLATION

New Legislation Would Ensure Stable Flu Supply

Senators Hillary Rodham Clinton (D-NY) and Pat Roberts (R-KS) last introduced legislation on Oct. 6 that would require the Department of Health and Human Services (HHS) to set annual goals for influenza vaccine production through stockpiling and buyback activities. In addition, a vaccine-tracking system would be established within two years of approval to keep track of available vaccines on a county-to-county basis.

"Despite three shortages of seasonal flu vaccine since 2000, we still don't have the flu-vaccine production and distribution infrastructure we need to ensure a stable supply and demand for seasonal flu vaccine, raising serious concerns about our ability to respond to a flu pandemic or an outbreak of avian flu," Clinton stated in a release.

The proposed bill also would allow the secretary of HHS to authorize temporary liability protection for pandemic vaccine products, and the government would assume "liability for personal injury or death resulting from the manufacture, administration, or use of qualified pandemic influenza technologies." While the Vaccine Injury Compensation Program covers liability for seasonal influenza vaccines, legal protection for the production of pandemic influenza strains has caused concern among vaccine manufacturers.

The Centers for Disease Control and Protection also would reach out to state and local health divisions to establish a registry that would list all medical personnel who could provide emergency services in the event of a health crisis or a flu-vaccine shortage.

–George Koroneos

Injectable Products Recalled

FDA has recalled all injectable products manufactured by Central Admixture Pharmacy Services, Inc. (CAPS, Lanham, MD, www.capspharmacy.com) because of sterility concerns. CAPS distributed the affected injectable products to hospitals in Maryland, Delaware, Washington DC, and Virginia. Gram-negative rods have been identified in two lots of the "Cardioplegia" solution manufactured by CAPS.

GUIDANCE

FDA Proposes PET CGMPs

On Sept. 15, the US Food and Drug Administration (Rockville, MD, www.fda.gov) proposed current good manufacturing practices (CGMPs) rules to govern drugs for positron emission tomography (PET) and simultaneously issued a draft guidance, PET Drug Products—Current Good Manufacturing Practice.

PET drugs are imaging agents, usually injected, with radioactive tags. The radioisotopes are produced in cyclotrons close to the point of use, typically have short half-lives, and must be administered within hours or minutes. Because the window of utility is so short, many traditional CGMP testing and validation requirements may not be appropriate. As production moves from academic medical centers into the commercial sector, however, standards are necessary.

The proposed rule exempts PET drugs from certain general provisions of 21 CFR Parts 210 and 211, and establishes a new Part 212 to cover PET production requirements. (The proposed rule also accepts the United States Pharmacopeia General Chapter ‹823› on compounding PET radiopharmaceuticals as the CGMP standard for investigational and research PET drugs.)

The proposed rule and draft guidance continue a process that began with public meetings and a preliminary guidance in 1999, and a "preliminary draft proposed rule" in 2002.

The 90-day comment period runs through mid-December. For information see www.fda.gov/cder/regulatory/pet/default.htm.

–Douglas McCormick

FDA

Ajaz Hussain Leaving FDA for Sandoz

Ajaz Hussain, the high-profile deputy director of the US Food and Drug Administration's Office of Pharmaceutical Science (OPS), left the agency on Oct. 28 to join Sandoz (Holzkirchen, Germany, www.sandoz.com) as vice-president and global head for biopharmaceutical development.

In announcing the departure, OPS Director Helen N. Winkle called Hussain "the tireless champion of pharmaceutical product quality and a leader of numerous initiatives in FDA such as the Pharmaceutical CGMPs for the Twenty-First Century—A Risk-Based Approach" and an "architect of CDER's Process Analytical Technologies efforts."

Earlier in his FDA career, Hussain played key roles in the Center for Drug Evaluation and Research's (CDER) Scale-up and Postapproval Changes (SUPAC) and Biopharmaceutics Classification System (BCS) initiatives.

Sandoz, the generics subsidiary of Novartis, sued FDA on Sept. 13, trying to force FDA to rule on the company's follow-on biologic application for "Omnitrope," a recombinant human growth hormone.

–Douglas McCormick