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Last updated: June 26, 2008
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Regulatory Roundup: Moving Forward, but Slowly

The FDA has been busy the first half of 2008, getting budgets approved, moving forward with various rules and regulations, and releasing new draft guidances for consideration. Much of this work has long needed resolution, some is in response to changes in technology and the overcrowding of the regulatory marketplace, little of it is a surprise. Following is a roundup of some of the more significant events.

New Plans and Programs

Several recently released plans and programs are moving key initiatives forward, including the release of the FDA’s Five-Year Drug Safety Plan and a pilot program designed to address the problems that occur when drugs are released with similar names.

The draft "Prescription Drug User Fee Act (PDUFA) IV Drug Safety Five-Year Plan" is initially focused on hiring additional staff through fiscal 2009, most particularly hiring more risk-management experts to review proposed and implemented Risk Minimization Action Plans or Risk Evaluation and Mitigation Strategies (REMS) and thus enhance their post-market drug-safety activities. The plan also addresses enhancements to the FDA’s technological capabilities and communications as it improves the drug-safety system. According to the draft, "it takes at least two to three years of intense training to prepare new staff to be seasoned experts in drug regulation."

A two-year pilot program has been developed to reduce medication errors caused by look-alike and sound-alike proprietary names. Expected to begin in 2009, the program is the focus of a draft concept paper released on June 5. The pilot program will be designed to let drug companies volunteer to evaluate proposed proprietary names and submit the data for review to CDER or CBER, as appropriate. The program addresses not only the problem of similar proprietary names, but also such factors as unclear label abbreviations, acronyms, dose designations and error-prone label and packaging design. In the pilot program, CDER and CBER will evaluate the safety and promotional implications of submitted drug names. If a name seems prone to cause confusion, the relevant center “will not recommend its approval for use in the market and will request the applicant propose an alternate name for evaluation,” the draft says. “Any preventable risk of error that can be identified prior to drug approval should be addressed.” Product names must be safe and promotionally acceptable, and CDER and CBER will determine whether the company submitting them used adequate reasoning to come up with them. For example, applicants are advised to avoid proprietary names that incorporate or suggest a dosing interval or dosage form since these may change, use common medical abbreviations or coined abbreviations, or include or suggest the composition of the drug product.

In addition, the FDA has been working with the European Medicines Agency (EMEA) on a joint good manufacturing practice (GMP) inspections program under a bilateral agreement. Earlier this year, the European Commission (EC) characterized the FDA and EMEA’s relationship as a beneficial cooperation, and listed new GMP initiatives the two agencies plans to undertake. The joint inspections program will apply to facilities in both the U.S. and the European Union (EU). Joint inspections of active pharmaceutical ingredient (API) facilities in countries outside the U.S. and the EU are expected to be part of the program as well.

Alternatively, while not a program per se, the FDA is expected to be more tough on Chinese importers, planning to be more vigilant in inspecting overseas active pharmaceutical ingredient (API) production facilities in the wake of the heparin contamination. Industry experts estimate that there are probably 30–40 counterfeiting rings operating in the U.S., some of which have substantial operations. For instance, a Florida counterfeiting ring set up wholesale distribution companies, established relationships with wholesalers and sold stolen medicines to them at discounted prices. The ring then started buying medications in foreign countries at substantial discounts and shipping them to the U.S. for distribution. Counterfeit pedigrees were used to authenticate the product, which was sold to wholesalers that then sold the drugs to other wholesalers. The counterfeit product ended up in warehouses of the big three distributors: McKesson, Cardinal Health and AmerisourceBergen. The FDA seeks to help distributors get a better handle on ensuring that their product is authentic.

New Rules and Regulations

There has been significant activity recently in the release of new and revised rules and regulations, including revisions to the new cGMP rule that is currently undergoing final scrutiny prior to clearance. The FDA has modified its proposed current good manufacturing practice (cGMP) rule, which could be published as early as this Fall. The FDA initially issued the regulation in late 2007 as both a proposed and final direct rule. The final rule was withdrawn however when industry strongly objected to several ofthe changes and modifications. One such modification would have explicitly required manufacturers to validate aseptic processes which according to the Parenteral Drug Association is not possible. This latest iteration of the new cGMP rule addresses the objections and provides additional clarification.
The recent release of a draft guidance that addresses post-market follow-up of individual case study reports now states that these must include the original report’s unique identification number to avoid duplication in the FDA’s Adverse Event Reporting System (AERS). The new draft guidance for electronically submitting post-market individual case study reports (ICSRs) instructs manufacturers on filing such reports to the AERS. The guidance replaces previous drafts on the topic, including “Providing Regulatory Submissions in Electronic Format — Postmarketing Expedited Safety Reports” issued in 2001 and the ICSR portion of “Providing Regulatory Submissions in Electronic Format — Postmarketing Periodic Adverse Drug Experience Reports” issued in 2003. The new draft, “Providing Regulatory Submissions in Electronic Format — Postmarketing Individual Case Safety Reports,” applies to unapproved drugs; drugs marketed under approved NDAs and ANDAs; biologics and therapeutic vaccines marketed under BLAs; human cells, tissues and cellular products regulated under Public Health Service Act section 361; and nonprescription drugs marketed without an approved application. Vaccines approved for prophylactic use are not covered by the guidance since adverse event reports for those products are submitted to the Vaccine Adverse Events Reporting System. Whole blood or components of whole blood are excluded as well.

Another guidance was recently released for comment by the FDA that addresses harmonization of pharmacogenomic definitions and sample coding with those of Japan and the EU. The guideline — “E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories” — provides definitions and additional information related to aspects covered by the definitions and notes that certain principles discussed in the document may be applicable to related disciplines such as proteomics and metabalomics. The guideline defines genomic biomarker as a measurable DNA or RNA characteristic that is an indicator of normal biologic or pathogenic processes or a response to therapeutic or other interventions. It defines pharmacogenomics as the study of variations of DNA and RNA characteristics as related to drug response. Pharmacogenetics is defined as the study of variations in DNA sequence as related to drug response. The guideline also offers harmonized definitions for the four general coding categories of biological samples used to generate data in pharmacogenomic and pharmacogenetic studies.

Plans and Rules Under Fire

As usual there was significant participation by the U.S. Senate in FDA affairs, from roadblocks against the controversial patent reform bill, Patent Reform Act, S. 1145, to criticism over funding and budget proposals.

The patent reform bill has stalled in the Senate because of a disagreement over its damages provision. Earlier this year, the Commerce Department notified the Judiciary Committee that the damages section, which would establish a codified system for courts to use when calculating reasonable royalty awards in patent litigation, would seriously harm the U.S. intellectual property system. Commerce states that the bill’s damages provision “will create more problems than it solves.” The window for considering the bill has closed, and the language is still in dispute, with no date set for further consideration.

The FDA is also under fire from lawmakers over the difficulty it is having regulating the quality of imported products. Recent adverse events and deaths linked to contaminated heparin [see New Plans above] have brought the drug’s supply chain under tremendous scrutiny as regulators worldwide have instituted testing programs to ensure the supply of the drug is genuine. The Government Accountability Office (GAO) estimated a significant gap in funding for overseas inspections. The GAO said it would take roughly $70 million annually for the FDA to inspect all overseas facilities every two years, $16 million to $17 million of which would be required for sites based in China. For fiscal 2008, the FDA estimates that it will spend $11 million for all foreign inspections. Currently, the FDA’s top priority is to institute an IT system that includes an inventory of every establishment importing products into the U.S., allowing the FDA to verify if the drugs should be allowed entry into the country. Although the FDA has a business plan to address its IT systems, additional resources are needed for laboratory and inspection operations. Increases in the budget for inspections would need to be substantial. In addition, the FDA needs more authority to pursue violators in the pharmaceutical supply chain.

As a result, momentum is building on Capitol Hill to enact legislation that would give the FDA greater resources and authority to strengthen its foreign inspections program. During an Oversight and Investigations Subcommittee hearing on the agency’s foreign drug inspection program, Marcia Crosse, director of the Government Accountability Office’s healthcare division, testified that the FDA would need significantly more funding to inspect foreign manufacturing facilities with the same frequency as domestic sites. Senior Democrats circulated a draft bill that would require the FDA to inspect foreign drug manufacturing sites every two years and impose a facility registration fee to defray the cost of the audits. Republicans on the committee also want action. Rep. Joe Barton (R-Texas), ranking member of the Energy and Commerce Committee, said the FDA should be required to conduct an inspection before a drug is approved. "The FDA needs an inspection program with many, many more full-time inspectors overseas and with the availability to go into these foreign plants and conduct the inspections in overseas plants like they’re allowed to conduct the inspections in domestic plants,” Barton said.

It is not surprising to learn then that the FDA not only plans to increase lab capacity in anticipation of performing more inspections, but has also increased their hiring in order to do so. As CDER anticipates increasing the number of manufacturing inspections, the FDA’s Office of Regulatory Affairs (ORA) plans to add capacity and staff to its laboratory operations. The focus for CDER over the next five years is to increase the number of inspections based on anticipated advances in manufacturing technologies. As part of this objective, the FDA is expected to hire more than 1,300 biologists, chemists, medical officers, mathematical statisticians, investigators, inspectors and other professionals by Sept. 30, the end of the fiscal year. More than 700 of the jobs to be filled are existing positions that are currently or will be vacant because the employees in them have announced plans to leave. Approximately 600 new positions remain to be filled at a time when congressional lawmakers have been pressuring the agency to increase inspections, improve IT systems and hire staff for other purposes. The FDA will be holding job fairs around the country to recruit needed professionals.

And how will the all be paid?

Budgeting for the Tasks

In May, FDA Commissioner Andrew von Eschenbach said that the agency needs an immediate $275 million infusion, including $100 million for drugs, biologics and medical devices. Subsequently, the Bush administration requested an additional $275 million for the FDA in fiscal 2009; a request that drew criticism by lawmakers who characterized it as too little, too late. "Though it’s taken an inexcusably long time, I’m glad to see the administration is finally acknowledging that FDA lacks the resources necessary to protect the public health,” Rep. John Dingell (D-Mich.), chairman of the House Energy and Commerce Committee, said. “Unfortunately, the administration’s proposed funding increase falls $100 million short of the amount FDA’s own advisory board determined is needed to ensure the safety of our food, drugs, cosmetics and medical devices. My committee has held more than a dozen hearings in the past 17 months on the safety of imported food, drugs and devices. It’s clear that FDA’s infrastructure has not kept up with the global marketplace.”

HHS Secretary Mike Leavitt subsequently announced the administration’s request for the additional funds for the FDA. “We are moving from an intervention strategy — where we stand at the border and try to catch things that are unsafe — to an integrated strategy of prevention with verification,” Leavitt said. “Combined with crucial legislative proposals, this increase will allow FDA to continue to transform its regulatory strategies to meet the challenges of the evolving global marketplace.” The additional funding includes $100 million for drug, device and biologic safety to help the FDA conduct more aggressive safety surveillance to identify early signs of adverse events linked to medical products and to implement new requirements under the FDA Amendments Act related to clinical trials, pediatric drugs and devices, postmarket study commitments and the labeling and safe use of drugs.

The latest word is that the FDA has received initial approval for $2.1 Billion for fiscal 2009. The amount includes $282 million more than originally requested by the administration, including the additional $275 million. The budget measure now goes to the House Appropriations Committee for a markup.

Moving forward, but slowly.