Stiffer Enforcement at the FDA

Published on: 
BioPharm International, BioPharm International-06-01-2009, Volume 22, Issue 6
Pages: 40–45

Agency officials promise swift action against violators of drug safety and quality regulations.

The US Food and Drug Administration is stepping up oversight and enforcement activity for medical products, advising industry to tighten up on data integrity and quality control to ensure compliance. "Enforcement will increase," warned Deborah Autor, director of the Office of Compliance in FDA's Center for Drug Evaluation and Research (CDER), at the April annual meeting of the Food and Drug Law Institute (FDLI). She pointed to a rise in injunctions, investigator disqualifications, and warning letters, and advised companies to avoid the Big Stick by "being pro-active about compliance." Autor's staff has grown to 250 from 150 five years ago, which increases its ability to take regulatory action; CDER had issued almost 40 warning letters as of April 14, 2009, nearly half of the total 87 sent out in 2008.

Jill Wechsler

Principal Deputy Commissioner Joshua Sharfstein, who was acting commissioner pending confirmation of Margaret Hamburg, took high-visibility enforcement actions to illustrate that a new sheriff is in town. Soon after coming to the FDA at the end of March, Sharfstein initiated a fast and more aggressive recall of pistachio products when evidence appeared of salmonella contamination. He also responded to criticism of the FDA's process for regulating medical devices by supporting a review of research requirements for device classes.

The global swine flu outbreak provided another opportunity for Sharfstein to display a highly proactive approach. He authorized emergency access to antiviral drugs and diagnostics, and established teams under Jesse Goodman, newly named deputy commissioner for scientific and medical programs and acting chief medical officer, to facilitate the development of new vaccines, antivirals, diagnostics, and other products needed in a pandemic.

As former director of the FDA's Center for Biologics Evaluation and Research (CBER), Goodman has been active in vaccine development and global health issues. In addition to heading up the response to the flu outbreak, Goodman will oversee the FDA's National Center for Testing and Research and agency public health and science programs, including pediatric therapeutics, combination products, women's health, Critical Path programs, good clinical practices, and the Sentinel Safety initiative. The assignment puts several hot topics on Goodman's plate, including comparative effectiveness research, biomarker identification, clinical trial design, personalized medicine, and manufacturing science.



Congressional leaders also seek to bolster FDA leadership and authority. The Senate Health, Education, Labor and Pensions (HELP) Committee and the full Senate moved quickly last month to confirm Harmburg as FDA commissioner, stressing the need for a strong agency to deal with the swine flu outbreak, and food and drug safety issues.

HELP Committee Chairman Edward Kennedy (D-MA) and Sen. Charles Grassley (R-IA) also reintroduced legislation authorizing the FDA to collect user fees to support more inspections of drug and medical product makers. The measure provides authority for the agency to issue subpoenas and to detain suspect products. Domestic and foreign manufacturers of regulated products would have to register with the FDA, including producers of active pharmaceutical ingredients.

The measure is similar to the drug section of legislation backed by Rep. John Dingell (D-MI), which is pending before the House Energy and Commerce (E&C) Committee. E&C Chairman Henry Waxman (D-CA) has indicated greater interest in enacting only the food safety portion of the bill, but even that would grant FDA subpoena authority for all regulated products.


These legislative proposals would enhance the enforcement powers already expanded by the FDA Amendments Act (FDAAA) of 2007, which authorized fines and criminal penalties for violative activity. So far, the FDA has not brought a case under these new authorities, Autor said, "but when we need to use it, we will." She pointed to the agency's speedy action to halt production of drugs by KV Pharmaceuticals, which resulted in a recall of 175 products and blocked shipment of thousands of lots. Data integrity is critical, Autor emphasized, citing FDA use of its Application Integrity Policy against Indian manufacturer Ranbaxy.

Autor also promised to continue the FDA's campaign to remove unapproved drugs from the market, which has affected over 200 manufacturers and 500 products, and involved action against 12 classes of drugs. In March, the FDA cited nine companies for marketing 14 unapproved narcotic products. "We still see industry as somewhat complacent" about this, she said, and wants manufacturers to understand that all drugs must have FDA approval.


Drug safety legislative proposals and FDA initiatives reflect the impact of globalization in biotech and drug manufacturing on drug safety and quality. Such "supply chain fragmentation and geographic dispersion of drug manufacturing add new risks," said CDER director Janet Woodcock at the FDLI meeting. Foreign drug manufacturing sites now exceed registered domestic facilities, and the volume of drug products made overseas continues to rise.

An eruption in apparently intentional contamination of imported food and drug products, including heparin, pet food, and infant formula, has prompted a more deliberate FDA effort to examine the factors behind incidents involving dilution or substitution of ingredients in drugs and foods primarily to increase profits. At a public meeting last month, agency officials heard from manufacturers and other parties on ways to predict, prevent, and address economically motivated adulteration (EMA). Attendees discussed which types of products are more vulnerable, how manufacturers track and verify product components and ingredients, where supply chains are open to abuse, and what analytical methods can best detect contamination.

Randall Lutter, FDA deputy commissioner for policy, defined EMA as the "fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain." This may involve diluting or watering down products, as in increasing the inactive ingredient in a drug. The FDA noted that dramatic shifts in product supply, perhaps to additional companies or new regions, could signal fraudulent activity. EMA may involve expensive biologics that are relatively easy to engineer, or less costly drugs that are widely used. At the public meeting, academic experts described models able to detect shifts in supply chains that can signal fraudulent activity. Roger Williams, CEO of the US Pharmacopeia (USP), urged broader FDA and industry support of efforts to update USP monographs that set a standard for product quality. The USP was in the process of revising the heparin monograph when the contamination crisis hit, Williams said, noting that "that revision came too late."

Manufacturers backed wider use of accredited third-party inspectors to audit foreign producers of active and inactive ingredients, required registration of all ingredient producers, and stiffer penalties for drug counterfeiting and adulteration. Martin Van Trieste, vice president for quality at Amgen and a member of the Pharmaceutical Research and Manufacturers of America (PhRMA) Quality Technical Group, voiced support for a proposed Qualified Trusted Importer Program (QTIP), a voluntary certification program for qualified and compliant importers.

Van Trieste also described industry efforts to form the Rx-360 consortium to develop best practices for supply chain management and new approaches for supplier auditing and adulteration detection. The group held a launch meeting earlier this month to discuss audit models and methods for monitoring suspicious events. Such efforts, he noted, would benefit from the assurance that manufacturers can share information on suppliers and other issues without running afoul of antitrust laws.

Criminal elements have entered into the drug supply chain, and it's only a question of when and where EMA will emerge again, Van Trieste predicted. The short supply of antivirals in a pandemic influenza outbreak, he commented, provides the "perfect opportunity for someone to come in and make a quick buck." The industry and the FDA, he advised, have to think like the criminals to detect adulterated products.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,