FDA Promotes Integrity and Compliance

October 1, 2009
Jill Wechsler

Jill Wechsler is ACT's Washington Editor

Applied Clinical Trials

Volume 0, Issue 0

Stiffer enforcement of research standards aims to restore the public's confidence in agency actions.

The new leadership at the Food and Drug Administration is wasting little time in taking steps to erase the charges of incompetency and ineffectiveness that have plagued the agency for several years. FDA is announcing new rules and policies almost daily and strengthening enforcement of research, manufacturing, and marketing requirements to show industry it means business.

Jill Wechsler

FDA Commissioner Margaret Hamburg began by reorganizing her immediate office to emphasize the importance of food safety and scientific integrity and to encourage speedy compliance with rules. There will be a new "food czar"—a deputy commissioner of food overseeing the Center for Food Safety and Nutrition and the Center for Veterinary Medicine. An expanded office of external affairs will improve communications with the media, health professionals, and interest groups. Several cross-cutting activities—bioresearch monitoring, combination products, orphan drugs, and pediatrics—will be managed by the Office of Special Medical Programs.

Budget development will shift to the policy office to improve the agency's ability to explain to Congress how FDA spends its resources and why it may need additional funding. Hamburg is benefiting from a record $3 billion budget for the coming year (including some $600 million in user fees), but will be hard-pressed to further expand resources.

A prominent addition is the Center for Tobacco Products, authorized by Congress in June and launched by FDA in record time. The Center is headed by Lawrence Deyton, an MD with experience in academia and public health and successful in revitalizing smoking cessation programs as a top health official at the Department of Veterans Affairs. The tobacco legislation charges FDA with enforcing tobacco marketing restrictions, regulating ingredients, and reducing youth smoking; leeway for FDA to promote smoking cessation could stimulate development of new nicotine replacement products.

Stress on science

Hamburg is intent on positioning FDA as a science-based regulatory agency where politics doesn't override medical judgment in making regulatory decisions. She hopes to deal effectively with internal disputes over product safety and approvals and to avoid public controversies, such as that which delayed approval of an over-the-counter version of the Plan B emergency contraception pill.

At the August meeting of FDA's Science Advisory Board, Hamburg highlighted the need to strengthen regulatory science as a field, noting that it has atrophied compared to the surge in biomedical research investment by the National Institutes of Health. She emphasized the importance of "revitalizing and reenergizing" support for FDA's Critical Path Initiative and acknowledged concerns about the slim pipeline for new drugs and medical products.

Efforts to make the FDA review process as efficient as possible can benefit R&D, she commented, while the current lack of transparency about FDA programs can be "very stifling to innovation." Here Hamburg echoed opinions expressed by biotech companies and venture capitalists at a recent meeting organized by FDA and the White House Office of Science and Technology Policy to address innovation and transparency.

One sign of the times is Hamburg's decision to appoint a new head of the Center for Devices and Radiological Health (CDRH). Veteran FDA official Dan Schultz resigned in August as CDRH director in the wake of several high-profile device safety cases, plus internal complaints about management ignoring staff concerns regarding safety and efficacy testing of new products seeking market approval.

Under the Hamburg regime, FDA Chief Scientist Jesse Goodman has the task of ensuring scientific integrity in agency deliberations, along with encouraging research and innovation. Goodman will head up a new office for resolving scientific disputes within the agency, coordinate responses to charges of inappropriate action, manage appeals, and oversee advisory committees.

Another assignment is to coordinate FDA's involvement in counter-terrorism and emerging threats, which involves managing the agency's response to the influenza pandemic as well as other diseases that threaten public health. Goodman's office will facilitate access to effective medical countermeasures, authorize emergency use of needed therapies, and oversee FDA counter-terrorism and pandemic planning.

Chief Scientist Goodman also will make the case for FDA support of high-quality scientific projects as head of the Office of Science and Innovation. That will involve expanding Critical Path, encouraging personalized medicine, and promoting comparative effectiveness research. FDA hopes to tap into data resources that can identify patient populations likely to benefit from certain treatments. Such information, says Goodman, should help design studies that can produce useful information on how medical products should best be used to yield benefits and avoid harm.

In addition to these organizational changes, FDA is rolling out new programs and policies important to drug development and research. One set of new rules aims to expand patient access to investigational medicines by finalizing proposals made in 2006 and long sought by patient advocates. The policy aims to make it easier for seriously ill individuals to obtain unapproved drugs under the treatment IND policy, or to have early access to an approved drug for an unapproved indication. And it provides sponsors with additional clarification on when they may charge patients for an experimental drug outside a clinical trial.

FDA also has issued a proposed rule requiring electronic submission of postapproval adverse event (AE) reports for drugs, biologics, and medical devices. Most of drug AEs (80%) already are submitted to the agency online or in digital media. FDA is establishing a new Web portal that aims to make it easier for small companies and individuals to report safety problems. There are no changes in the scope and timing of AE filings, and therefore fairly easy for sponsors to comply. However FDA estimates it will save $2.4 million a year and, more importantly, will gain access to safety information much faster.

Spurring compliance

Hamburg's most high-profile initiative is to streamline the process for issuing warning letters and for taking enforcement actions against companies that violate agency rules.

Many serious violations "have gone unaddressed for far too long," including problems in product quality and false and misleading labeling and advertising, Hamburg commented at an August meeting sponsored by the Food and Drug Law Institute. The Commissioner wants to limit all the back-and-forth wrangling with regulated companies that delays compliance and says that FDA may implement recalls or seizures if serious health and safety issues are not corrected promptly.

In addition to establishing tighter time frames for issuing warning letters following field inspections that uncover quality control issues, FDA is taking steps to respond quickly to companies that address cited problems. If violations are corrected promptly, FDA will issue a formal close-out letter indicating that the firm is back in compliance. If failings are not fully addressed, FDA says it won't just issue another warning letter, but may seize products or impose additional penalties.

This campaign to step up enforcement extends to ensuring compliance with good clinical practices (GCPs), according to FDA officials. The agency issued new policies in August to speed up procedures for disqualifying and debarring clinical trial investigators who violate the rules, instead of allowing such proceedings to drag on for years. FDA also is making debarment and disqualification information more visible so that sponsors can avoid hiring individuals debarred from conducting regulated studies.

Even before announcing these changes, FDA officials were expanding enforcement efforts.

An analysis by the Center for Drug Evaluation and Research reveals an increase in warning letters (from 10 in 2006 to more than 20 this year) related to violation of rules governing trial conduct or human subject protection. While it's less common for FDA to cite sponsors for GCP violations, in August the agency sent a strong letter to Johnson & Johnson citing numerous deficiencies and failure to monitor a problematic investigator at a site conducting research on a new treatment for skin infections, ceftobiprole.

Hamburg expects to see such an increase in warning letters initially, but anticipates that the volume will level off as industry recognizes that strong compliance programs are good for business and for consumers. FDA's success in spurring compliance "should be measured not by the number of warning letters or injunctions or seizures," she said, but by "our impact on the health and welfare of the public."

Failure to meet FDA standards means that a company is "putting the public at risk" and also "jeopardizing the public's confidence in your industry." Alternatively, speedy corrective efforts by companies and broader compliance throughout industry will increase public confidence in FDA and better educate consumers about potential risks in medical products.