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Strict enforcement, new rules, and organizational changes signal an activist tone.
US Food and Drug Administration officials are moving aggressively to address the charges of incompetence and ineffectiveness that have roiled the agency in recent years. In January 2009, the Government Accountability Office (GAO) added FDA to its list of high-risk government programs that should be reorganized to better ensure drug safety. GAO and other critics acknowledged a lack of government funding as a prime factor, along with the rising complexity of medical technology and the increased globalization of biomedical production.
To make FDA more efficient and competent, Commissioner Margaret Hamburg is taking action on several fronts. She has reorganized her immediate office to emphasize food safety and scientific integrity and to quickly inaugurate agency involvement in regulating tobacco. FDA is announcing new rules and policies almost daily and broadcasting its intent to enforce manufacturing and marketing requirements aggressively. Hamburg is highly visible in all these initiatives, outlining new policies at press briefings and public meetings and emphasizing that she is calling the shots at the agency.
Changes at the top
In August, Hamburg formally unveiled a modest reorganization of the Office of the Commissioner (OC). A new food czar—a deputy commissioner of food—will oversee FDA's Center for Food Safety and Nutrition and the Center for Veterinary Medicine. Former FDA official and food regulatory expert Michael Taylor recently returned to the agency as Hamburg's special advisor on foods and is a likely candidate to fill the new position. However, Hamburg is not appointing a comparable official in charge of drugs, biologics, and medical devices as observers had speculated that she would.
Other changes include establishing an office of external affairs to better communicate FDA decisions and proposals to the media, health professionals, and interest groups. A new Office of Special Medical Programs will oversee several interrelated activities such as bioresearch monitoring, combination products, orphan drugs, and pediatrics. Budget development will be the responsibility of the policy office, which will explain to Congress how FDA will spend its resources and justify requests for additional funding. Hamburg is benefiting from a record $3-billion FDA budget for the coming year (including roughly $600 million in user fees), but will face a tough fight to keep the increases coming.
A prominent addition to FDA is the Center for Tobacco Products, which was authorized by Congress in June 2009 and established by the agency in record time. Hamburg announced in August that the Center would be headed by Lawrence Deyton, a physician with experience in academia, public health, and Congress. Deyton successfully revitalized smoking-cessation programs as a top health official at the Department of Veterans Affairs.
The tobacco legislation charges FDA with enforcing marketing restrictions on tobacco products, regulating product ingredients, and taking action to reduce youth smoking. FDA also has leeway to promote smoking cessation, which could stimulate the development and approval of more nicotine-replacement therapies such as patches, gums, and lozenges. The new tobacco center will start operations with $5 million from FDA and the expectation that industry user fees will provide sufficient resources to support research on tobacco use and regulatory and enforcement programs.
Stress on science
Hamburg is intent on positioning FDA as a science-based organization whose regulatory decisions are based on medical and technical judgments rather than politics. The agency hopes to deal effectively with internal disputes over product-safety and approval actions 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 importance of strengthening regulatory science as an academic field, noting that it has atrophied compared with biomedical research, which has surged following investment by the National Institutes of Health and other research organizations. She emphasized the need to "revitalize and re-energize" support for the Critical Path Initiative and acknowledged concerns about the slim pipeline for new drugs and medical products.
An increased focus on regulatory science can support the development of new pharmaceutical products, but a lack of transparency about FDA's review process and regulations can be "stifling to innovation," Hamburg noted. She echoed opinions expressed by biotechnology companies and venture capitalists at a recent meeting organized by FDA and the White House Office of Science and Technology Policy to discuss industry concerns.
One sign of the times is Hamburg's decision to replace the 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 problems. CDRH staff had complained that management had ignored its concerns regarding the safety and efficacy testing of new products seeking market approval.
Under the Hamburg regime, FDA Chief Scientist Jesse Goodman will ensure scientific integrity in agency deliberations and encourage research and innovation as the head of a new Office of Science and Innovation (OSI) for resolving scientific disputes within the agency. Goodman will coordinate responses to charges of inappropriate action, manage appeals, and oversee advisory committees.
Another of Goodman's assignments will be to coordinate FDA's involvement in counterterrorism and emerging threats, which involves managing the agency's response to the influenza pandemic and to other diseases that threaten public health. Goodman's office will facilitate access to effective medical countermeasures and authorize emergency use of needed therapies.
As head of OSI, the chief scientist also will make the case for FDA support of high-quality scientific projects. That effort will involve expanding the Critical Path Initiative and working with FDA's Center for Toxicological Research in Arkansas. Goodman anticipates playing a role in encouraging personalized medicine and in promoting comparative-effectiveness research. FDA hopes to tap into biomedical data resources at the Department of Health and Human Services that can identify patient populations likely to benefit from certain treatments. Such information should help design clinical studies that can produce useful information about how medical products should best be used to yield benefits and avoid harm.
Access and information
In addition to these organizational changes, FDA is rolling out new programs and policies important to manufacturers. One set of new rules aims to expand patients' access to investigational medicines by finalizing proposals made in 2006 and long sought by patient advocates. The policy makes it easier for seriously ill individuals to obtain unapproved drugs under the treatment investigational new drug policy and to have early access to an approved drug for an unapproved indication. Manufacturers also gained clarification about when they may charge patients for an experimental drug outside a clinical trial.
An important FDA initiative is to promote the electronic submission of postapproval adverse event (AE) reports for drugs, biologics, and medical devices, as outlined in a new proposed rule that aims to eliminate paper submissions of safety reports. Many large pharmaceutical manufacturers already use FDA's Electronic Submission Gateway to file about 80% of individual case safety reports under a pilot program. The new policy aims to prompt small biotechnology firms and device makers to follow suit by offering a new web portal for agencywide safety reporting. FDA is establishing the portal as part of its MedWatch Plus initiative.
The proposed rule makes no changes in the scope and timing of manufacturers' AE filings and continues to use the standards for data elements and format established by the International Conference on Harmonization (ICH) and adopted in Europe and Japan. For these reasons, FDA anticipates that firms already submitting AE reports electronically will have few additional costs to comply with the new requirements. FDA, however, will save $2.4 million per year by eliminating the manual conversion of paper reports to electronic form. More important will be speedier access to important safety information. FDA says that reviewers can obtain electronic safety submissions in two days, compared with two weeks to get paper reports into the agency's Adverse Event Reporting System.
Hamburg's most high-profile initiative so far is to streamline the process for issuing Warning Letters and for taking enforcement action against manufacturers that fail to comply with good manufacturing practices (GMPs) and other agency rules. Many serious violations "have gone unaddressed for far too long," including manufacturing violations, product adulteration, 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 the wrangling with regulated companies that delays compliance. And if a situation raises serious health and safety issues, FDA may launch a recall or seizure before even issuing a Warning Letter, she said.
Under the new policy, a manufacturer has 15 working days after receiving a 483 inspection report to provide information about how it will address cited violations to prevent enforcement action. If FDA doesn't receive an adequate response in that time, the agency may issue a Warning Letter or take other steps to enforce compliance. The 15-day policy went into effect for violation notices issued after Sept. 15, 2009, and it may prove a challenge for manufacturers to meet, points out former FDA regulatory official David Chesney, vice-president of Parexel Consulting. Although manufacturers are not legally required to respond to 483s, and only about 10% of inspection problems traditionally lead to Warning Letters, Chesney considers a timely response advisable to avoid a more serious regulatory action.
Hamburg also aims to issue Warning Letters more promptly by ending an extra internal legal review of the documents before they are sent out. The Bush administration required the FDA chief counsel to examine all proposed Warning Letters, a policy that was criticized for delaying and reducing agency enforcement actions. "This created very cumbersome practices without a lot of benefit," observed Hamburg. Now the chief counsel will review only proposed Warning Letters that raise "novel, complex, and sensitive issues" such as an activity at the center of a lawsuit or a requirement recently established by legislation.
For its part, FDA is offering a carrot to encourage industry to take corrective actions quickly. The agency aims to promptly reinspect or evaluate a company's remedial efforts and not leave manufacturers wondering whether a corrective action is adequate. If a review indicates that problems have been corrected, FDA will issue a formal close-out letter and make an announcement on its website. This policy provides manufacturers with an official statement to show investors and customers that they're back in FDA's good graces and that a facility or product is no longer tainted by quality or safety concerns.
"There's a lot of room to improve FDA's side of the equation," Chesney comments, noting that the agency often fails to follow up with companies for months, or even years, after issuing violation notices or Warning Letters. Conversely, if reinspection shows that cited problems have not been corrected, FDA says it won't just issue another Warning Letter, but may initiate product seizures, shut down plants, or impose additional penalties.
Even before announcing these changes, FDA officials were stepping up GMP enforcement and making compliance actions more visible. Earlier this year, for example, FDA banned the import of Ranbaxy products from two plants in India following a series of Warning Letters and inspections. KV Pharmaceuticals (St. Louis, MO) received a consent decree in March 2009 after years of inadequate responses to inspection reports and letters citing GMP violations. More recently, FDA instigated a high-profile seizure of drugs produced at the Michigan facilities of Sun Pharmaceutical's (Mumbai) Caraco subsidiary because of the company's failure to fully address earlier inspections that revealed variation in the size of digoxin tablets, among other problems. FDA quickly imposed a permanent injunction in July 2009 to halt the manufacturing and distribution of products from Teva Animal Health's (St. Joseph, Missouri) facility. FDA recently froze imports from Apotex (Toronto) because of inadequate correction of manufacturing violations cited in a June 2009 Warning Letter.
Biotechnology companies face particular scrutiny because of the high risks of toxicity from substandard injectables. Genzyme (Boston) has been struggling for more than a year to address serious manufacturing problems. It had to shut down its Allston Landing, Massachusetts, facility in June 2009 because of viral contamination, thus leading to serious shortages of enzyme-replacement therapies such as Cerezyme (imiglucerase). A threat to revoke Immucor's (Norcross, GA) biologics license for poor quality control of blood-diagnostic products prompted fast development of a corporate remediation plan and quality-process improvements.
Hamburg expects that FDA's enforcement campaign will increase the volume of Warning Letters initially, as already seen this year. However, she anticipates that the volume will level off over the long run as industry recognizes that a strong compliance program is 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." Conversely, speedy corrective efforts and broader compliance throughout industry will increase public confidence in FDA and better educate patients and consumer about potential risks in medical products.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org
In Washington this month