[Justin]

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Matthew Meselson

Co-director of the Harvard Sussex Program on chemical and biological weapons, Harvard University, USA.

Vast biosecurity expenditures require better oversight and monitoring.

It is seven years since envelopes containing anthrax spores were mailed to news media offices and to two US Senators, causing 11 cases of identified inhalation anthrax, five of which were fatal. In August 2008, the FBI announced that they had traced the source of the spores to the United States Army Medical Research Institute of Infectious Diseases at Fort Detrick in Maryland, one of the many US facilities conducting biodefence research. Although there has been no repetition of such attacks, the episode underscores the need for better oversight of biodefence activities and of the individuals conducting them.

Federal expenditure for civilian biodefence during 2001–08, conducted mainly by the departments of health and human services, homeland security, and defence is estimated at about US$50 billion, of which roughly one-third was for research1. Department of Defense (DoD) outlays for biodefence research, development and testing for strictly military objectives currently run at several hundred million dollars per year2. Relevant expenditures by the various intelligence agencies have not been made public.

Oversight of biodefence — to ensure that activities comply with existing laws and international agreements — varies from agency to agency, with perhaps the most advanced being that of the Department of Homeland Security (DHS). In addition to scientific peer-review to assess scientific merit, the DHS has a Compliance Review Group (CRG) that reviews all DHS-sponsored research for compliance with the 1972 Biological Weapons Convention and with US criminal law. It also applies the criteria of the National Science Advisory Board for Biosecurity in assessing proposed projects that have potential for hostile misuse. The CRG meets at least twice a year, and before each meeting there is a call for abstracts of proposed projects to be submitted by their respective principal investigators, who at the same time are reminded of their responsibility to ensure compliance with treaty commitments and applicable US law.

CRG members, therefore, are informed about all projects before they commence and the group continues to oversee them as they evolve. Projects deemed by CRG staff to pose risks of actual or perceived non-compliance, or which are likely to pose a dual-use potential for misapplication, are individually briefed to the group and, in some cases, the CRG members are required to acknowledge personal responsibility by signing their names to decisions regarding approval or denial of support for a project.

The compliance procedures in other departments are not as rigorous and there is no process to ensure consistency across government agencies. The DoD, for example, reviews biodefence projects at a broader 'programme' level rather then reviewing individual projects.

Oversight of biodefence activities is likely to come under examination by the new Congress, which could devise guidelines and procedures applicable throughout government. Topics to be considered should include the authority and composition of compliance review boards, criteria for approval of projects, harmonization of procedures, procedures for ensuring the reliability of personnel engaged in biodefence work, provision for site visits, a requirement for periodic reports, and the inclusion of State and Justice Department observers to promote both independence from parochial influences and familiarity with treaty commitments and applicable US law.

The resulting procedure could then serve as a model for consideration by the state parties of the Biological Weapons Convention at its seventh review conference in Geneva, Switzerland, in 2011. The aim would be to agree on a requirement for detailed periodic submissions from each nation describing the oversight procedures it employs to ensure compliance with the convention. The objective would be to increase awareness of the need for improved oversight and to facilitate the development of international measures for enhanced exchange and transparency regarding implementation of the convention.

Steven E. Nissen

Chairman of the department of cardiovascular medicine, Cleveland Clinic, Ohio, USA.

An end to secrecy will revive the Food and Drug Administration.

After an unprecedented series of revelations about drug and device safety issues, many observers consider the Food and Drug Administration (FDA) a failed agency. The Obama administration has the opportunity to reinvigorate the FDA, but only through major restructuring and policy changes that are designed to protect the agency from undue influence, and to promote transparency.

The next FDA commissioner should serve a fixed six-year term to insulate the agency from political influence. Moreover, the system by which pharmaceutical companies fund a major portion of the FDA's budget through user fees requires re-evaluation.

Secrecy is antithetical to both science and good government, but much of what the FDA knows about drugs, it never publicly discloses. The agency must cease to regard clinical-trial data as proprietary and provide access to all available information on safety and efficacy. This policy should apply to information gathered during approval for drugs, and to post-approval surveillance. The agency needs better harmonization between its Office of Surveillance and Epidemiology, which monitors post-marketing safety, and its Office of New Drugs, which is responsible for post-marketing regulatory decisions.

The current voluntary mechanism for adverse-event reporting is relatively ineffective, because only 1%–10% of events are actually reported. Partnerships with large health-care providers, such as health maintenance organizations that supply care through hospitals, doctors and other providers, are needed to prospectively assess drug safety.

The approaches used to approve drugs need attention. Drug approvals are often based on placebo-controlled clinical trials. However, appropriate use of therapies requires understanding comparative effectiveness. The FDA has increasingly used 'non-inferiority' study designs to support efficacy. In these, a treatment is considered 'approvable' if it retains 50% or more of the effectiveness of a comparable product, which may represent too lenient a standard. The agency has also increasingly used 'surrogate endpoints' (biomarkers or laboratory measures) to support approvals without subsequently requiring more informative clinical-outcome studies.

For medical devices, the agency has authority to clear a product for market if it is deemed 'substantially equivalent' to devices already being sold. This rule has become the principal approach used to approve medical devices. However, even small changes to a device can affect safety, which has resulted in major safety recalls, such as for defective pacemaker leads.

Stronger enforcement capabilities are required throughout the agency. The Division of Drug Marketing, Advertising, and Communications needs the right to restrict direct-to-consumer advertising during the first two years a drug is marketed and to preview advertising to ensure it is not misleading. An FDA policy introduced in 2008 unwisely allows off-label promotion of drugs and devices through distribution of article reprints, an approach that may encourage unsafe use for unapproved indications and discourage appropriate clinical trials to establish new indications.

Currently, about 1,600 facilities in China manufacture drugs or components of drugs marketed in the United States. Recent high-profile cases — such as contaminated heparin — poignantly illustrate the risks inherent in globalization. The FDA must increase inspections and foreign governments must be held accountable for setting regulatory and safety standards for local manufacturing. All of these initiatives require more robust funding of the FDA, which currently has a budget of $2.3 billion with which the Agency must regulate $1 trillion worth of food, drugs, cosmetics and medical devices. The agency's budget is quarter that of the Centers for Disease Control and Prevention, which has a significantly more limited mission. Congress must re-evaluate priorities and recognize that ensuring the safety of food and drugs is a crucial national priority.