Appendix B
Recommendations from Related IOM Reports



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Appendix B Recommendations from Related IOM Reports 

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0 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS BOX B-1 Summary of Recommendations to Develop Biomarker-Based Tools for Cancer Methods, Tools, and Resources Needed to Discover and Develop Biomarkers 1. ederal agencies should develop an organized, comprehensive approach F to biomarker discovery, and foster development of novel technologies. 2. ndustry and other funders should establish international consortia to gen- I erate and share precompetitive data on the validation and qualification of biomarkers. 3. unders should place a major emphasis on developing quantitative path- F way biomarkers to broaden applicability. 4. unders should sponsor demonstration projects to develop biomarkers F that can predict efficacy and safety in patients for drugs already on the market. 5. overnment agencies and other funders should sustain support for high- G quality biorepositories of prospectively collected samples. Guidelines, Standards, Oversight, and Incentives Needed for Biomarker Development 6. overnment agencies and other stakeholders should develop a transpar- G ent process to create well-defined consensus standards and guidelines for biomarker development, validation, qualification, and use. 7. he Food and Drug Administration (FDA) and industry should work togeth- T er to facilitate the codevelopment and approval of diagnostic–therapeutic combinations. 8. he FDA should clearly delineate and standardize its oversight of bio- T marker tests used in clinical decision making. 9. he Centers for Medicare & Medicaid Services (CMS) should develop T a specialty area for molecular diagnostics under the Clinical Laboratory Improvement Amendments. Methods and Processes Needed for Clinical Evaluation and Adoption 10. MS should revise and modernize its coding and pricing system for diag- C nostic tests. 11. MS, as well as other payers, should develop criteria for conditional cover- C age of new biomarker tests. 12. s a component of conditional coverage, establish procedures for high- A quality, population-based assessments of efficacy and cost effectiveness of biomarker tests. SOURCE: IOM (2007a).

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 APPENDIX B BOX B-2 Summary of Recommendations for The Future of Drug Safety: Promoting and Protecting the Health of the Public Organizational Culture 3.1 he committee recommends that the Food, Drug, and Cosmetics Act T (FDCA) be amended to require that the Food and Drug Administration (FDA) Commissioner currently appointed by the President with the advice and consent of the Senate also be appointed for a 6-year term of office. The Commissioner should be an individual with appropriate expertise to head a science-based agency, demonstrated capacity to lead and inspire, and a proven commitment to public health, scientific integrity, transpar- ency, and communication. The President may remove the Commissioner from office only for reasons of inefficiency, neglect of duty, or malfeasance in office. 3.2 he committee recommends that an external Management Advisory T Board be appointed by the Secretary of Health and Human Services (HHS) to advise the FDA Commissioner in shepherding the Center for Drug Evaluation and Research, or CDER (and the agency as a whole) to implement and sustain the changes necessary to transform the center’s culture—by improving morale and retention of professional staff, strength- ening transparency, restoring credibility, and creating a culture of safety based upon a lifecycle approach to risk–benefit. 3.3 he committee recommends the Secretary of HHS direct the FDA Com- T missioner and director of CDER, with the assistance of the Manage- ment Advisory Board, to develop a comprehensive strategy for sustained cultural change that positions the agency to fulfill its mission, including protecting the health of the public. 3.4 he committee recommends that CDER appoint an Office of Surveillance T and Epidemiology (OSE) staff member to each New Drug Application (NDA) review team and assign joint authority to the Office of New Drugs and OSE for postapproval regulatory actions related to safety. 3.5 o restore appropriate balance between the FDA’s dual goals of speeding T access to innovative drugs and ensuring drug safety over the product’s lifecycle, the committee recommends that Congress should introduce specific safety-related performance goals in the Prescription Drug User Fee Act IV in 2007. (See Chapter 3 for suggested goals.) Science and Expertise 4.1 he committee recommends that in order to improve the generation of T new safety signals and hypotheses, CDER should take the following actions:

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS BOX B-2 Continued (a) onduct a systematic, scientific review of the Adverse Event Report- C ing System; (b) dentify and implement changes in key factors that could lead to a I more efficient system; and (c) ystematically implement statistical surveillance methods on a regu- S lar and routine basis for the automated generation of new safety signals. 4.2 he committee recommends that in order to facilitate the formulation and T testing of drug safety hypotheses, CDER should do the following: (a) ncrease their intramural and extramural programs that access and I study data from large automated healthcare databases; (b) nclude in these programs studies on drug use patterns and back- I ground incidence rates for adverse events of interest; and (c) evelop and implement active surveillance of specific drugs and D diseases as needed in a variety of settings. 4.3 he committee recommends that the Secretary of HHS, working with the T Secretaries of Veterans Affairs and Defense, develop a public–private partnership with drug sponsors, public and private insurers, for-profit and not-for-profit healthcare provider organizations, consumer groups, and large pharmaceutical companies to prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health impor- tance. Congress should capitalize the public share of this partnership. 4.4 he committee recommends that CDER assure the performance of timely T and scientifically valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs). The assessment of risks and benefits is an activity that does not end at approval, and risk and benefit cannot be considered in isolation of one another. 4.5 he committee recommends that CDER develop and continually improve T a systematic approach to risk–benefit analysis for use throughout the FDA in the preapproval and postapproval settings. 4.6 he committee recommends that CDER build internal epidemiologic and T informatics capacity in order to improve the postmarket assessment of drugs. 4.7 he committee recommends that the Commissioner of FDA demonstrate T commitment to building the Agency’s scientific research capacity by: (a) ppointing a Chief Scientist in the office of the Commissioner with A responsibility for overseeing, coordinating, and ensuring the quality and regulatory focus of the agency’s intramural research programs;

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 APPENDIX B BOX B-2 Continued (b) esignating the FDA’s Science Board as the extramural advisory D committee to the Chief Scientist; (c) ncluding research capacity in the Agency’s mission statement; I (d) pplying resources to support intramural research approved by the A Chief Scientist; and (e) nsuring that adequate funding to support the intramural research E program is requested in the Agency’s annual budget request to Congress. 4.8 he committee recommends that the FDA have its advisory committees T review all NMEs either prior to approval or soon after approval to advise in the process of ensuring drug safety and efficacy or managing drug risks. 4.9 he committee recommends that all FDA drug product advisory com- T mittees, and any other peer-review effort such as mentioned above for CDER-reviewed product safety, include a pharmacoepidemiologist or an individual with comparable public health expertise in studying the safety of medical products. 4.10 he committee recommends the FDA establish a requirement that a sub- T stantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee’s deliberations. 4.11 o ensure that trial registration is mandatory, systematic, standardized, T and complete, and that the registration site is able to accommodate the re- porting of trial results, the committee recommends that Congress require industry sponsors to register in a timely manner at ClinicalTrials.gov, at a minimum, all phase II through IV clinical trials, wherever they may have been conducted, if data from the trials are intended to be submitted to the FDA as part of an NDA or supplemental NDA, or to fulfill a postmarket commitment. The committee further recommends that this requirement include the posting of a structured field summary of the efficacy and safety results of the studies. 4.12 he committee recommends that the FDA post all NDA review packages T on the agency’s website. 4.13 he committee recommends that the CDER review teams regularly and T systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information. Regulation 5.1 he committee recommends that Congress ensure that the Food and T Drug Administration has the ability to require such postmarketing risk as- sessment and risk management programs as are needed to monitor and ensure safe use of drug products. These conditions may be imposed both

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS BOX B-2 Continued before and after approval of a new drug, new indication, or new dosage, as well as after identification of new contraindications or patterns of adverse events. The limitations imposed should match the specific safety concerns and benefits presented by the drug product. The risk assessment and risk management program may include: (a) istribution conditioned on compliance with agency-initiated changes D in drug labels; (b) istribution conditioned on specific warnings to be incorporated into D all promotional materials (including broadcast direct-to-consumer [DTC] advertising); (c) istribution conditioned on a moratorium on DTC advertising; D (d) istribution restricted to certain facilities, pharmacists, or physicians D with special training or experience; (e) istribution conditioned on the performance of specified medical D procedures; (f) istribution conditioned on the performance of specified additional D clinical trials or other studies; and/or (g) istribution conditioned on the maintenance of an active adverse D event surveillance system. 5.2 he committee recommends that Congress provide oversight and enact T any needed legislation to ensure compliance by both the Food and Drug Administration and drug sponsors with the provisions listed above. The FDA needs increased enforcement authority and better enforcement tools directed at drug sponsors, which should include fines, injunctions, and withdrawal of drug approval. 5.3 he committee recommends that Congress amend the FDCA to require T that product labels carry a special symbol such as the black triangle used in the United Kingdom or an equivalent symbol for new drugs, new com- binations of active substances, and new systems of delivery of existing drugs. The FDA should restrict DTC advertising during the period of time the special symbol is in effect. 5.4 he committee recommends that the FDA evaluate all new data on new T molecular entities no later than 5 years after approval. Sponsors will sub- mit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer-reviewed journal, and will report on the status of any applicable conditions imposed on the distribu- tion of the drug called for at or after the time of approval. Communication 6.1 he committee recommends that Congress enact legislation establishing T a new FDA advisory committee on communication with patients and con- sumers. The committee would be composed of members who represent consumer and patient perspectives and organizations. The advisory com- mittee would advise CDER and other centers on communication issues

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 APPENDIX B BOX B-2 Continued related to efficacy, safety, and use during the lifecycle of drugs and other medical products, and it would support the centers in their mission to “help the public get the accurate, science-based information they need to use medicines and foods to improve their health.” 6.2 he committee recommends that the new Office of Drug Safety Policy T and Communication should develop a cohesive risk communication plan that includes, at a minimum, a review of all center risk communication activities, evaluation and revision of communication tools for clarity and consistency, and priority setting to ensure efficient use of resources. Resources 7.1 o support improvements in drug safety and efficacy activities over a prod- T uct’s lifecycle, the committee recommends that the Administration should request and Congress should approve substantially increased resources in both funds and personnel for the Food and Drug Administration. SOURCE: IOM (2007b). REFERENCES IOM (Institute of Medicine). 2007a. Cancer biomarkers: The promises and challenges of improving detection and treatment. Washington, DC: The National Academies Press. IOM. 2007b. The future of drug safety: Promoting and protecting the health of the public . Washing- ton, DC: The National Academies Press.

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