The Future of Drug Safety Promoting and Protecting the Health of the Public (2007) / Chapter Skim
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4 The Science of Safety
4 The Science of Safety
Pages 105-150
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From page 105... ...
There will always be a need for clinical trials and postmarket, populationbased studies to fully understand the risks and benefits associated with 0
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From page 106... ...
CDER clinical reviewers are expertly trained to analyze the efficacy and safety data from clinical trials. Individual case reports of adverse events from the trials are reviewed, as are comparisons of event rates of many safety outcomes in the overall product database, including those in uncontrolled safety studies.
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From page 107... ...
2Efficacy refers to effects in controlled clinical trials; effectiveness refers to effects in the "real world."
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From page 108... ...
The committee offers specific recommendations to CDER and other federal departments and agencies for improving postapproval assessment of drug-related risks and benefits. Signal Generation Although some safety signals are generated in laboratory tests and clinical trials conducted in the preapproval setting or from known or suspected biologic actions of a drug, the primary method by which FDA documents new adverse events in the postmarket setting is monitoring of suspected adverse drug reaction reports entered into the Adverse Event Reporting System (AERS)
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From page 109... ...
The Centers for Education and Research on Therapeutics (CERTs) are assessing the potential use of health care databases for enhanced identification of adverse drug events.
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From page 110... ...
The committee does not intend that review of AE reports, whether submitted by manufacturers as mandatory under federal regulation or submitted by patients or their providers through the MedWatch program, be the primary tool used by CDER for postmarket safety analysis. The committee does not support making AE reporting mandatory.
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From page 111... ...
Signals or hypotheses about safety issues may arise from other sources, including known or suspected biologic drug effects that become evident through animal and human studies. Once a potential signal is identified, followup studies are likely to involve the use of a variety of study designs and data sources, including large electronic administrative databases.
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From page 112... ...
2006, funding for FDA drug safety contracts totals only $1.6 million, and it is scheduled to decrease to $900,000 in FY 2007. According to an ODS annual report, the contract program in 2004 supported five feasibility7 studies and three in-depth studies, but in FY 2006 the program will have sponsored feasibility studies for two drug safety questions and will not have sufficient funds to execute one highpriority in-depth study fully -- on the cardiovascular risks posed by drugs prescribed for attention deficit hyperactivity disorder (ADHD)
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From page 113... ...
FDA has endorsed a proposal, lacking in detail, to establish a postmarketing surveillance system for prescription drugs that would use billing data and health care information collected from Medicare beneficiaries (Kaiser Family Foundation, 2005)
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From page 114... ...
increase their intramural and extramural programs that access and study data from large automated healthcare databases and (b) include in these programs studies on drug utilization patterns and background incidence rates for adverse events of interest, and (c)
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From page 115... ...
In some instances, full-scale observational studies or clinical trials will be required to answer key questions, particularly if the outcome of interest is common in the patients taking a drug. Such studies are often expensive and time-consuming, but they provide valuable information that less rigorous studies cannot provide.
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From page 116... ...
The study designs can be inadequate, and there is little opportunity given time constraints imposed by the Prescription Drug User Fee Act (PDUFA) , for CDER to bring in outside experts when they are needed to help with study design.
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From page 117... ...
Congress should capitalize the public share of this partnership. The program for confirmatory studies should focus on the conduct of large, long-term phase 4 clinical trials to evaluate the health risks and benefits associated with chronic-disease medications approved on the basis of short-term trials of surrogate endpoints -- such as blood pressure and lipid and hemoglobin A1c concentrations -- and on comparative safety and effectiveness studies.
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From page 118... ...
The committee believes that industry bears the responsibility for paying for clinical trials and other observational studies which support a product's approval and its safe and effective use (e.g., specific 11DoD and other agencies have collaborated in planning and analyzing complementary studies of the safety of the smallpox and anthrax vaccines. 12This could be accomplished by training CDER staff to use the databases directly or to work with staff in the other agencies.
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From page 119... ...
constitute a relatively new approach to minimizing known risks of a drug beyond the standard industry responsibilities related to routine risks, such as labeling and reporting of AEs. According to the guidance entitled "Guidance for Industry, Development and Use of Risk Minimization Action Plans," "RiskMAP means a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits.
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From page 120... ...
The risk minimization activities for this drug have increased in complexity. The Pregnancy Prevention Program (PPP)
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From page 121... ...
of Risk Minimization Action Plans (RiskMAPs)
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From page 122... ...
Spontaneous reports of adverse events may indicate a potential safety problem and warrant a safety study. Safety and effectiveness data from studies on uses other than the approved indication are gathered if the sponsoring company is studying the drug in clinical trials for a supplemental NDA for a new indication or if sufficient off-label use occurs.
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From page 123... ...
. The WHI was three large clinical trials in one, and the major interventions were hormone replacement therapy, low-fat diets, and calcium plus vitamin D
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From page 124... ...
Nevertheless, the potential advantages of having a systematic approach to risk-benefit analysis for prescription drugs include increasing consistency of approach to approval decisions among the review divisions; a growing common understanding about the criteria for approval and other regulatory actions; increased transparency for the industry, health care providers, patients, and researchers; increased credibility of FDA and CDER; and direct assessments of comparable drugs. Ideally, the weighing of a product's risks and benefits will be both transparent and reproducible.
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From page 125... ...
Risks can be summarized in terms of incidence, risk difference, excess risk, severity, and duration. Rates and risks are quantitative, but only the more common events that occur with enough frequency in premarket clinical trials can be incorporated into the metrics with any precision.
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From page 126... ...
The benefits of the effort will be harmonization of the work of different review divisions, a growing understanding of the criteria for approval and other regulatory actions, and increased transparency for the industry, healthcare providers, patients, and researchers. The committee believes that with the tools described above, the evidence base on the risks and benefits associated with drugs will be more complete and will serve the health of the public better.
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From page 127... ...
Expertise in the Center for Drug Evaluation and Research The committee has made several recommendations to expand the data on drug risks and benefits to improve decisions. However, appropriate expertise must be brought to bear to plan research and use the resulting data.
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From page 128... ...
With expanded expertise and resources, CDER could be a more effective steward of postmarket safety and a more credible scientific partner with industry and academe by actively participating in defining important 15The committee has not done an independent assessment of how those options are used but understands that they are all viable options.
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From page 129... ...
. The FDA Center for Biologics Evaluation and Research, CDER's sister center, has a long history of research publication in many areas, including postmarket surveillance, as do epidemiologists at CDC, and the committee urges that CDER encourage such efforts.
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From page 130... ...
0 THE FUTURE OF DRUG SAFETY BOX 4-1 History of Reports Regarding Research at FDA In 1955, the report of the Citizen's Advisory Committee on the Food and Drug Administration to the secretary of health, education, and wel fare, stated: "Research is the heart of any scientific operation. Although the FDA is primarily a regulatory agency, it must engage in research of the sort that leads to more accurate scientific methods for determining whether a food or drug is safe.
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From page 131... ...
Scientific advances, changing technology, and the increasing complexity of new drug products have necessitated the establishment of a strong advisory committee system. Through its advisory committees, FDA can seek advice experts from outside the agency who serve as "special government employees".
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From page 132... ...
, the agency is hard pressed to complete its review, formulate its questions for the advisory committee, and then schedule the meeting within a timeframe that permits these 6-month deadlines to be met. Such committees typically must be scheduled 2 months in advance, so regulators cannot fully anticipate the questions or problems that they will encounter in the review process (DHHS and OIG, 2003; IOM Staff Notes, 16It is precisely the practice of following advisory committee recommendations that makes the Plan B controversy so notable.
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From page 133... ...
. NMEs and in particular priority-rated drugs are the most innovative and complex new drug products and have been shown to be associated with increased drug risks (Olson, 2004)
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From page 134... ...
. The guidance "FDA Guidance on Conflict of Interest for Advisory Committee Members, Consultants and Experts" describes the type and amount of information that is considered in deciding whether a financial interest presents a potential conflict of interest that needs to be merely disclosed or needs to be reviewed by the ethics staff for consideration of a waiver regarding a topic to be discussed by the advisory committee whose meeting the special government employee is attending (FDA, 2000)
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From page 135... ...
THE SCIENCE OF SAFETY TABLE 4-2 Conflicts of Interest That Lead to a "Cover Memo" Only (Disclosure Required, but Waiver) Type of Conflict of Interest Party Matters General Matters Any Matter Stocks and Stock value is less than Stock value is less than Investments or equal to $5,000 or equal to $25,000 per in aggregate ( CFR entity/$50,000 in aggregate 0.0(a)
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From page 136... ...
SGE receives between SGE receives between $10,000 and $50,000 $10,000 and $50,000 per source per year and per source per year and consulting on related or consulting on unrelated unrelated issue completed issue in the past or within the past 12 months completed within the past (all monies paid) 12 months (all monies paid)
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From page 137... ...
THE SCIENCE OF SAFETY TABLE 4-2 Continued Type of Conflict of Interest Party Matters General Matters Any Matter Contracts/ Remuneration is less than Remuneration is less than Grants/ $100,000 per source per $100,000 per source per CRADAs year to institution/$10,000 year to institution/$10,000 per source per year as per source per year as salary support to the SGE salary support to the SGE and work on unrelated and work on unrelated product is currently active matter is current or or completed within the completed within the past past 12 months 12 months Remuneration is less than $100,000 per source per year to institution/$10,000 per source per year as salary support to the SGE and work on related matter has been completed over a year ago Remuneration is between $100,000–$300,000 per source/year to institution/$10,000– $15,000 per source/year as salary support to the SGE and work on unrelated matter is current or completed within past 12 months Patents/ SGE receives less than Royalties/ $15,000 in royalties per Trademarks affected source annually and SGE has a patent on an unrelated product, licensed by a competing firm, and receives royalties Expert Remuneration is less than Witness $5,000 per affected source per year and SGE makes no statement for or against any product of a sponsor or competitor continued
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From page 138... ...
THE FUTURE OF DRUG SAFETY TABLE 4-2 Continued Type of Conflict of Interest Party Matters General Matters Any Matter Teaching/ SGE receives Speaking/ less than $5,000 Writing per source per year and topic is unrelated to the particular matter and SGE receives no compensation SGE receives less than $5,000 per source per year and topic is unrelated and SGE is compensated SGE receives less than $5,000 per source per year and topic is related but SGE receives no compensation (including travel) SGE receives less than $5,000 per source per year and topic is related but not specific to the matter under discussion by the committee and SGE is compensated
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From page 139... ...
THE SCIENCE OF SAFETY TABLE 4-2 Continued Type of Conflict of Interest Party Matters General Matters Any Matter Department Remuneration is less than Remuneration is less than Heads -- $300,000 per source per $300,000 per source per Contracts/ year to SGE's department year to SGE's department Grants/ and work on unrelated and work on unrelated CRADAs matter is current or has matter is current or has been completed within the been completed within the past 12 months past 12 months Remuneration is less than Remuneration is less than $300,000 per source per $300,000 per source per year to SGE's department year to SGE's department and work on related and work on related matter has been completed matter has been completed within the past 12 months within the past 12 months, and SGE had only an and SGE had only an administrative role administrative role Remuneration is between Remuneration is between $300,000–$600,000 per $300,000–$600,000 per source per year to SGE's source per year to SGE's department and work on an department and work on unrelated matter is current unrelated matter is current or has been completed or has been completed within the past 12 months within the past 12 months Remuneration is between $300,000–$600,000 per source per year to SGE's department and work on related matter has been completed within the past 12 months and SGE had only an administrative role Exceptions The interests reported are for unrelated to the product at Institutional issue or to the competing Directors products (up to $750,000 per source per year)
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From page 140... ...
The committee recognizes that many leaders in academic medicine with experience designing and conducting clinical trials receive research support from the pharmaceutical industry and that they conduct their research in an unbiased manner. The committee also recognizes that researchers who consult for industry gain important insights that are needed in the review process.
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From page 141... ...
. NIH, for example, funds clinical trials, and investigators associated with those would bring necessary practical expertise to a drug products advisory committee.
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From page 142... ...
Many data are made public in some form, at some time, and at some place on the FDA or another government or industry Web site, but the process is not systematic, comprehensive, or well organized. The committee believes strongly in the importance of increasing the availability to the public and to researchers of information about drug risks and benefits, whether specific study results or analyses of concerns by agency staff, and it provides several recommendations related to clinical trial registration and results reporting, Web-site posting of all NDA-review packages, and timely public release of all CDER summaries of emerging data relevant to the safety and effectiveness of a drug after approval.
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From page 143... ...
A review of the site shows great variability in the ease of accessibility and completeness of the information. In addition, in the past few years many drug sponsors have created their own "registries" on company Web sites, which list their clinical trials, and may list summaries of trial results.
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From page 144... ...
The information should then be posted either on an easily accessible Web site at FDA with linkage to the trial's registration on clinicaltrials.gov, or posted directly on the latter. For those clinical trials covered by this recommendation, every completed trial would have to comply with this mechanism of results reporting, regardless of trial outcomes.
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From page 145... ...
The format of clinical trial registration and results reporting should be done in a way that harmonizes with emerging international standards (such as those specified by WHO, for example, the minimum required dataset for registration, and the requirements for results reporting, in the ICH E3 Summary of Clinical Trial Results)
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From page 146... ...
The synthesis by CDER of postmarketing information that is made public about risks and benefits is minimal. The committee believes that CDER has a role to play in putting forth the views of the regulatory agency about emerging information and should not leave that task in the hands of the pharmaceutical industry or the academic community.24 Periodic and regular review by CDER of risk and benefit information is consistent with a lifecycle approach to drug regulation.
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From page 147... ...
2006. Medicare Prescription Drug Data Deelopment: Methods for Improing Patient Safety and Pharmacoigilance Using Obserational Data.
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From page 148... ...
2006. Medicare: Prescription Drug Coerage Among Medicare Beneficiaries.
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From page 149... ...
2006. Clinical trial investigators and their prescribing patterns: another dimension to the relationship between physician investigators and the pharmaceutical industry.
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From page 150... ...
2005. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions.
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