The Future of Drug Safety Promoting and Protecting the Health of the Public (2007) / Chapter Skim
Currently Skimming:
2 Natural History of a Drug
2 Natural History of a Drug
Pages 31-64
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The material in this chapter is drawn largely from Center for Drug Evaluation and Research (CDER) documents -- both guidance documents for sponsors and internal manual of policies and procedures that describe a wide variety of official policies -- and from conversations with current and former FDA staff.
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, which monitors postmarket risks and undertakes risk assessments. (Other divisions and offices of ODS/OSE address safety issues, such as medication errors and drug names.2)
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. FDA produces numerous guidance documents to steer sponsors through the regulatory process.
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. Clinical trials are conducted under the sponsor's auspices by commercial, academic, or other entities in the United States or, increasingly, overseas.
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Phase 2 studies are typically well controlled and closely monitored. Phase 3 Formal clinical trials.
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OND clinical reviewers typically are physicians, some with epidemiology training, who are skilled in review of clinical trials. DDRE staff are mostly pharmacists and epidemiologists whose expertise tends to be in observational studies and whose primary focus has been on monitoring and evaluating postmarket data.
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From page 37... ...
Two possible explanations for why that has not occurred were offered: shortage of safety officers and the fact that some divisions do not review enough applications to support a full-time safety officer. Completion of Clinical Trials and Their Limitations Clinical trials typically take 2–10 years to complete (PhRMA, 2006)
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From page 38... ...
Furthermore, clinical trials usually do not represent the full array of patients who will use the product once it is approved. Trials often exclude patients with comorbidities or those taking other medications, although both may be common among future users of the marketed drugs.
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For example, a 2006 report indicated that when sponsors met with CDER staff before submitting an NDA, there was a greater likelihood that the drug was approved on the first cycle (FDA News, 2006b)
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. Prescription Drug User Fee Act Timetables and Performance Goals Triggered When FDA receives the final piece of an NDA the Prescription Drug User Fee Act (PDUFA)
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Reviewers' workloads typically include premarket reviews and supplemental NDA reviews and issues arising with marketed drugs that they previously reviewed. They may also be involved in writing guidance documents or may be participating in other CDER or FDA initiatives; in the wake of highly publicized concerns about safety, CDER has launched a number of initiatives in the last year to evaluate, articulate, and improve procedures.
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FDA Oversight and Review of Clinical Trial Protocols During Development Under PDUFA, FDA will evaluate specific questions about the sponsor's spe cial study protocol designs for carcinogenicity, stability and phase 3 for clinical trials that will form the primary basis of an efficacy claim. • FDA will review scientific and regulatory requirements for which the sponsor seeks agreement.
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The primary review summarizes and analyzes the clinical data in the NDA and provides the reviewer's assessment and conclusions regarding the effectiveness and safety data. It also sets out the reviewer's assessment of the proposed directions for use and includes a recommendation for regulatory action.
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. That has required FDA staff to devote many hours to planning, conducting, and following up on the meetings.
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• FDA staff (advisory committee oversight and management) must determine whether existing advisory committee members have a conflict of interest (COI)
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Case studies of specific drugs point out both the strengths and the weaknesses of FDA's investigation of safety signals in specific instances, but there seems to be no overall metric in place comparable with measures of speed to track how safety is being monitored and assessed. Individual drug evaluation offices in OND seem to differ in how and the extent to which they track safety issues regarding drugs that they are reviewing.
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. Surveys of CDER staff reveal some concern about decision-making regarding postmarketing safety (DHHS/OIG, 2003)
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. They go beyond the requirements for all sponsors to minimize risks through such efforts as accurate labeling and adverse event reporting.
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CDER staff have challenging scientific, policy, and resource issues to work out, both in general and for specific drugs or classes of drugs. Postapproal Requirements and Labeling The final days of NDA review typically involve negotiations between the sponsor and the regulators about the drug label and postmarket requirements.
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These may be added to marketed drugs when new data become available. A recent example are antidepressant medications, which now require a black box warning describing the risk and emphasizing the need for close monitoring of suicidality of patients (FDA News, 2004)
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The budget for postmarketing surveillance and assessment is not commensurate with FDA's growing scope. DDRE in ODS/OSE monitors marketed drugs and prepares safety reviews and risk assessments.
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. In recent years, it has also assumed expanded responsibilities, and its pharmacists and safety officers are monitoring more products and conducting more assessments, relying on the array of data sources and technologies described below (FDA and CDER, 2005)
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Spontaneous Aderse Eent Reporting System The FDA's primary source for managing and monitoring new adverse effects of marketed drugs is the Adverse Event Reporting System (AERS) , an automated system for storing and analyzing safety reports.
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From page 54... ...
FDA is making limited use of data mining software to identify early drug safety signals in the AERS database via automated searching. AERS is an important component of the postmarket surveillance system, particularly for identifying unexpected and rare adverse events (Rodriguez et al., 2001)
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. Another source of postmarket safety data is studies of marketed drugs designed to investigate new or expanded indications.
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Identifying and Ealuating Spontaneous Safety Signals As CDER receives new information related to a drug's safety profile, it makes risk assessments and determines how risks can best be managed. For monitoring purposes, every marketed drug is assigned to a safety evaluator, usually a pharmacist in DDRE.
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FDA has been criticized for waiting too long and has proposed a Drug Watch Web site that would give the public and providers information about potential problems with marketed drugs earlier than in the past. The proposed Drug Watch program has been subject to criticism from the pharmaceutical industry.
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The threat of such an action (although for critical or popular therapies such a threat may not be credible) and the agency's ability to use the mass media to call attention to the controversy give the agency some teeth in getting sponsors to comply with regulatory actions.
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November 1999 -- FDA advisory committee recommends approval February 2000 -- FDA approves Alosetron for treatment of "diarrhea predominant irritable bowel syndrome" in women June 2000 -- FDA advisory committee meeting discusses evidence of serious adverse events and votes to retain the drug on the market November 2000 -- FDA and the sponsor meet, sponsor withdraws Alosetron December 2001 -- sponsor proposes returning Alosetron to market with restrictions April 2002 -- FDA advisory committee recommends return to market with restrictions June 2002 -- FDA approves Alosetron's return to market, with less rigor ous restrictions than those recommended by the advisory committee SOURCE: Moynihan (2002)
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From page 60... ...
. Available: www.fda.gov/cder/offices/ods/medica tion_guides.htm [accessed July 6, 2006]
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2005d. White Paper, Prescription Drug User Fee Act (PDUFA)
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. FDA Announces New Prescription Drug Information Format to Improe Patient Safety.
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2005. Numbers of active investigators in FDA-regulated clinical trials drop.
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From page 64... ...
thememoryhole.org/crs/more-reports/RL30989.pdf [accessed June 27, 2005]
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