Federal Agency Roles in Cancer Drug Development from Preclinical Research to New Drug Approval The National Cancer Institute and the Food and Drug Administration (2005) / Chapter Skim
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3 The Food and Drug Administration
3 The Food and Drug Administration
Pages 28-53
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From page 28... ...
Although few of the statutory provisions carried out by the FDA relate specifically to cancer, dedicated groups within FDA have been assigned to specific disease areas, including cancer; cancer-specific advisory bodies and guidance documents have helped to customize and standardize procedures for cancer drugs; and procedures for accelerated or conditional approvals of products have become increasingly important for cancer drugs more so than for any other disease category. The time that passes in the course of FDA review of INDs and NDAs is short relative to total R&D time (said to be 5-10 percent of total clinical development time)
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. About 40 oncology drugs have been approved with orphan designation, but the program was not intended to address approval criteria or review times (Roberts and Hirschfeld, 2005)
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Accordingly, in July 2004, FDA announced further changes to the agency's organization with the objective of strengthening review of products to diagnose, treat, and prevent cancer. These changes had been preceded by years of discussions with cancer advocacy organizations, industry representatives, and NCI about the need to consolidate oncology expertise across the agency,15 and they followed several other changes FDA had recently made to cancer review, such as the formation of the FDA/NCI Interagency Oncology Task Force (see below)
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Pre-IND consultation improves the chances that the IND will be allowed. It is not binding on FDA during subsequent review of the development of the drug, but the special protocol assessment process described below does commit the FDA short of evident public health concerns.
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Clinical protocols and investigator information -- detailed protocols for proposed clinical studies to assess whether initial-phase trials will expose subjects to unnecessary risks, information on the qualifications of clinical investigators (professionals, generally physicians, who oversee the administration of the experimental compound) , and commitments to obtain informed consent from the research participants, to obtain review of the study by an institutional review board (IRB)
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FDA staff with a range of technical expertise undertake an independent analysis of the clinical trial data. The final assessment balances the positive effects (benefits)
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The 1992 Prescription Drug User Fee Act (PDUFA) addressed that critique, not by relaxing any FDA regulatory requirements, but by responding to FDA's position that long review times resulted from insufficient funds to hire enough reviewers.
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PDUFA set performance goals for review times for both standard approvals and priority approvals, as follows: · For standard NDAs and applications to add indications to the labeling (supplements) with clinical data, FDA agreed to review and act on 90 percent of such applications within twelve months from the date of submission.
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· FDA agreed to establish a joint agency/industry working group to oversee efforts to improve review times; implement a project management system within twelve months for NDA reviews and within 18 months for PLA/ELA reviews; implement within CBER a performance tracking and monthly monitoring system similar to that in place in CDER; adopt uniform standards for computer-assisted NDAs in FY 1995; and initiate a pilot computer-assisted PLA program in FY 1993. FDA review time is defined by the agency as "the time it takes FDA to review a new drug application" (U.S.
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From page 37... ...
PDUFA, then, encouraged a balancing of consumer protection and public health, on the one hand, and a more cooperative, science-based interaction with industry, on the other. Special Protocol Assessments Drug sponsors have complained about the lack of consistency by the FDA in communicating to sponsors about drugs from IND through NDA.
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Although animal cancinogenicity and final product stability protocols are covered, the type most directly relevant to cancer drugs involves clinical protocols for phase III trials whose data will form the primary basis for an efficacy claim in an original NDA, BLA, or supplement when the trials had been the subject of discussion at an end-of-phase II/prephase III meeting with the FDA review division, or, in certain other instances, if the FDA was aware of the developmental context in which a protocol was being reviewed with a sponsor and questions answered. Sponsors are required to submit their protocols before the anticipated start of the study (FDA recommends at least 90 days)
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Until the mid-1980s, FDA approved cancer drugs on the basis of a better tumor response rate (partial response, the proportion of tumors shrinking by defined degrees; or complete response, the disappearance of the tumor) that was better than the standard treatment.
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Table 3: End points for oncology drug marketing applications, January 1, 1990November 1, 2002 40
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Clinical trials designed to demonstrate improved survival are usually the most time-consuming and often require the largest numbers of patients. They nearly always require a randomized design, which is also true for trials designed to detect prolonged disease-free survival.
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and the benefit was considered to be of great enough value to patients. In general, for 90 separate claims from 1985 to 2003, approvals have usually been based on multiple end points, with response rate most frequent (60 percent of all claims and 75 percent of accelerated approvals)
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The same source also reported, that from the time of the first oncology accelerated approval in 1995, about one third of all cancer drug approvals were accelerated based on surrogate endpoints (Roberts and Chabner, 2004) One observer has asked "...whether the accelerated approval mechanism enhances or hinders a sponsor's ability to complete definitive clinical trials with a new agent and, therefore, whether this regulatory strategy is in the best interest of cancer 43
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the totals reported here and concluded that 62 percent of accelerated approval indications were based on trials of fewer than 200 patients and that safety data were often incomplete Veronese, ML. Report card for accelerated FDA approval oncology drugs (1995-2003)
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Other designs such as A+B versus A+C, where B is the only experimental agent have also been used. For example, in a trial of a new agent for advanced or metastatic non-small cell lung cancer, approval was based on a small survival advantage in an A+B vs A trial and an improved TTP and response rate (but no survival advantage)
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demonstrated that the drug had essentially no activity as a single agent in colorectal cancer, but in combination with standard therapy, it clearly enhanced the time to progression and response rate of patients. On this basis approval was granted.
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. Differences among cancer patients and different cancers in responsiveness and sensitivity to anticancer drugs pose additional problems.
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science to develop the tool kit for evaluation of products and faster, less costly, and more predictable approvals. Extensive input was solicited in 2004 from interested parties and the public and a Critical Path Opportunities List is being developed with challenges and opportunities such as biomarkers, improved clinical trials, molecular imaging, data mining from FDA experience, and other possible science and technology 20Guidance for Industry Pharmacogenomic Data Submissions http://www.fda.gov/cder/guidance/6400fnl.pdf 48
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As noted below, NCI has been supportive of the Initiative through the task force described next. FDA and NCI Initiatives to Enhance Cancer Drug Development and Approval The FDA/NCI Oncology Task Force In May 2003, the Commissioner of the FDA and the NCI Director established the joint FDA/NCI Oncology Task Force "to enhance the efficiency of clinical research and the scientific evaluation of new cancer medications" (Barker, July 10, 2003 testimony http://www3.cancer.gov/legis/testimony/barker.html)
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With NCI involvement, FDA has worked with the American Society of Clinical Oncology to identify biomarkers of clinical benefit as appropriate end points for cancer clinical trials by type of cancer and stage of disease. End points identified through this process will be published in FDA guidance documents.
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Even though FDA is generally meeting its targets of 10 months for standard NDA reviews and six months for priority reviews, total approval times are often longer because NDAs fail to gain approval in a single cycle. CDER analyzed FDA experience with long review times for new molecular entity NDAs that were approved from January 2000 through either August 2001 (for priority reviews)
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Under the new FDA initiative to speed approvals, the Center for Oncology Drug Products is undertaking to produce better guidance for oncology products on key topics and has been in discussion with the American Society of Clinical Oncology about appropriate endpoints for cancer clinical trials, as well as developing other documents within the agency. Several hundred current FDA guidance documents address a wide range of topics, including several dozen related to cancer.
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From page 53... ...
The Congress has kept a close watch on the FDA, and has enacted legislation (for example, through FDAMA and PDUFA, as mentioned several times in this chapter) facilitating accelerated approval, expedited reviews, and other innovations that have allowed the agency to speed the drug development and approval process.
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