The FDA in 2006: Reasons for Optimism

An interesting analysis has come to our attention. The Stanford Policy Research Group, a private investment advisory firm, examined the time from submission to approval for new molecular entities approved by the Food and Drug Administration (FDA) in the last two years [1]. Cancer drugs fared very well, indeed. It found that the five cancer drugs approved in 2006 required an average of 176 days (5.9 months) to complete the review process, as compared to 278 days (9.3 months) for twenty noncancer drugs. In its analysis, Stanford did not include Merck’s landmark human papilloma virus vaccine (185 days in review), a major contribution to the cancer portfolio, in its list of new cancer medicines. Each of the five new cancer drugs completed the process in 200 days or less, compared to only six of the 20 (30%) noncancer drugs.

Even more impressive was the comparison for all drugs approved in 2005 and 2006. In 2005, the average review time for 20 new molecular entities approved by the FDA was 454 days, as compared to only 258 days for 25 drugs in 2006. Only three new cancer drugs were approved in 2005, a number too small to draw any comparisons, but the improvement in approval metrics for all drugs from 2005 to 2006 is encouraging. Amidst all the recent criticism of the FDA for problems in postmarketing surveillance for drugs (e.g., rofecoxib, Vioxx®; Merck & Co., Inc., Whitehouse Station, NJ) and devices (e.g., drug-eluting stents), steady progress has occurred for the drug-approval process, particularly for the cancer community.

Is 6 months for review fast enough? All of us would like to see faster action, but keep in mind that it takes the “average” cancer center 6 months to review and activate a single protocol, let alone review manufacturing, toxicology, and clinical data as part of the approval process. The FDA staff, and particularly Dr. Richard Pazdur, who leads the newly established Office of Oncology Drug Products, deserves much credit. There is no question that his team understands the need for speedy approval, and has worked diligently, in an increasingly complex regulatory environment and with entirely new kinds of drugs, to help facilitate the process. In particular, through the Special Protocol Assessment mechanism [2], they are working effectively with biotech and pharmaceutical companies to lay out clear approval strategies as soon as positive results are forthcoming in early trials. They have also reached out to organizations such as the American Society of Clinical Oncology (ASCO) and the National Cancer Institute (NCI) to hold public workshops to discuss appropriate endpoints for clinical trial design. Such workshops, along with frequent public meetings of the Oncologic Drug Advisory Committee (ODAC), have worked to increase transparency and consistency in approval criteria. Finally, they have been flexible in recognizing alternative endpoints and increasingly have used time to progression or progression-free survival as an option for new entities in otherwise difficult-to-treat malignancies. A list of drugs approved in 2005–2006, their sponsor, indication, approval pathway (regular or accelerated), and the days from submission to approval, is provided in Table 1, and illustrates the variety of agents and endpoints meeting their approval.

These new figures come to our attention as the debate heats up in Congress over new legislation designed to tighten review and postmarketing surveillance. The Institute of Medicine (IOM) released a recent report emphasizing the lack of efficient FDA oversight of drug toxicity and its slow response to early warning signs in the Vioxx toxicity fiasco [3]. The IOM expert panel called for much greater investment in postmarketing surveillance and in toxicity reporting systems. It also emphasized the need for staff training, and considered a separation of responsibility between staff concerned with review and those concerned with monitoring postmarketing safety. The latter is a controversial stance. One could easily question the wisdom of establishing separate review and surveillance units with parallel expertise, but opposing perspectives. For cancer drugs, our primary concern in the past has been the development of effective new treatments for untreatable and fatal malignancies, and not as much worry about the late consequences of therapy. To date, no cancer drug has been withdrawn from the market due to safety concerns. In part due to heavy postmarketing investment in clinical trials for most new cancer drugs, sponsors have been able to characterize postmarketing safety signals (e.g., trastuzumab-related cardiotoxicity) relatively quickly, allowing for rapid adjustments in care. Certainly, as patients live longer, and as new therapeutics are used for adjuvant regimens and for prevention, delayed effects will become increasingly important. Congress will undoubtedly listen carefully to the argument for increased surveillance.

The FDA has already announced, in January, a series of comprehensive actions already taken or planned in response to last September’s IOM report. The plans include the introduction of a pilot program that will track new molecular entities for a year after approval, after which the FDA will issue a new drug “report card” that includes data on newly discovered side effects, adverse events reported to the FDA, and relevant postmarketing studies. The agency plans to publish a regular newsletter to inform health-care professionals of emerging drug-safety issues and is also working to improve communications between premarketing reviewers and employees who deal with postmarketing safety issues. Neither the FDA initiatives nor the recently introduced Enzi-Kennedy drug-safety legislation in the Senate appear particularly onerous for sponsors seeking approvals for cancer drugs, but other drug-safety bills are likely to follow.

Friends of Cancer Research, an advocacy group led by former National Cancer Advisory Board member Ellen Sigel, have contributed an important alternative point of view in the debate. Their white paper can be found online at http://www.focr.org, and recognizes the need for investment in surveillance, but urges Congress to preserve and enhance initiatives to speed drug development and approval for cancer. Emphasis on surveillance is of limited value if it diverts attention from the equally important drug development and approval process.

Time to approval is a function of both the approval process and the quality of the application. This is a unique time in the history of cancer therapeutics. We now have the opportunity to radically improve the quality of drug development through coupling that process with the tools and approaches of molecular medicine. Thus far that coupling has been incomplete in the clinical phases of cancer drug development. The use of biomarkers has not had a major impact on the approval of drugs listed in Table 1, with the exception of lenalidomide, which received its initial approval in the subset of myelodysplastic patients with the 5q chromosomal deletion. However, the potential for biomarkers serving as the basis for rational drug development is clear. In the field of hormonal therapy, steroid receptors have served as a critical biomarker for patient selection. Biomarkers have guided the development and use of several important monoclonal antibodies (trastuzumab and rituximab). In molecularly targeted cancer therapeutics, biomarkers have provided early evidence of target engagement (epidermal growth factor receptor [EGFR] inhibition) [4], biological activity (positron emission tomography [PET] scanning in gastrointestinal stromal tumor [GIST]) [5], and clinical response (early vascular changes with antiangiogenic therapy in gliomas) [6].

Both the FDA and NCI are pushing the field in the direction of a more science-based approach. The FDA, together with the National Institutes of Health and the Foundation for the National Institutes of Health, has recently announced an important new initiative, the Biomarkers Consortium, to support the development of biomarkers to guide premarketing drug development and identify the right patient for the right drug (see Commentary in this issue [7]). The Foundation will provide private funds to support pilot research, and cancer researchers will be the first recipients of its grants. Its first projects are the use of fluorodeoxyglucose (FDG)-PET to assess response in non-small cell lung cancer and lymphoma. Biomarker development is an important objective of the FDA’s Critical Path Initiative, which aims to modernize all aspects of the drug-development process.

Some of the most innovative thinkers in cancer drug discovery believe that in order to move the field from empiricism to rationality, all current drug discovery and development should be based on strategies that target unique genetic lesions, with the use of biomarkers to guide drug evaluation and patient selection in the clinic. The tumor-specific translocations found in leukemias [8], lymphomas [9], and sarcomas [10] offer prime opportunities for such efforts, and animal models of these malignancies are being developed. The presence of tumor-specific targets in the major human solid tumors (lung, breast, colon) is less clear, although EGFR mutations and HER-2 amplification are important leads. Whether or not targeting unique molecular lesions and employing associated biomarkers will achieve the ultimate goal, to cure the major solid tumors found in humans, remains to be proven. Although it may be unproductive to focus further effort on the traditional cytotoxics, an argument can still be made for exploring natural products as an alternative approach. From the recent success of targeted therapies in hematologic malignancies, renal cancer, GIST, and other solid tumors, it is safe to conclude that cancer drug development is now on a more rational, and ultimately more successful, track.

The past year represented an important milestone for the FDA, a 100-year anniversary of sorts. In 1906, Congress passed the original Pure Food and Drugs Act. The law, signed by Theodore Roosevelt, prohibited misbranded and adulterated foods, drinks, and drugs in interstate commerce. The Bureau of Chemistry in the Department of Agriculture, which enforced the law, later became the FDA. At the 100-year mark, we have confidence that the FDA is doing a good job in its regulation of cancer therapy approvals, and that science, and not tradition or politics, should drive our future investments in the agency’s business.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Dr. Thomas G. Roberts is the senior health care analyst at Noonday Asset Management, L.P., a private investment management firm. In the normal course of its business, the firm manages an investment portfolio that contains the securities of public and private companies, among which are pharmaceutical companies that have developed or may be developing products for the treatment of cancer

REFERENCES
# Frykman GK, Shepard J. FDA New Cancer Drug Approvals Remain Expeditious: CDER New Drug Approvals in 2006 Most and Speediest in 3 Years. Stanford Policy Research Group Pharmaceutical Policy Bulletin 2007 January 18.
# U.S. Food and Drug Administration Critical Path Initiative. The Critical Path to New Medical Products.
# Finkelstein JB. Institute of Medicine, Congress seek solutions to FDA’s safety woes through reform, funding. J Natl Cancer Inst 2007;99:104–107.
# Sequist LV, Joshi VA, Janne PA. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. The Oncologist 2007;12:90–98.
# Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.
# Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83–95.
# Zerhouni EA, Sanders CA, von Eschenbach AC. The Biomarkers Consortium: Public and private sectors working in partnership to improve the public health. The Oncologist 2007;12:250–252.
# Wernig G, Mercher T, Okabe R et al. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006;107:4274–4281.
# Galkin AV, Melnick JS, Kim S et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A 2007;104:270–275.
# Smith R, Owen LA, Trem DJ et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell 2006;9:405–416.

Bruce A. Chabner, Editor-in-Chief, Thomas G. Roberts

Clinical Director, Massachusetts General Hospital Cancer Center; Senior Health Care Analyst Noonday Asset Management, L.P.