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DOI: 10.1093/jnci/djr104
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EDITORIALS
Accelerated Approval of Oncology Drugs: Can We Do Better?
Susan S. Ellenberg
Correspondence to: Susan S. Ellenberg, PhD, University of Pennsylvania School of Medicine, 423 Guardian Dr, Philadelphia, PA 19104 (e-mail: sellenbe@
upenn.edu).
The modification of Food and Drug Administration (FDA) investigational new drug regulations to provide for “accelerated approval”
of promising new drugs was put in place in 1992 (1), motivated
largely by the emergence of HIV/AIDS. The increasing rigor of
FDA review, beginning with the 1962 passage of the Kefauver–
Harris amendments to the Federal Food, Drug and Cosmetic Act,
and the resulting changes to the FDA regulations regarding evaluation of investigational drugs, were perceived as intolerable obstacles to making potentially life-saving therapy available in the most
rapid way possible to those suffering from a deadly disease with very
limited therapeutic options. Accelerated approval was to be based
on positive results for surrogate endpoints that were considered
likely predictors of clinical benefit, as typically measured for oncological drugs by an improvement in survival. The application of this
less restrictive pathway to drug approval was quickly used in other
medical areas; among the first eight drugs to receive accelerated
approval, four were for HIV/AIDS indications, two were for cancer
treatment (one was for Kaposi sarcoma, an AIDS-related malignancy), one was for multiple sclerosis, and one was for bacterial
infection.
The article by Johnson et al. (2) in this issue of the Journal
updates the FDA experience with accelerated approval of oncological drugs and biologics that first appeared in 2004 (3). Over
18 years, from the initiation of the accelerated approval process
in 1992 through 2010, 35 products for 47 indications have been
approved in accelerated fashion; 20 of these products have so far
received regular approval for one or more indications. In only
three cases has a product that received accelerated approval
clearly failed to have clinical benefit confirmed (although it
appeared that for one of these—gefitinib—the drug was, in fact,
effective in a small subset of patients with certain tumor characteristics). The final status of many products that have received
accelerated approval is as yet undefined because the clinical trials
that were mounted to confirm clinical benefit of these products
have either not yet been completed or remain under FDA
review.
Of the 47 accelerated approvals, 28 were based on single-arm
trials and 19 were based on randomized trials. The proportion
based on randomized trials has increased somewhat in recent years.
Since 2005, half of accelerated approvals for oncology drugs were
based on data from randomized trials; before 2005, the proportion
was about 2:1 in favor of single-arm studies. Most of the accelerated approvals for a first-line or adjuvant treatment indication have
been based on data from randomized studies. Only imatinib gained
approval for first-line indications (for gastrointestinal stromal
tumor and pediatric Philadelphia chromosome–positive chronic
myeloid leukemia) based on data from single-arm studies.
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An important question related to accelerated approvals for oncology products that is not fully addressed by these data is the
extent to which accelerated approval actually speeds the availability
of products that offer an important advance in cancer treatment. In
2009, Richey et al. (4) challenged the assumption that accelerated
approval actually did accelerate the availability of new oncology
drugs. They based their argument on comparisons of time from
investigational new drug application to accelerated vs regular approval of oncology drugs approved between 1995 and 2008. In
response, Lanthier et al. (5) from the FDA noted that products for
which accelerated approval is not considered an option might be
different in many ways from products with perceived potential for
accelerated approval, and these differences may have major effects
on the time needed to evaluate the product, so that such comparisons are not very meaningful. Although this is certainly a valid
point, the time saving estimated by Johnson et al. (2) is equally
questionable. They point to the median and mean times between
accelerated and regular approvals (for those drugs receiving the
latter) of 4–5 years and interpret this number as the time saved in
making these new drugs available. However, this surely overstates
the case. The time to complete a study aimed at achieving regular
approval from the start would likely be far shorter than the time
under the current scenario to complete an initial study to achieve
accelerated approval plus the time to conduct a confirmatory story
aimed at regular approval, unless (perhaps) the confirmatory study
was a continuation of the initial study. Thus, the time to availability of a new drug, although undoubtedly shorter with accelerated approval as an option, may not be as impressive as Johnson
et al. (2) suggest.
Other issues of interest also cannot be addressed from the
data provided by Johnson et al. (2). For example, one cannot tell
from the tables how many of the accelerated approvals based on
randomized trials (table 1) and ultimately converted to regular
approval (table 3) were converted based on continued follow-up
of the trial on which the accelerated approval was based. The
FDA argues for this strategy as the most efficient and the most
reliable approach. One would like to know often this strategy is
actually used, and how the time between accelerated and regular
approval for this strategy compares with the time for other
strategies.
Johnson et al. (2) do not address the obstacles—real or perceived—
that may dissuade drug manufacturers from initiating randomized
trials designed to assess a survival or other clinical benefit but with
the potential for supporting accelerated approval on the basis of a
surrogate endpoint (eg, progression-free survival or response rate).
One likely obstacle is the anticipated difficulty in completing a
study when preliminary data on surrogate endpoints suggest that
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the treatment under study is superior to the control treatment.
Individuals receiving control treatment in such a trial may wish
to cross over to the potentially superior treatment. If that treatment is already marketed for other indications (as would often be
the case), there would be no way to prevent such crossovers,
which have the potential to substantially diminish the observable
differences in the outcomes needed for regular approval (eg,
survival). Drug manufacturers may find it less complicated to
mount an independent study [possibly in a population with less
advanced disease, as the Johnson et al. (2) suggest] to support regular approval.
The accelerated approval process has been criticized on a
variety of grounds. Many have noted the risks associated with
making toxic drugs available rapidly on the basis of surrogate endpoints that may not translate into real clinical benefit (6–8). Others
deplore the delays in completing the required studies to demonstrate a survival advantage or other established clinical benefit
following an accelerated approval (9), a problem that Johnson et al.
(2) acknowledge. Still others, such as Richey et al. (4), are concerned that the process has been insufficiently accelerated.
The FDA is routinely castigated for proceeding too cautiously
and slowly, and at the same time, for rushing drugs to market too
rapidly without adequate study. What some might consider a
happy medium will inevitably leave many other scientists, clinicians, and consumers dissatisfied. The recent decision by the FDA
to remove the breast cancer indication from the label of bevacizumab when clinical trials following the drug’s accelerated approval in 2008 did not confirm any survival advantage in this
population is an excellent example: the FDA has received both
great praise and harsh criticism for this decision. There is always
room to improve regulatory processes and analyses such as the
one conducted by Johnson et al. (2) are an essential step in identifying and implementing such improvements. The FDA’s new
regulatory science initiative announced in the fall of 2010 (10)
jnci.oxfordjournals.org should support more in-depth analyses of regulatory data that
could provide valuable insights regarding optimization of regulatory approaches.
References
1. “Applications for FDA Approval to Market a New Drug.” Code of Federal
Regulations Title 21 Part 314. Washington, DC: U.S. Government
Printing Office; 2010 ed.
2. Johnson JR, Ning Y-M, Farrell A, Justice R, Keegan P, Pazdur R.
Accelerated approval of oncology products: the Food and Drug
Administration experience. J Natl Cancer Inst. 2011;103(8):636–644.
3. Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated approval of oncology products: a decade of experience. J Natl Cancer Inst.
2004;96(20):1500–1509.
4. Richey EA, Lyons EA, Nebeker JR, et al. Accelerated approval of cancer
drugs: improved access to therapeutic breakthroughs or early release of
unsafe and ineffective drugs? JCO. 2009;27(26):4398–4405.
5. Lanthier ML, Sridhara R, Johnson JR, et al. Accelerated approval and
oncology drug development timelines. JCO. 2010;28(14):e226–e227.
6. Fleming TR, Rothmann MD, Lu HL. Issues in using progression-free
survival when evaluating oncology products. JCO. 2009;27(17):
2874–2880.
7. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we
being misled? Ann Intern Med. 1996;125(7):605–613.
8. Schatzkin A, Gail M. The promise and peril of surrogate endpoints in
cancer research. Nat Rev Cancer. 2002;2(1):19–27.
9. Government Accountability Office. (September 23, 2009). New Drug
Approval: FDA Needs to Enhance its Oversight of Drugs Approved on the Basis
of Surrogate Endpoints. (Publication No. GAO-09-866). Government
Printing Office, 2009. Retrieved from http://www.gao.gov/new.items/
d09866.pdf. Accessed March 15, 2011.
10. FDA Office of the Commissioner, Office of Chief Scientist. (October
2010). Advancing Regulatory Science for Public Health. U.S. Food and
Drug Administration. Accessed at http://www.fda.gov/ScienceResearch/
SpecialTopics/RegulatoryScience/ucm228131.htm. Accessed March 15,
2011.
Affiliation of author: Department of Biostatistics and Epidemiology,
University of Pennsylvania School of Medicine, Philadelphia, PA.
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