Letters
observed results for patients with Dukes B (stage II) disease Corresponding Author: John N. Primrose, MD, FRCS, University of
(eFigure 2 in the article). Can the authors comment on this?
Marsela Sinjari, MD
Giada Zoccoli, MD
Giovanni Codacci-Pisanelli, MD, PhD
Author Affiliations: Department of Medical and Surgical Sciences and
Biotechnology, Sapienza University of Rome, Rome, Italy.
Corresponding Author: Giovanni Codacci-Pisanelli, MD, PhD, Department of
Medical and Surgical Sciences and Biotechnology, Sapienza University of Rome,
Corso della Repubblica 76, Latina 04100, Italy (giovanni.codacci-pisanelli
@uniroma1.it).
Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Primrose JN, Perera R, Gray A, et al; FACS Trial Investigators. Effect of 3 to 5
years of scheduled CEA and CT follow-up to detect recurrence of colorectal
cancer: the FACS randomized clinical trial. JAMA. 2014;311(3):263-270.
In Reply Dr Fujita questions our conclusion that follow-up strat-
egies should not be stage-specific based on 2 previous stud-
ies: (1) the results of a trial of follow-up strategies1 that re-
ported a differential effect by stage and (2) a report2 that only
8% of patients undergoing curative resection of metastases
originally present with stage I tumors.
In the trial by Rodríguez-Moranta et al,1 the less inten-
sive follow-up group included neither colonoscopy nor CT
scanning; colonoscopy alone was responsible for detection
of 44% of resectable recurrences in the intensive surveil-
lance group. In our trial, even patients in the minimum
follow-up group were offered colonoscopy at trial entry plus
a CT scan of chest, abdomen, and pelvis at 12 to 18 months if
requested by the patient and clinician (which it usually
was). The difference in stage-specific outcomes between the
trials likely reflects the difference in follow-up interventions
in the 2 studies.
It would be surprising if metastatic resection rates were not
higher for later-stage tumors, as in the report by Zakaria et al,2
given that current guidelines suggest more intensive follow-up
for later-stage tumors. We disagree with current guidelines in
that if the clinical effectiveness (and therefore almost cer-
tainly cost-effectiveness) of follow-up does not differ by stage,
then all patients should receive the same follow-up irrespec-
tive of the stage distribution.
Dr Sinjari and colleagues draw attention to the relatively
small difference in cumulative mortality at 5 years between our
patients with Dukes stage A and B cancers. Even though this
is the high end of the expected range, the absolute number of
patients with Dukes A (stage I) was not large. We did not use
central pathology in this study and it is conceivable that some
patients might be upstaged by such a system—for instance, by
a more fastidious search for lymph nodes. Such issues are in-
trinsic to large randomized multicenter trials.
John N. Primrose, MD, FRCS
David Mant, FRCGP, FRCP
Author Affiliations: University of Southampton, Southampton, England
(Primrose); University of Oxford, Oxford, England (Mant).
2128 JAMA May 28, 2014 Volume 311, Number 20
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Southampton, Tremona Road, Southampton SO16 6YD, England (j.n.primrose
@soton.ac.uk).
Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Rodríguez-Moranta F, Saló J, Arcusa A, et al. Postoperative surveillance in
patients with colorectal cancer who have undergone curative resection:
a prospective, multicenter, randomized, controlled trial. J Clin Oncol. 2006;24
(3):386-393.
2. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal
metastases: value for risk scoring systems? Ann Surg. 2007;246(2):183-191.
Trial Evidence and Approval of Therapeutic Agents
To the Editor In a study of clinical trial evidence used by the US
Food and Drug Administration (FDA) for approval of novel
therapeutic agents, Mr Downing and colleagues1 stated that the
“quality of clinical trial evidence used by the FDA as the basis
for recent approvals of novel therapeutic agents varied widely
across indications.” However, the parameters cited in their re-
search—number of pivotal trials performed and assessed, me-
dian number of patients enrolled per indication, and number
of pivotal trials with a duration of 6 months or more—speak
to the quantity of evidence accepted for approval, not the qual-
ity of that evidence.
The FDA is obligated by Congressional statute2 to require
applicants for new drug approval to present “substantial evi-
dence that the drug will have the effect it purports or is rep-
resented to have under the conditions of use prescribed, rec-
ommended, or suggested in the proposed labeling.” Arguably,
while Congress has sought to serve the public purpose by al-
lowing more rapid approval for new drugs that might provide
therapeutic opportunities otherwise unavailable for patients
with serious diseases, the FDA has sought to maintain the qual-
ity of the evidence on which it considers approval of new drugs.
The flexibility of the agency to vary the quantity of evi-
dence required for approval of a new agent reflects the obli-
gations of the FDA to safeguard the public health. One of the
major tasks of FDA review of new therapeutic agents is the as-
sessment of potential or measured harm vs the achieved ben-
efit. The ratio of benefit to harm required for new drug ap-
proval is not fixed; indeed, the amount of risk that may be
acceptable will vary depending on the seriousness of the tar-
geted disease, the availability of therapeutic alternatives, and
the nature of the observed safety signal.
Similar public health considerations govern the quantity of
the specific clinical data that may be required for approval. More-
over, the principle of equipoise in the law and its administra-
tion through regulation requires the FDA to act consistently with
regard to requirements for consideration of approval of simi-
larly situated therapeutic agents. Thus, law and regulation re-
quire the quality of clinical studies to be maintained.
Allan M. Green, MD, PhD, JD
Lee S. Simon, MD
Author Affiliations: SDG LLC, Cambridge, Massachusetts.
Corresponding Author: Allan M. Green, MD, PhD, JD, SDG LLC, One Mifflin
Place, Ste 400, Cambridge, MA 02138 (amgreen@fdalawboston.com).
jama.com

Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported
being co-managing directors of SDG LLC, which provides consulting support to
FDA-regulated industry. No other disclosures were reported.
1. Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. Clinical trial
evidence supporting FDA approval of novel therapeutic agents, 2005-2012.
JAMA. 2014;311(4):368-377.
2. Federal Food, Drug, and Cosmetic Act, 21 USC §355 (2010).
In Reply Drs Green and Simon express their concern that our
recent study mistook quality for quantity. The statute govern-
ing the approval of new drugs does not explicitly define the
clinical trial evidence needed to obtain FDA approval.1 In the
absence of direct guidance, the FDA uses a flexible approach
to drug approval that allows the agency to weigh factors (eg,
therapeutic innovation and unmet medical need) in its evi-
dentiary requirements and subsequent approval decisions.2
To be clear, the purpose of our study was to better under-
stand what the FDA’s flexible approval standard means for pa-
tients and physicians in terms of the clinical trial evidence avail-
able on new drug approval because they are in the position of
having to interpret the results of these trials to make deci-
sions about whether to use or prescribe these medications. We
did not evaluate whether the clinical trial evidence was suf-
ficient for FDA approval.
We found that both the quality and quantity of the clini-
cal trial evidence varied. Not only were some therapeutic agents
approved on the basis of a single small trial and others on the
basis of several large trials, but there were important differ-
ences in the way the pivotal trials were designed (eg, use of
randomization, blinding, study comparators, size and dura-
tion, and selection of study end points). This variation has im-
portant implications for patients because it leads to differing
levels of certainty about the safety and effectiveness of newly
approved drugs. This is particularly salient because some pa-
tients will prefer to have great certainty before deciding to use
a medication, whereas others may be more willing to tolerate
uncertainty, likely related to the seriousness of their disease,
alternative treatments, physicians’ recommendations, past ex-
perience, and personal beliefs.
There will always be uncertainty about newly approved
drugs, no matter how well studied. However, it is important
that the evidence that supports the use of any therapeutic
agent, whether newly approved or used for decades, be effec-
tively communicated to patients and physicians to enable them
to make fully informed decisions. This evidence should in-
clude both evidence of medication efficacy and safety, ide-
ally placed in an easy-to-understand context, using decision
tools, FDA summaries, or a drug facts box.3
The Institute of Medicine is currently convening work-
shops focused on identifying effective methods to communi-
cate uncertainty in the assessment of benefits and risks of phar-
maceutical products.4 Equipped with information effectively
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Letters
conveying the quality of the clinical trial evidence that formed
the basis of FDA approval, including the strengths and weak-
nesses of that evidence, patients will be able to make more in-
formed decisions about the use of novel therapeutic agents.
Nicholas S. Downing, AB
Joseph S. Ross, MD, MHS
Author Affiliations: Yale University, New Haven, Connecticut.
Corresponding Author: Joseph S. Ross, MD, MHS, Yale University, PO Box
208093, New Haven, CT 06520 (joseph.ross@yale.edu).
Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr Downing
reported being a consultant to Moderna. Dr Ross reported receiving support
from Medtronic Inc and Johnson & Johnson Inc to develop methods of clinical
trial data sharing, the Centers for Medicare & Medicaid Services to develop and
maintain performance measures used for public reporting, the FDA to develop
methods for postmarket surveillance of medical devices, Pew Charitable Trusts,
National Institute on Aging, and the American Federation for Aging Research
through the Paul B. Beeson Career Development Award Program; and being a
member of a scientific advisory board for FAIR Health Inc.
1. Federal Food, Drug, and Cosmetic Act, 21 USC §355 (2010).
2. Hamburg MA. Why the FDA supports a flexible approach to drug
development. http://blogs.fda.gov/fdavoice/index.php/2014/02/why-fda
-supports-a-flexible-approach-to-drug-development/. Accessed March 5, 2014.
3. Schwartz LM, Woloshin S. The drug facts box: improving the communication
of prescription drug information. Proc Natl Acad Sci U S A. 2013;110(suppl 3):
14069-14074.
4. Institute of Medicine. Meeting: characterizing and communicating
uncertainty in the assessment of benefits and risks of pharmaceutical products.
http://www.iom.edu/Activities/Research/DrugForum/2014-FEB-13.aspx. Accessed
March 5, 2014.
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