To: LCDR Tara Turner, PharmD
Tara.turner@cms.hhs.gov
1-410-786-0180
From: Merrill Goozner
Director, Integrity in Science Project
Center for Science in the Public Interest
1875 Connecticut Ave., NW, Suite 300
Washington, DC 20005
202-777-8374
mgoozner@cspinet.org
Re: Medical Literature for Local Medical Contractors to Determine Medically Accepted
Indications for Drugs and Biologicals Used in Anticancer Treatment
Dear Ms. Turner,
Thank you for the opportunity to comment on the proposed expansion of the
number of journals that Medicare recognizes as acceptable outlets for published clinical
trials that can be used to determine “medically accepted indications” for the off-label use
of anticancer drugs and biologicals. The list of eight proposed by Dr. Joseph S. Bailes of
the American Society of Clinical Oncology has serious shortcomings. Indeed, the list of
15 journals already in the Medicare manual has problems that the Center for Medicare
and Medicaid Services should address. Allow me to explain.
You list the following criteria that acceptable journals should follow:
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Use of a rigorous impartial peer review process;
Lack of publication bias;
Full and timely public disclosure of potential conflicts of interest of authors,
reviewers and editorial staff; and
Reputation for scientific integrity and authoritative stature in the field of
cancer treatment.
My comments are based on the middle two of these four criteria.
Publication Bias
Publication bias is defined as the propensity to publish positive results, and ignore
negative results. Virtually all fields of medicines have a rich literature documenting the
problems caused by publication bias in reporting the results of clinical trials in their
fields. The International Committee of Medical Journal Editors in its “Uniform
Requirements for Manuscripts Submitted to biomedical Journals” (updated February
2006) unequivocally states that editors have an obligation to publish negative studies as
long as they are conclusive.
In recent years, registration of clinical trials has been seen as one way to limit the
effects of publication bias. It allows peer-reviewers to compare submitted results to
original protocols. Registries can be used by editors and reviewers to compare new
results to previous trials. Registries can also be extremely useful tool for researchers
conducting meta-analyses or writing clinical practice guidelines, which are very
important in driving clinical practice.
I would encourage you to explicitly add the following criteria:
Any clinical trial used to justify reimbursement for the off-label use of anticancer
drugs must have registered in a publicly available database such as ClinicalTrials.gov
prior to a trial’s enrolling its first patient; if a journal wants to be included on
Medicare’s list of publications where acceptable studies may appear, that journal must
make prior registration a condition of publication.
The reason for including this criterion is straightforward and based on your
previous rule. Any journal that does not require clinical trial registration before
publishing is susceptible to publication bias.
Sadly, none of the eight journals suggested for inclusion in the Medicare
payments manual requires that its authors register clinical trials as a condition of
publication, according to the authors’ guidelines contained on their websites. An email
survey to the eight editors on November 2nd by my organization generated just two
responses. We asked if they would consider making this part of their guidelines. Only the
editor of Gynecologic Oncology indicated he would, although it is not now required. The
editor of the Journal of Thoracic Oncology said his organization would consider it. The
rest did not respond.
We also surveyed the 15 journals listed in your payments manual. Six (6) did not
require clinical trials registration. They were the American Journal of Medicine; Journal
of Clinical Oncology, published by ASCO; the British Journal of Cancer; Cancer
(published by the American Cancer Society); Drugs; and Leukemia. When we contacted
these journals, we received varying replies. The managing editor of Cancer, for instance,
said the editors will consider this issue soon. A spokeswoman for the Journal of Clinical
Oncology said the journal was immediately amending its policy to include clinical trial
registration as a condition of publication, although it will only apply to trials that begin
enrolling patients after Nov. 1, 2006.
Conflict-of-Interest Disclosure
We also surveyed the journals for their policies on conflict of interest disclosure.
While all eight journals on the proposed list required authors to disclose to editors their
conflicts of interest, three did not say that publication would be automatic. In other
words, it was up to the editor’s discretion whether a conflict of interest would be
published along with the study’s results. One respondent, the editor of the Journal of
Thoracic Oncology, said they were amending their policy beginning in January or
February of 2007 to include mandatory publication of conflict of interest disclosure
alongside articles.
Among the 15 journals already on your list, all but one (the British Journal of
Cancer) required conflict of interest disclosure to editors. But at least six (in some cases
the language was unclear) stated in their guidelines that it would be up to the editors’
discretion if they would be published.
In recent months, several prominent journals, including the Journal of the
American Medical Association, have been involved in mini-scandals involving authors
who did not disclose relevant conflicts of interest to editors. Only after other physicians
in the field pointed this out did the transgressions come to light. The authors in at least
one of these cases claimed that they did not believe the financial ties were “relevant.” The
editor of JAMA, Catherine DeAngelis, took a number of steps to reinforce the journal’s
guidelines, including publication of high profile errata. However, she refused to adopt
penalties for non-disclosure, citing antitrust concerns and the possibility that it would
only succeed in driving authors to competitor journals.
CMS can bring some much-needed policing to this field by adopting uniform
rules for all journals mentioned in its rules. Medicare should adopt a rule that states that if
it comes to light that a published study did not include relevant conflicts of interest, that
study cannot be used to justify the off-label use of anticancer drugs. The threat of
irrelevancy will go a long way toward ensuring compliance with conflict of interest
disclosure rules.
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This brief survey suggests your current guidelines are incomplete. Moreover,
compliance is poor. To recap, I would suggest you take the following steps:
1. Update your guidelines for journals that are permitted to justify payment for offlabel use of anticancer drugs to expressly require clinical trial registration as a
condition of publication; you should also require the journals to publish the
clinical trial identifier as part of the study abstract so it will show up in any
PubMed search;
2. Update your guidelines to expressly require publication of conflict-of-interest
disclosure information for authors; and require journals to include a statement in
the abstract available on PubMed that a conflict of interest disclosure statement
exists. In cases where authors declare they have no conflicts of interest, that
statement should also be published in the abstract and made part of the PubMed
record;
3. Update your guidelines to include a rule stating that any failure to disclose
relevant conflicts of interest will permanently exclude that study from being used
to justify payment for the off-label use of anticancer drugs;
4. Institute a formal review of the journals on your list to ensure they comply with
the expanded guidelines; remove any that do not immediately take steps to
comply; and
5. Inform the editors of the eight journals proposed for your list of the details of your
inclusion criteria, and inform them that their inclusion depends upon adopting all
the criteria.
In preparing these comments, it has come to my attention that payment policy can
also be justified by reference to protocols listed in various compendia. I’ve also learned
that the National Comprehensive Cancer Network compendium has applied for inclusion
on that list. Because they have a proprietary information site that requires membership to
gain access, I cannot review the quality of information contained in its compendium.
Suffice it to say that Medicare should extend the journal criteria to all compendia, both
existing and proposed.
In closing, allow me to state that I was somewhat surprised to learn about this system
for justifying reimbursement for the off-label use of anticancer drugs. My comments are
an attempt to make this existing system more transparent. They are not in any way an
endorsement of the current system.
I believe reimbursement should be based on adherence to peer-reviewed clinical
practice guidelines. Those guidelines should be written by physicians without conflicts of
interest. When clinicians veer from existing clinical practice guidelines, such off-label
use should be reimbursed only if the patients have been enrolled in a clinical trial (even if
only an observational trial) so the experience with that off-label use can be captured in
retrievable data. If needed, physicians should be reimbursed for collecting and reporting
this information under CMS’s evolving guidelines for reimbursing physicians that enroll
their patients in clinical trials.
With 700,000 Medicare beneficiaries contracting cancer every year and the number of
new therapies addressing this patient population expected to grow, it is time for the
Center for Medicare and Medicaid Services to construct an information system capable of
helping physicians make the right choices for their patients. I hope you will see my
proposals as a constructive step toward creating such a system.