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Who owns truth?
“Truth” includes evidence, E
, a part of
relative to evidence, P(H,E), and
the utility of actions, U(A,E),
Who selects investigator, analyst and writer?
Who decides whether to submit to publish?
Who possesses clinical trial data and at whose
exclusive discretion over design and
conduct of experiment? who selects the investigator, analyst, and writer? who has discretion to submit for publication?”
exclusive discretion is access data to
studies, analyzed and interpreted the data, wrote the papers, and decided where and how to report the results.”
Company contracts include “gag” clauses
denying investigators publication without prior company approval.
Companies hire “ghost” writers and “guest”
authors, and submit partial results for publication to promote sales and return to investors.
Investigators denied access to evidence.
of corporate sponsors.
Sponsors design, conduct, analyze, report and decide whether to submit for publication.
“As owners of the study database,
sponsors have discretion to determine who will have access to the database.”
Pharmaceutical Research and Manufacturers of America.
“Sponsors conduct clinical trials….”
“Investigators are selected….”
“Investigators and their staff are trained
of the particular clinical trial.”
“Sponsors will make a summary of the study
results available to the investigators.”
Winning advocacy for public policies that encourage the
discovery of life-saving and life enhancing new medicines for patients by pharmaceutical/biotechnology research companies. To accomplish this mission, PhRMA is dedicated to achieving in Washington, D.C., the states and the world:
1. Broad patient access to safe and effective medicines
through a free market, without price controls;
2. Strong intellectual property incentives, and; 3. Transparent, efficient regulation and a free flow of
PhRMA's mission is winning advocacy for public policies
that encourage the discovery of life-savingand life enhancing new medicines for patients.
To accomplish this mission, PhRMA is dedicated to
achieving in Washington, D.C., the states and the world:
1. Broad patient access to safe and effective medicines;2. Strong incentives for contributing to more QALY and to
3. Public access to clinical trial data, transparent,
regulation and a free flow of information to patients checked by reliable independent science audits.
ICMJE, International Committee of Medical
Journal Editors, has taken exception to drug company claims.
Pharmacia published in JAMA Celebrex results
from first 6 months, ostensibly showing fewer side effects, though company knew 12 months results showed nothing.
Merck published in NEJM without including
three myocardial infarctions in theVioxx, group.
n engl j med 353;26 www.nejm.org december 29, 2005
As CROs, Commercial Research Organizations,
and academic medical centers compete, corporate sponsors dictate the terms of participation, terms not always in the best interests of the advancement of science….
Investigators may have little or no input into trial
design, no access to raw data, and limited participation in data interpretation.
Even when an investigator has had substantial
input, results of the finished trial may be buried,if they are unfavorable.
“…in 2000 in the United States, Commercial
Research Organizations received 60% of the research grants from pharmaceutical companies….”
“Annual CRO-industry revenues have increased
from about $7 billion in 2001 to an estimated $17.8 billion today ….”
Commercializing Clinical Trials — Risks and Benefits of the CRO Boom
Miriam Shuchman, M.D. Volume 357:1365-1368 2007
• Do CROs report adverse events, evidence of
unexpected side effects, to companies or FDA?
• Company contracts with CROs, CROs contract
with management companies that recruit and coordinate physician and subjects around the world.
• Physician investigators contract with research
subjects. No drug company contract with a research subject.
The United States Court of Appeals for the Sixth Circuit unanimously affirmed the District Court's refusal to force Amgen, Inc. ("Amgen") to continue supplying an experimental drug during litigation over claims for breach of contract after finding that:
(1) no contract directly arose between Amgen and Abney, et al. (the
(2) the principle investigators and physicians lacked agency status or
apparent authority to bind Amgen and the Volunteers to a contract or quasi-contract; and(3) Amgen undertook no fiduciary duties with respect to the Volunteers.
1980 Boyle-Dohl Act: Extramural NIH funded is
by investigator and university.
1980 Stevenson-Wydler: Intramural NIH funded is
to company for royalties.
1984 Hatch-Waxman: Drug Price Competition and
1991 Bristol Myers Squibb given five years exclusive marketing
rights for Taxol (developed with NCI funding) for royalties equal to 0.5% of sales.
Biomedical Research and Health Policy
committed the organization to working with industry and other groups to eliminate gag clauses in clinical trial agreements and to "take all appropriate action to protect the rights of physician researchers to present, publish and disseminate data from clinical trials."
ICMJE submission requires investigator with authority and
PhRMA companies voluntarily commit to timely publication,
public registration, investigators with authority to publish after consultation; access to summaries within a year of -marketing.
FDA 2007 Revitalization Act requires public registration;
access to summaries within year of marketing.
n engl j med 357;17 www.nejm.org october 25, 2007 1756
• Conflict-of-interest must be disclosed.
• COI may not exceed $10,000.
• Authors must claim authority over trial and
• Trial must be publicly registered upon
Uniform Requirements for Manuscripts Submitted to Biomedical
Journals: Writing and Editing for Biomedical Publication (Updated
“the act requires sponsors of all clinical trials to
register studies in a public registry sponsored by the National Library of Medicine.”
“not ideal [is] the delayed public availability of
registration information and the non-inclusion of phase 1 trials….”
Open Clinical Trials, Jeffrey M. Drazen, M.D., Stephen Morrissey, Ph.D., and
Gregory D. Curfman, M.D.
n engl j med 357;17 www.nejm.org october 25, 2007
requests have gained access to data submitted with applications.
The picture presented by all
differed from that presented by just those published or published prestigiously.
Paty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for
Alzheimer disease or cognitive impairment: a case study based ondocuments from rofecoxib litigation. JAMA
PhRMA commitments are voluntary, nonbinding.
– Requires public access only to summaries. – Does not require access to exploratory studies, phase
– Does not require pro-active check for safety and side-
Editors complain phase IV studies are designed to lack
statistical significance to be spun as insignificant if negative and promising if positive and used to support payment for off-label prescriptions.
Biopure seeks a preliminary and permanent
injunction against Natanson barring him from publishing "malicious, false, defamatory, and/or misleading statements concerning Biopure." Biopure v. Natanson
, No. 1:08-cv-01732 (D. D.C.)
Should individuals be liable to corporate lawsuits?
“…medical school researchers who had
conducted industry-sponsored studies of the use of antidepressants in children and adolescents were denied access to unpublished data from their own studies about the relation between the medications and the risk of suicide.”
Kondro W, Sibbald B. Drug company experts advised staff to withhold data
about SSRI use in children. CMAJ
• Comparing 40 units of Nexium with 20
• Studying Clarinex for indoor use, but not
• Comparing 80 milligrams of Lipitor with
• Testing Crestor at higher dose than other
statins to claim it is the “strongest” statin.
• Premenstrual Dysphoric Disorder PMDD.
"Some company-sponsored trials of approved
drugs appear to serve little or no scientific purpose…they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company.“
Former FDA Commissioner Kessler wrote about phase 4 trials.
“The article provides clear evidence that the
intent of ADVANTAGE was to increase prescriptions of Vioxx (the study outcome of greatest interest to Merck seems to have been Vioxx prescribing rates). The documents tell us that deception is the key to a successful seeding trial.”
“…companies sometimes put marketing ahead of science
when reporting clinical trial results. Merck's apparent misrepresentation of data about deaths among Vioxxpatients is just one example….
Pharmaceutical companies "are doing their darnedest to
hide the side effects of the drugs they are developing,". Everybody who uses a drug has to judge its cost — not just the financial cost but cost in terms of side effects —to understand its benefits. But you can't do that unless you have the data. Some of them are trying to suppress the data on side effects.“
Catherine De Angelis, Editor, Journal of the American Medical Association
“It is simply no longer possible to believe
much of the clinical research that is published or to rely on the judgment of trusted physicians or authoritative medical guidelines.”
2009, Marcia Angell, former editor of New England
• Independent Federal Science Auditing Agency?
• Independent Individual Investigators?
• IRB protection of purpose, integrity, publicity for
the sake of human subjects’ intent and their informed consent?
“Academic institutions routinely engage in
industry-sponsored research that fails to adhere to ICMJE guidelines regarding trial design, access to data, and publication rights. Our findings suggest that a reevaluation of the process of contracting for clinical research is urgently needed.”
The New England Journal Of Medicine [N Engl J Med] 2002 Oct 24; Vol. 347 (17), pp. 1335-41\
Members of medical school faculties should
take nothing else from sponsors supporting their research
control over design, interpretation and publication of research results.
Enforced by schools. No institutional dollars from sponsors to
Steven Nissen MD, Cleveland Clinic Foundation
“…unless the investigators have direct and
full access to the database, there is too much opportunity for sponsors to provide incomplete information and overemphasize the benefits or underestimate the risks of therapy.
"At our coordinating center, we require the
study contract to guarantee the transfer of the trial database to the investigators at the conclusion of the trial and to guarantee the independent right to publish."
• National Center for Health Care Technology Assessment
created in 1980s shut down not long after it started.
• Congressional Office of Technology Assessment
After several decades of excellent work shut down when applied to surgery in 1995.
• AHCPAR Agency for Health Care Policy and Research
Professionals lobbied it dead before it functioned.
• Centers for Education and Research in Therapeutics
CERT is underfunded, drug company dominated.
“When patients put themselvesat risk to participate in clinical trials, they do so with the tacit understanding that their risk is part of the public record, not merely the secret record of the sponsor.”
Trial Registration Report Card
Jeffrey M. Drazen, M.D., and Alastair J.J. Wood, M.D.
n engl j med 353;26 www.nejm.org december 29, 2005
research subjects for public ownership or public access.
• Clinical trial consent form is a contract
• Contract ought to serve subjects’ altruistic
intent including desire to be part of a scientific demonstration for the good of society with expectation of public access.
“Clinical research should not be left primarily
or solely to sponsoring companies. An Institute for Prescription Drug Trials should be established within the NIH to administer clinical trials of prescription drugs, including the premarketing trials that will be submitted to the FDA as a part of new drug.”
“…institutional review boards could
routinely ask, ‘Is this a seeding trial?’ Sponsors would think twice about lying to an institutional review board….”
19 August 2008 | Volume 149 Issue 4 | Pages 279-280
IRBs Screen for Scientific Integrity for the
“…researchers should review all relevant evidence
before they submit a new protocol for ethical assessment. This injunction asks no more of researchers than respect for the principle that science is cumulative. Patients being invited to participate in a clinical trial have a right to expect that its design has been informed by a scientifically defensible review of what is known already.”
THE LANCET • Vol 361 • March 22, 2003 p 978
IRBs Screen for Public Registry and
“…those responsible for the work of research ethics
committees need to reconsider their apparent acquiescence in this state of affairs. We believe that they should require registration of clinical trials as a component of ethical review, and ensure that patients are advised to withold their consent to participateunless there is publicly accessible information about the trial and the investigators have undertaken to make the results of the study publicly available within a reasonable time after its conclusion.”
• Whether to improve treatment, to extend a patent
– Access to studies relevant to proposed study?
• Public access to all the relevant data?
Protection of human subjects places clinical trials
under the first principle of medical ethics and the first virtue of practice. Do no harm!
Protecting altruistic and scientific intent of research
subjects brings pharmaceutical development under the second principle, beneficence.
Protecting fair opportunity to register brings under
Protecting public access for informed consent is
Does autonomy of research subjects-- their
interest in contributing to good of society, their right to informed consent– challenge sponsors’ proprietary claims. Does autonomy in this sense deserve greater public protection and, specifically, IRB protection?
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