Transcript HERE - Simon Fraser University

Ethical Transparency and
Government Regulation of Canada’s
Medical Research Industry
Lindsay Meredith and
Geoffrey Poitras
Simon Fraser University
Vancouver, BC CANADA
Ethical Transparency
• The ability to perceive ethical intentions is a key
element in the approval of medical research studies
• Transparency is opaque when the ethical intention is
difficult to perceive
• The primary corporate objective of shareholder
wealth maximization (SWM) is ethically opaque
 SWM depends on the expected price for the
corporation’s common stock
Ethics and Pharmaceuticals
• Prescription drugs are among the most important
miracles of modern science
• Development and marketing of such drugs are
largely the preserve of corporations (Pfizer, Merck,
AstraZeneca, GlaxoSmithKline …)
• Is SWM consistent with ethical standards required
to maintain public safety?
Examples of pre- FFDCA (1938)
Problems
• Banbar, a worthless "cure" for diabetes
• Lash-Lure, an eyelash dye that blinded some
women
• Foods deceptively packaged or labeled
• Radithor, a radium-containing tonic that
sentenced users to a slow and painful death
• Wilhide Exhaler, which falsely promised to cure
tuberculosis and other pulmonary diseases
The 1937 Elixir Sulfanilamide Incident
• The FFDCA (1938) was inspired by the deaths of over 100 people in the US
in Sept. and Oct. 1937 due to the introduction of use of diethylene glycol
(antifreeze) to create an liquid elixir for delivery of Sulfanilamide (an
effective drug in pill and tablet form for treatment of ailments such as
streptococcal infection)
• Operative legislation at that time was the Food and Drugs Act of 1906
– Recognized as obsolete.
– Circa 1937, Congressional action was stalled.
FFDCA (1938) required:
-- drugs be labeled with adequate directions for safe use
-- mandated pre-market approval of all new drugs: a manufacturer had to prove
to FDA that a drug were safe before it could be sold.
-- prohibited false therapeutic claims for drugs,
Pre-1962 Regulation of Medical
Products and Devices in the US
• The 1957-1961 thalidomide tragedy is the horrific story often
associated with the lack of adequate oversight of drug
marketing
• Unlike other countries such as UK, Canada, Australia, Sweden,
and Germany, the US was able to avoid a widespread impact
from thalidomide due to Frances Kelsey repeatedly exercising
the limited powers under the 1938 Federal Food, Drug and
Cosmetics Act (FFDCA 1938)
– The operative regulatory authority under this law gave the FDA 60
days to review a drug application to determine ‘safety’ not efficacy.
• If the FDA reviewer told a drug company that its application for a
medication was incomplete, it was considered withdrawn and the
company would have to submit more data when it resubmitted the
application (starting another 60 day approval cycle).
Unethical Actions of Drug Companies
• US drug company did low level recall when deaths
from Elixir Sulfanilamide identified in 1936
• German pharmaceutical company Chemie
Grunenthal objected when German government
withdrew thalidomide in Nov. 1961
• Tragic consequences continue in the modern era
with OcyContin, Neurontin, Paxil, Accutane, Baycol,
Aprotinin and Vioxx where the dangers of long-term
cumulative effects emerged only after extended
periods of time in the market place.
Merck and Vioxx
• Dr Bruce M Psaty (Cardiovascular Health Research Unit, University of
Washington, Seattle) traced some of the path of Vioxx development,
drawing on internal Merck communications.
– In November 1996, Merck scientists hypothesized that patients taking Vioxx
would have higher rates of heart disease than those taking an aspirinlike
comparison treatment
– By April 1998, Merck scientists knew of evidence that COX-2 inhibitors such as
Vioxx reduce the production of prostacyclin, which prevents platelet
aggregation.
– On the basis of this biologic evidence, it would be reasonable to hypothesize
that the treatment of patients with Vioxx might increase the risk of heart
attack and stroke compared with either an aspirinlike treatment or with
placebo (no active treatment)
– Merck knowingly excluded patients with heart problems from clinical trials
required for FDA approval
Ethical Approval of Medical R&D
• Failures of the past have resulted in an elaborate
system of regulation of the safety and efficacy of
medical products and devices
– Phase I-III + IV combined with patent protection
– Much the same structure in Canada as in US
• The regulatory process has institutionalized the place
of ethics in the approval process
– Institutional Review Boards (IRB) in US
– Research Ethics Boards (REB) in Canada
Diagram 3
Source: P. 286 Steinman et al., “Narrative Review: The Promotion of Gabapentin:
An Analysis of Internal Industry Documents” Annals of Internal Medicine Volume 145 Number 4, August 2006.
Recommendations
Review Ethics Boards
• Set countrywide REB adjudication
standards
• Harmonize standards within &
among REB’s
Recommendations
Clinical Trials
• Record ALL trials (positive & negative) by
public central registry (Phase 4 esp.)
• Source all Phase 1 & 2 trials by country of
origin
• Set “real” research standards
Recommendations
Clinical Trials
• Watch for Market Seeding trials hidden in
research protocols
(Phase 3 & 4 “Me Too” drugs – statins,
NSAIDS, mood disorder drugs)
• Create independent research evaluation
agencies
Recommendations
Opinion Leaders
• Full disclosure for corporate/opinion leader
relationships viz. conflicts of interest on REB’s
and formulary boards
• Full disclosure of all corporate educational
sponsorships
Recommendations
Opinion Leaders
• Transparency of “Research Front” firms acting for
pharmaceutical companies or doctors
• Ban on “Ghost Writing”
• Opinion leader disclosure of clinical trial recruitment
fees, consultancies, speaker fees, on-line conference
fees, etc.
Recommendations
General Practitioners
• Disclosure of clinical trial recruitment fees
• Evaluate Phase 4 protocols for research
standards and/or market seeding
Recommendations
General Practitioners
• Ensure all Phase 4 trials are registered
and results made public
• Track “Off-Label” prescription patterns
Recommendations
Institutional Facilities
• Ban “Facilities Infiltration” via donated
drugs/supplies
• Set policies for sales rep access to
medical personnel and patients
Recommendations
Institutional Facilities
• Ban preceptorships or allow only after
institutional review
• Public disclosure of corporate
marketing expenditures to doctors,
hospitals & universities
Recommendations
Opinion Leader/GP Interaction
• Improve monitoring to minimize biased
information transfer from opinion leaders
due to less than arm’s length relationships
with companies
• Educate residents to recognize B2B
“relationship marketing” & filtered
information from sales reps
Recommendations
Business to Consumer
(B2C) Marketing
• REB’s should ensure full clinical file
reporting
• Competition Bureau should monitor to
ensure complete disclosure of side effects
and contraindications in B2C advertising
Recommendations
Public/Private Sector Accord
• Public sector participation in formulating
research & marketing regulations for the
Canadian medical products industry
• Monitored trial period of self-regulation in
research and marketing practices by private
sector corporations and The Canadian
Medical Association