Ethical Transparency and Government Regulation of Canada

1
Ethical Transparency and Government Regulation
of Canadas Medical Research Industry

• Lindsay Meredith and Geoffrey Poitras
• Simon Fraser University
• Vancouver, BC CANADA

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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
  corporations common stock

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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?

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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

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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,

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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).

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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.

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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

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Ethical Approval of Medical RD

• 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

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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.
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Recommendations
Review Ethics Boards

• Set countrywide REB adjudication standards
• Harmonize standards within among REBs

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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

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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

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Recommendations
Opinion Leaders

• Full disclosure for corporate/opinion leader
  relationships viz. conflicts of interest on REBs
  and formulary boards
• Full disclosure of all corporate educational
  sponsorships

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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.

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Recommendations
General Practitioners

• Disclosure of clinical trial recruitment fees
• Evaluate Phase 4 protocols for research standards
  and/or market seeding

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Recommendations
General Practitioners

• Ensure all Phase 4 trials are registered and
  results made public
• Track Off-Label prescription patterns

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Recommendations
Institutional Facilities

• Ban Facilities Infiltration via donated
  drugs/supplies
• Set policies for sales rep access to medical
  personnel and patients

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Recommendations
Institutional Facilities

• Ban preceptorships or allow only after
  institutional review
• Public disclosure of corporate marketing
  expenditures to doctors, hospitals universities
  

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Recommendations
Opinion Leader/GP Interaction

• Improve monitoring to minimize biased information
  transfer from opinion leaders due to less than
  arms length relationships with companies
• Educate residents to recognize B2B relationship
  marketing filtered information from sales reps

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Recommendations
Business to Consumer (B2C) Marketing

• REBs should ensure full clinical file reporting
• Competition Bureau should monitor to ensure
  complete disclosure of side effects and
  contraindications in B2C advertising

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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