Commercialisation Throughout Clinical Development Commercial Awareness from Bench to Market Ethical

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Commercialisation Throughout Clinical
DevelopmentCommercial Awareness from Bench to
Market Ethical and Academic AspectsPeter Paul
De DeynMiddelheim Hospital University of
AntwerpACRP - 14.12.02 - Brussels
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Contents

• Introduction
• Examples
• Planning
• Execution
• Data Analysis
• Reporting
• Recommendations

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Industrys mission

• Industrys Ethical Obligation towards society
• Contributing to biomedical sciences
• Providing good products or appliances
• Improve human well-being world wide
• Requires marketing / commercialisation
• Industrys obligation towards shareholders and
  employees
• Economic Mission
• Patents 20 yrs - 12 yrs development leaves 8
  years with a possible extension for profit making
• Marketing / commercialization are needed to be
  able to finance new programmes

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Interests of the industry in conducting research

• Different individuals or departments in
  pharmaceutical companies can behave differently
  in this proces
• Research and Development personnel will want to
  innovate, and come up with new molecules
• Marketing personnel will want to increase
  marketshare
• Marketing people tend to get involved in earlier
  development stages

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Phases in the accomplishment of the common
mission of industry, researchers and authorities

• Preclinical development
• Clinical development (RCTs)
• Registration
• Commercialisation, distribution, marketing
• Meta-analysis
• Evidence-based medicine clinical practice
  guidelines

Planning Execution Data analysis Reporting
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Actors in marketing and clinical development

• Patients
• Researchers
• Pharmaceutical companies
• Government and regulatory authorities
• Journals
• Financial market

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What this presentation in not about

• Fraud and Research
• Fraud hinders the quest for knowledge by
  promulgating falsehoods
• It indirectly hinders knowledge advancement by
  destroying trust among researchers
• It undermines the public support for science
• There is little ethical doubt that a researcher
  has a duty not to falsify data

Resnick 1996, Science Communication
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WHO

• 2001 WHO editorial by Jonathan Quick
• Clinical trials form the basis of effective
  research
• Three major perils exist
• Conflict of interest on the part of the
  investigator
• Inappropriate involvement of research sponsors in
  study design and management
• Publication bias in result dissemination

Quick 2001, Editorial, Bulletin of the World
Health Organization, 79 1093
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Sponsorship, authorship and accountability

• Position paper by editors of several general
  medical journals
• Clinical trials can have substantial economic
  impact
• Until recently, academic, independent clinical
  investigators were key players in the design,
  recruitment and data interpretation of clinical
  trials

Davidoff et al 2001, Lancet 358 854-856 (and 12
other journals)
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Sponsorship, authorship and accountability

• However, economic pressures mount
• Many clinical trials are done to facilitate drug
  approval, rather than to test a novel scientific
  hypothesis
• Trials have increased in size and cost
• The average cost of bringing a new drug to market
  in the USA is estimated at 802 million

Davidoff et al 2001, Lancet 358 854-856 (and 12
other journals) Healthcare Economist, April 2006.
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Sponsorship, authorship and accountability

• Corporate sponsors can dictate the terms of
  participation in the trial
• Little or no input into trial design
• No access to raw data
• Limited participation in data interpretation
• Results may be buried if they are unfavourable

Davidoff et al 2001, Lancet 358 854-856 (and 12
other journals)
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Sponsorship, authorship and accountability

• Action taken by the editors
• Guidelines for publication ethics were adapted
• Authors are requested, upon manuscript
  submission, to confirm in writing that they
• accept full responsibility for the trial
• had access to the data
• and controlled the decision to publish

Davidoff et al 2001, Lancet 358 854-856 (and 12
other journals)
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Examples

• Planning
• Execution
• Data Analysis
• Reporting

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Bias in Research Planning

• EVIDENCE trial
• Orphan drugs
• Non-commercial bias
• Seeding trials

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Bias in Research Planning

• Neurology editorial published November 2002
  Needed in MS Evidence, not EVIDENCE
• It is unfortunate that the large investment made
  in this trial was not directed toward comparing
  the impact of different preparations or routes or
  frequencies of administration (while holding the
  other factors constant) on disability
• The same study generated controversy following
  the 2001 AAN meeting in Philadelphia

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What research does not get done ?

• Everyone has the right to health and wellbeing
  (Helsinki Declaration)
• R D for new treatments risky business
• Unpredictability whether drugs that passed
  pre-clinical development lead to a new
  registration (Ernst and Young)
• Industry prefers
• topics which lead to end-products with commercial
  application
• diseases that affect patients who can afford
  treatment
• Giving products a legal orphan drug status is
  one answer

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What research does not get done ? Thioctacid

• Thioctacid is an agent with presumed efficacy in
  the treatment of diabetic and alcoholic
  polyneuropathy.
• The compound is being marketed in Germany without
  extremely convincing evidence of its activity,
  the manufacturing and marketing company prefers
  not to take the option to distribute their
  compound throughout Europe since this would
  entail a registration procedure necessitating
  additional placebo-controlled randomized clinical
  trials.
• In case their compound has indeed specific
  efficacy, it would be unethical not to provide
  the compound to all patients world-wide.
• As a matter of fact, this specific company
  prefers to keep a significant market for a
  possible placebo or pseudo-placebo instead of
  developing a potential standard therapy for
  patients suffering from diabetic and alcoholic
  neuropathy world-wide.
• De Deyn et al. In Ethics of animal and human
  experimentation. Eds. De Deyn et al. John Libbey,
  London, 1994.

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What research gets done or repeated too often?

• Companies can develop me too molecules to
  compete with existing products
• eg triptans, statins, cephalosporins,
  thrombolytics
• Sometimes these are not actually me too
  products
• Development may occur quasi-simultaneously in two
  or more different companies
• It can be difficult to assess which ones were the
  first for the break-through idea

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Bias in research planninghead-to-head studies

• In this trial design, choice of dosages is
  crucial
• For the comparator, sub-optimal dosing would lead
  to a bias in favor of the new product
• Bias might also occur when the comparator,
  against which superiority is proven, is not any
  longer the treatment of choice at completion of
  the study
• Alternatively, an open label study could also
  induce bias when patients and investigators
  expect better results for the new product

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Basic Research Planning

• Basic research can also be funded by industry
• This can help to position a certain drug, by
  highlighting mechanisms of action.
• Correct and objective papers may still lead to
  some bias, if certain directions in research are
  explored more then others

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Examples

• Planning
• Execution
• Data Analysis
• Reporting

FDA GCP ICH
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Commercial Biasoutcome

• Safety of calcium antagonists in arterial
  hypertension (Stelfox NEJM 1998)
• researchers had ties with the industry in 96 of
  supportive studies
• researchers had ties with the industry in 37 of
  critical studies
• Thrombosis risk with 3rd generation oral
  contraceptives
• Sponsored relative risk 1.1
• Public financing 2.5

Ned Tijdschrift Geneeskunde 2002
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Diagnostic Trials biological markers eg.
Tuberculosis

• Errors in design or reporting are common
• Significance of trial results are routinely
  overstated
• A commercial kit for detecting IgG antibody to
  (LAM) lipoarabidomannan showed 79 sensitivity
  for pulmonary tuberculosis
• Several studies later, an overall sensitivity of
  26 was found in a well designed trial

SmallPerkins 2000, Lancet 356 1048-1049
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Ten ways to cheat on statistical tests when
writing up results (1)

• Throw all data into a computer and report as
  significant any relationship where p lt 0.05
• If baseline differences between the groups favour
  the intervention group, remember not to adjust
  for them
• Do not test your data to see if they are normally
  distributed
• Ignore all withdrawals
• Always assume that you can plot one set of data
  against another and calculate an r value
  (Pearson correlation coefficient), and that a
  significant r value proves causation
• If outliners are messing up your calculations,
  just rub them out

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Ten ways to cheat on statistical tests when
writing up results (2)

• If the confidence intervals of your result
  overlap zero difference between the groups, leave
  them out of your report
• If the difference between two groups becomes
  significant four and a half months into a six
  month trial, stop the trial and start writing up.
  Alternatively, if the results are nearly
  significant, extend the trial for another three
  weeks
• If your results prove uninteresting, ask the
  computer to go back and see if any particular
  subgroup behaved differently
• If analysing your data the way you plan does not
  give the result you wanted, run the figures
  through a selection of other tests.

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Bias in Data Analysis

• Primary versus secondary outcome measures
• Predefined levels of clinical significance of an
  outcome difference
• Post-hoc analyses (data dredging)
• Severity of disease
• Therapeutic time window
• Subpopulations
• Arbitrary use of cut-offs after statistical
  analyses ...

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Pharmaco-Economic Analysis Science or Marketing
?

• May be used by industry to justify high prices
• Positive outcomes can be used as marketing tools
• Authorities request pharmaco-economic analysis in
  phase III studies

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Examples

• Planning
• Execution
• Data Analysis
• Reporting

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Reporting channels

• Peer reviewed journals
• Supplements of peer reviewed journals
• Sponsored (sattelite) symposia
• Abstracts, posters
• Proceedings
• Sponsored monographies
• Marketing leaflets, booklets
• Web-sites, Mainstream media
• Information towards financial analysts

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Publication Bias Examples

• Satellite symposia and their proceedings can
  create false impressions of objectivity
• Peer review remains necessary for these symposia,
  and for special issues of journals
• Sometimes clear deception is used, cfr
  announcement of EVIDENCE trial results during
  the 2001 AAN meeting in Philadephia
• At the meeting, attendees were correctly informed
  of a press release
• Outside of the meeting, the impression was
  created that the data was presented as a paper
  during the meeting

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Publication Bias Studies

• Objective to determine the extent to which
  publication is influenced by study outcome
• Method 748 studies submitted to a hospital
  ethics committee in Australia over 10 years
• Main outcome measure time to publication

Stern Simes 1997, Publication bias evidence
of delayed publication in a cohort study of
clinical research projects, BMJ 315 640-645
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Publication Bias Studies

• Results response to questionnaire was received
  in 70 of cases
• 218 studies were statistically analysed
• Those with positive results (p lt 0.05) were much
  more likely to be published than those with
  negative results (p 0.10)
• Median time to publication after submission to
  IRB 4.7 and 8.0 years

Stern Simes 1997, BMJ 315 640-645
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Economics and scientific journals

• The articles editors write give little public
  accounting of how much money their journals make
  and what they do with the profits or surpluses
• in 1998 Reuters news agency said it would defy
  the embargo or Ingelfinger rule if findings in a
  paper affected the stock market
• Wigzell on Nature and Science behaving just
  like pharmaceutical companies - gagging the
  scientists to protect some commercial interest of
  their own

Altman 1996, Lancet 3471459-1463
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Partial Diagnosis and now PreventionRecommendati
ons

• Orphan drug status
• Planning
• GCP and ICH guidelines
• Execution
• Conflict of interest disclosure policy
• Execution and reporting
• Contract between researcher and industry
• Execution and reporting/publication policy
• Trial database
• Reporting

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Conflict of interest disclosure policy

• This may seem trivial, but is often not
  explicitly stated
• Review Science and Engineering Ethics in 2001
• Only 16 of 1396 highly ranked scientific and
  biomedica journals had conflict of interest
  disclosure policies
• Has been implemented on a larger scale during the
  last years
• Nature did not have a financial disclosure policy
  before 23 August 2001

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Contract

• Researchers should be careful about the contracts
  they close with the industry
• Agreement to publish only after approval of the
  sponsoring company should be limited
• The sponsors advice should be given within a
  predefined and acceptable period
• The sponsor should not have power of veto
• Independent publication committee and steering
  committee should be negotiated
• Publication policy should be stated in the
  contract in very clear terms

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International Standard Randomised Controlled
Trial Number

• Negative trials tend not to be published and
  postive trials tend to be published repeatedly
• The Cochrane Olanzapine review found 162 reports
  of 15 trials (Duggan et al 2001)
• Prospective registration should help to prevent
  publication bias
• Developed by a working group (UK MRC, UK Cochrane
  Centre, trialists, consumers and industry

Cochrane 2001 1online pb093
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Academic advisers

• Use of academic advisers in RD is evident
• Experts in the pathology under study are
  mandatory
• Needs and tools in the specific domain have to be
  identified with their help
• Use of academic advisers in marketing efforts
• Acceptable provided contribution to accessible
  and correct information

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In Conclusion
Industrys and researchers ethical obligation
towards society, industrys obligation towards
shareholders and employees, and researchers
personal ambitions should be further reconciled
through increased awareness, selfregulation, GCP
and ICH guidelines and a series of recently
introduced recommendations