Posting Clinical Study Summaries and the Marketing of Unsafe Drugs - By Bryan Johnston

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> SSRI-Research

> Tue, 7 Sep 2004 22:39:54 -0400

> [sSRI-Research] Posting Clinical Study

> Summaries and the Marketing of Unsafe Drugs - By

> Bryan Johnston

>

> Drug Safety and the Hawthorne Effect

> Posting Clinical Study Summaries and the Marketing

> of Unsafe Drugs

 

> By Bryan Johnston

>

> In the recent settlement of GlaxoSmithKline

> (GSK) with the Attorney General of the State of New

> York, Eliot Spitzer sought to provide the public

> with protection from undisclosed adverse drug events

> caused by FDA approved medications. However, by not

> insuring that the raw data from all clinical study

> reports (CSR) are available for public review prior

> to the active marketing of any medication, the

> public remains at risk.

> The consent order of August 26, 2004, was

> advantageous for GSK, and the pharmaceutical

> industry as a whole, for it did not address the

> concerns of; 1) the bias inherent in the published

> evaluations of clinical studies performed by the

> pharmaceutical industry, nor 2) the industry's

> ability to influence the prescription habits of

> physicians as a group prior to the public posting of

> CSR summaries and thereafter.

> The Timing of New Black Box Warnings (1)

> exemplifies this controversy regarding the safety

> and efficacy of prescription drugs. One significant

> result is an increase in litigation and Physician

> insurance generated by the harm imposed upon the

> general public.

> One of the recognized causes of this public

> health risk is the pharmaceutical industry's

> practice of withholding negative CRS from

> publishing. Marketing has become the preferred

> strategy for CRS publishing, hindering the

> dissemination of scientifically valid information.

> While the industry's move towards publishing

> summaries of all CSRs is a step toward full

> scientific disclosure, it will not provide

> physicians with the information necessary to

> objectively determine a new drugs safety and

> efficacy.

> The Placebo Effect has been long recognized for

> its potential to generated biased results. Clinical

> trial test subjects also have a recognized

> sensitivity for Experimenter expectations. The

> Randomized Controlled Double-Blind Testing Trial

> (RCT) was created to control for these recognized

> forms of experimental bias. However, the Evaluators

> of clinical trials are being influenced by the

> Hawthorn Effect, as applied by the drug companies,

> causing a new but uncontrolled form of bias.

> The Hawthorn Effect has been well established

> in the field of Industrial Psychology since Western

> Electric's Organizational Studies, led by Elton

> Mayo, discovered it in the 1930's (2). It has its

> roots in the Heisenberg's Uncertainty Principle in

> quantum physics that was being investigated at about

> the same time, stating that one cannot measure an

> outcome without affecting the outcome. Mayo's

> discoveries of the psycho/social influences that

> effect motivation in the work place forever

> revolutionized business, creating the School of

> Human Resources at Harvard University.

> The Hawthorne Effect states that anyone can be

> motivated, by the proper implementation of

> psycho/social influences, to naturally want to

> achieve that which will satisfy those who observe

> and evaluate them. The most important influences

> that affect motivation are the satisfaction of a

> person's need for security, recognition and a sense

> of belonging.

> Drug companies apply the Hawthorne Effect by

> funding the RCT Evaluators, promoting their sense of

> importance and creating an aura of inclusion on a

> team. They then express an explicit desire for

> positive results and closely observe and evaluate

> the testing process. Drug companies know that under

> these conditions, their observation and evaluation

> naturally affects the performance of the Evaluators.

> Scientific evaluation, which values safety and

> efficacy over profits, is being compromised.

> Research is showing that RCTs conducted by

> for-profit companies approve 51% of the drugs they

> test, while those RCTs conducted by independent

> non-profit companies only approve 16% of the drugs

> they test, casting doubt on the validity of results

> published by for-profit companies (3). The

> scientific integrity of RCT evaluation cannot be

> properly maintained when profit oriented drug

> companies provide oversight and control the release

> of the raw data.

> This business driven research bias was not

> foreseen 40 - 50 years ago when RCT protocols were

> developed and conducted by medically driven

> researchers. In medically driven research, the

> Hawthorne Effect would act to uphold the values of

> medicine and the integrity of science.

> Information being released through the court

> system and by investigative journalists reveal that

> the Drug Company/ RCT Evaluator relationship can

> lead to publishing a more favorable outcome for new

> drugs than the raw data supports.

> One such example of this bias is that of the

> evaluation for Eli Lilly's Prozac. Evaluators for

> Prozac did not publish the administration to test

> subjects of benzodiazepines to control the

> akinesia/agitation that was developing during the

> first two weeks of the RCTs. Lilly's CEO in

> Germany, Claude Bouchy, sent a memo in 1990 to Lilly

> executives in the US, demonstrating his dismay of

> Lilly evaluators, at the bequest of the Drug

> Epidemiology Unit, hiding attempted and successful

> suicides in the published results by reclassifying

> this information as 'agitation', 'aggression' or

> 'depression.'(4, p.86). The withdrawal of Lilly's

> drug Oraflex from the market in 1982 exemplifies the

> ongoing nature of this industry-induced bias.

> Manipulation of the raw data occurred with

> GSK's drug Paxil. An investigative reporter

> discovered that some suicidal reactions occurring

> during clinical trials had been classified as

> 'emotional liability'. This discovery precipitated

> GSK's June 2003 warning regarding suicidal reactions

> in children and adolescents (5).

> Summaries of CSRs that do not provide access to

> the raw data will not reveal enough information to

> safely protect doctors and patients from foreseeable

> adverse drug reactions.

> The pharmaceutical industry's marketing

> departments have long recognized Mayo's discovery of

> motivational influences and the effect they can have

> upon individuals and groups. They have become adept

> at understanding and manipulating the behavior of

> groups.

> Another of Mayo's findings was the realization

> that when ever a group starts to act in a coherent

> and productive fashion, it becomes impervious to

> change, more so than an individual would. A group

> resists examining their behavior when isolated

> events occur that contradict the group's beliefs.

> It takes an enormous event, or an intensive

> sustained effort, to alter group behavior. The

> pharmaceutical industry understands this.

> Once drug companies convince physicians as a

> group, of a drug's ability, that belief is not

> easily changed. Utilizing Mayo's finding, drug

> companies contract with large public relations

> firms. These firms insure the immediate and massive

> dissemination of medical representations supportive

> of drug company interests when adverse drug related

> events become public. With the use of ghost

> writing, drug companies strive to promote their

> interests in professional publications. The end

> result is credible research that contradicts

> established drug company representations cannot have

> the impact necessary to generate a balanced

> perspective. The pharmaceutical industry relies upon

> this phenomenon of group cohesion and their ability

> to manipulate it to maintain physician prescription

> habits. They excel at marketing their products.

> The busy physician cannot afford the time to

> evaluate all the information necessary, prior to

> deciding upon prescription, when it is publically

> posted in mass after intensive marketing. The

> publishing of all CSR summaries will help to bring

> scientific integrity back to the prescription drug

> market only if all the results become available

> before the pharmaceutical industry is allowed to

> market their drugs. GSK's voluntary publication of

> summaries from all CSRs within 10 months of approval

> for marketing allows ample time to actively motivate

> physicians, as a group, to adopt a prescription

> practice that includes their new drug.

> This necessity for timely public disclosure

> comes from the behavior of the drug companies

> themselves, who can make false and misleading

> representations to physicians about their drugs.

> One example is Warner-Lambert (W-L) and it's drug

> Neurontin. W-L recently paid a $430 million

> settlement for having its top executives encourage

> its sales reps to fabricate positive assurances to

> Physicians that Neurontin had treatment capabilities

> that it clearly did not, while down playing known

> risks. In accord with the Hawthorne Effect, all

> involved, from the sales reps through management,

> naturally sought to produce only that which their

> superiors wanted to see, disregarding established

> safety procedures, creating a public health risk.

> The pharmaceutical industry realizes that

> providing public summaries of all CTRs will not

> reveal any bias in the evaluation of the raw data,

> or interfere with their ability to influence

> prescription practices by controlling the

> dissemination of information. While publishing CSR

> summaries will make it more difficult to withhold

> negative results from public disclosure, all major

> corporations accept that the litigation, which

> develops regarding their products, is often a lesser

> expense than further R & D. The FDA is unable to

> adequately police the enormous volume of industry

> representations. Drug companies realize that the

> FDA's enforcement is generally limited to

> cease-and-desist letters. W-L's Neurontin is

> currently generating $2.7 billion in annual sales.

> Only an informed medical opinion concerning a

> drug's safety and efficacy, rendered prior to

> marketing, can avoid the emergence of adverse drug

> related events that pharmaceutical industry would

> prefer not be made public.

> To control for the Hawthorne Effect this author

> supports having the results of all clinical trials,

> from Phase III on, be published as they occur. This

> would allow medicine to track a drugs progress well

> in advance of approval, allowing a general consensus

> of safety and efficacy to develop based upon

> accepted medical standards. Physicians need to be

> able to access the raw data to verify the

> conclusions of the original evaluation as a

> non-biased third party.

> The creation of an independent, non-profit,

> international agency to conduct all RCTs would also

> insure scientific integrity. Such an agency could

> use its expertise to adequately test all new

> compounds using improved protocols that would be

> sensitive to all experimenter bias and to a myriad

> of adverse effects, as well as for additional

> effects that could generate an unexpected marketing

> ability.

>

> References

>

> 1 - Lasser KE, Allen PD, Woolhandler SJ, Himmelstein

> DU, Wolfe SM, Bor DH.

> Timing of new black box warnings and

> withdrawals for prescription medications.

> JAMA. 2002;287(17):2215-20

> 2 - Manufacturing Knowledge : A History of the

> Hawthorne Experiments

> Richard Gillespie

> Cambridge University Press August 30, 1991

> 3 - Bodil Als-Nielsen, MD; Wendong Chen, MD;

> Christian Gluud, MD, DMSc; Lise L.

> Kjaergard, MD

> Association of Funding and Conclusions in

> Randomized Drug Trials

> A Reflection of Treatment Effect or Adverse

> Events?

> JAMA. 2003;290:921-928

> 4 - The Anti-depressant Fact Book

> Peter R. Breggin, MD

> Perseus Publishing, Cambridge Massachusetts

> 2001

> 5 - How Pharmaceutical Companies Mold our

> Perceptions of Mental Illness

> David Healy, M.D., F.R.C. Psych

> UCLA Neuroscience Lectures Oct. 28, 2003

> http://www.mentalhealth.ucla.edu/opce/gr.html