January 22

Role of Litigation in Defining Drug Risks_JAMA / BMJ

Below are excerpts from two timely articles that offer persuasive arguments backed by evidence demonstrating that litigation provides vital drug safety information that physicians and the public need to protect consumers from drug-induced hazards. Documents uncovered during the course of litigation shed light on real risks of drug-induced harm that would not otherwise be known.

The Role of Litigation in Defining Drug Risks by Drs. Aaron Kesselheim and Jerry Avorn is in the current issue of the Journal of the American Medical Association (JAMA). [1] What have we learnt from Vioxx? by Drs. Harlan Krumholz, David Egilman and colleagues appears in the current BMJ. [2] 

1. The authors of the JAMA article examined some 9 case examples finding that: "there are often important gaps in the ascertainment and reporting of adverse effects associated with prescription drugs" that the surveillance system simply does not address.
The case examples: Valdecoxib (Bextra); Olanzapine (Zyprexa); Paroxetine (Paxil); Cerivastatin (Baycol); Trogitazone (Rezulin): Rofecoxib (Vioxx); Defenfluramine (Redux); Cisapride (Propulsid).

A common theme in these cases was delay in revealing adverse event data, usually accompanied by efforts to minimize their prevalence and / or severity. The FDA approved drug label "can vary in its completeness and balance and may not be updated in a timely way to reflect new data."
The FDA may be in possession of evidence that it does not share with physicians and the public.

 "In both premarketing and postmarketing stages, lawsuits have helped uncover important and previously unavailable data about major adverse events."  Indeed, litigation, whether brought by government agencies –such as Attorney Generals–or individual patients "can help uncover previously unavailable data on adverse effects, questionable practices by manufacturers, and flaws in the drug regulatory system." 

The concealed evidence uncovered during litigation demonstrates FDA's failure to adequately stay abreast of adverse effects, and manufacturers' failure to provide case reports to the FDA. Lawsuits have also exposed important limitations in the FDA information collection and dissemination procedures.  FDA has, in some cases, negotiated with manufacturers for five years over a label change.

Furthermore, during the Bush Administration, the FDA submitted legal briefs in support of manufacturers who failed to disclose lethal risks–specifically the increased risk of suicide for those who consume SSRI antidepressants–arguing that the courts should not expect the industry to provide any risk information beyond what is contained in the drug's official label.
"These case studies indicate that clinical trials and routine regulatory oversight as currently practiced often fail to uncover important adverse effects for widely marketed products.  In each instance, the litigation process revealed new data on the incidence of adverse events, enabled reassessments of drug risks through better evaluation of data, and influenced corporate and regulatory behavior."

2. The authors of the BMJ article show how prominent medical journals are culpable in transmitting manipulated reports that are then widely circulated to physicians and cited in public pronouncements. The article examines the case of Vioxx and the evidence showing that even as concern about its cardiovascular risk was articulated by Merck's own chief scientist, Dr. Edward Scolnick, the company submitted a manipulated rendition of the VIGOR report which was published in The New England Journal of Medicine (NEJM).

The NEJM report contained partial data from an interim analysis that omitted three additional myocardial infarctions that occurred in the Vioxx group, and it concealed the cardiovascular risk by failing to report the absolute number of such events.  Yet, the study with its "colossal economic implications, made it through the journal peer review process to the profession and the public." 

"The publication concealed the cardiovascular risk even further by presenting the hazard of myocardial infarction as if naproxen was the intervention group (relative risk 0.2, 0.1 to 0.7) and without reporting the absolute number of cardiovascular events, even though all other results were presented appropriately with rofecoxib as the intervention group.w11"

Krumholz and colleagues go beyond demonstrating corrupt practices in the prescription drug industry. They lift the lid on those who, in our opinion, bear a heavy burden of responsibility for aiding and abetting corporate crime that can be measured in preventable deaths.

 "The journals published the studies, and the academic community accepted the findings without expressing much concern."

They call journal editors to task for failure to recognize that reports "with immense financial implications require a higher level of scrutiny than others." Indeed, as the documents show, Merck promoted the manipulated VIGOR study aggressively–purchasing 1 million reprint copies which it distributed to physicians and health professionals who were thereby misled about the actual risks.

Other journals also failed to detect fraud: for example, in 2001, Circulation, published a misleading favorable report about the Vioxx' safety. But documents uncovered during litigation show that the article was severely criticized even by an executive Merck scientist:
"The data appears to have been interpreted to support a preconceived hypothesis rather than critically reviewing the data to generate hypotheses."

The Annals of Internal Medicine published a ghostwritten Vioxx report–the ADVANTAGE study–then issued a correction.

The authors note that even though Merck and the NEJM eventually admitted that the published VIGOR statistical analysis was wrong,  none of the academic authors who signed off on the flawed and misleading VIGOR study–all of who were paid by Merck–"have conceded error or taken responsibility for the biased presentation of the study results." 

In fact, "few academic researchers publicly questioned the company before its voluntary withdrawal of the drug." 

"Nearly 107 million prescriptions for [Vioxx] were dispensed in the US between 1999 and September 2004, when the drug was withdrawn from the market, and none of the people picking up those prescriptions had the opportunity to consider the true balance of it risks and benefits."

These very timely articles underscore the urgent need for meaningful consumer protection laws to hold those who engage in fraudulent drug promotion accountalbe. Consumers need protection not provided by the FDA. Not only do consumers need to be protected from Big Pharma and its aggressive marketing of lethal drugs, but from academic "authorities"–a.k.a. key opinion leaders (KOLs)–who cash in on their reputation and the prestige of the universities they are affiliated with. Without these academic fronts industry could not possibly succeed in the magnitude of its deceptive drug marketing.

Contact: Vera Hassner Sharav

1. Aaron S. Kesselheim, MD, JD and Jerry Avorn, MD. The Role of Litigation in Defining Drug Risks, JAMA, January 17, 2007. 297(3) 308-311. http://jama.ama-assn.org/current.dtl

………We sought to define the intersections among the civil justice system,
the regulatory apparatus, and the science of pharmacoepidemiology,
including the effects of those interactions on drug safety research, clinical
 knowledge, and regulatory policy.

Sources of Knowledge About Drug Safety:

Most physicians and patients learn about prescription drugs
from publications of clinical trials or case reports, promotional
materials or alert letters provided by pharmaceutical manufacturers,
and formal documents such as the FDAapproved
label. These sources, however, sometimes provide
a limited perspectiveona drug’s benefitsandrisks.Forexample,
a drug’s label can vary in its completeness and balance and
may not be updated in a timely way to reflect new data.
In both the premarketing and postmarketing stages, lawsuits
have helped uncover important and previously unavailable
data about major adverse events. For example, the selective
cyclooxygenase inhibitor valdecoxib was submitted for
approval in 2001 for treatment of dysmenorrhea, osteoarthritis,
rheumatoid arthritis, and acute pain. The FDA approved
the drug, but only for the first 3 indications. At the request of
the manufacturer, the agency then refused to release safety and
efficacy data from the pain-related trials, arguing that this information
constituted a trade secret, even though physicians
were widely expected to use the drug “off label” for that purpose.

Only when the consumer group Public Citizen initiated
a lawsuit did the FDA release most of the contested safety
information. According to Public Citizen, the redacted information
revealed that the FDA medical officer found “an excess
of serious adverse events including death.”4 Valdecoxib
was withdrawn from the market a year later.

Litigation has also helped the medical community reassess
drugs by bringing to light new information about adverse
effects. In the case of the selective serotonin reuptake
inhibitor antidepressant paroxetine, New York Attorney General
Eliot Spitzer found that GlaxoSmithKline had failed to
make public clinical trial data that found an increased risk
of suicide in adolescent patients taking the drug. The company
claimed that the FDA had not specifically approved
the use of paroxetine in adolescents, so it was “under significant
restraints imposed by federal law in communicating with physicians
about those studies.”5 The government lawsuit and investigations
led GlaxoSmithKline and other selective serotonin reuptake inhibitor
manufacturers to release the data.  An FDA health advisory followed
that warned physicians to “carefully monitor patients receiving
antidepressants for possible worsening of depression or suicidality”
and emphasized that only fluoxetine had been approved
to treat pediatric major depressive disorder.6

For the antipsychotic olanzapine, studies emerged a few
years after its approval linking it to weight gain and diabetes7;
a series of patient-initiated lawsuits in early 2003 charged
that Lilly did not adequately warn about these adverse effects.
By September 2003, the FDA required that olanzapine’s
label be changed to provide a more prominent warning
about diabetes-related adverse effects. In June 2005, the
manufacturer announced a $690 million settlement of more
than 8000 olanzapine lawsuits. The settlement required that
documents revealed during the discovery process—
including data on the actual rates of such adverse effects—
not be disclosed publicly. However, documents recently made
public from concurrent olanzapine litigation reveal that Lilly
long downplayed and kept secret research that linked use
of the drug to weight gain and hyperglycemia, telling its salespeople,
“Don’t introduce the issue!!!”8

Effect of Litigation on Corporate Behavior

……..xxx CUT xxx

2. Harlan Krumholz ,Harold H Hines, Joseph S Ross, Amos H Presler, David S Egilman. What have we learnt from Vioxx? BMJ 2007;334:120-123 (20 January),   http://www.bmj.com/cgi/content/short/334/7585/120

Rofecoxib (Vioxx) was introduced by Merck in 1999 as an effective, safer alternative
 to non-steroidal anti-infl ammatory drugs for the treatment of pain associated with osteoarthritis.
It was subsequently found to increase the risk of cardiovascular disease and withdrawn from
the worldwide market. Merck now faces legal claims from nearly 30 000 people who
had cardiovascular events while taking the drug.1 The company has stated that it will
fi ght each case, denying liability.2 Our recent participation in litigation at the request of
plaintiffs provided a unique opportunity to thoroughly examine and refl ect on much of
the accumulated court documents, research, and other evidence. This story offers
important lessons about how best to promote constructive collaboration between
academic medicine and industry.

Early suspicion of cardiovascular risk Since the early development of rofecoxib,
some scientists at Merck were concerned that the drug might adversely affect the cardiovascular
system by altering the ratio of prostacyclin to thromboxane, which act in opposition, balancing blood
flow and clotting. w1 A study sponsored by Merck during 1996-7 reported that rofecoxib reduced urinary
metabolites of prostacyclin in healthy volunteers by about half.w2 In internal emails made public through
litigation,3 Merck officials sought to soften the academic authors’ interpretation that cyclo-oxygenase-2
(COX 2) inhibition within the vascular endothelium may increase the propensity for thrombus
formation, the basis of what became known as the FitzGerald hypothesis.w3

The academic authors changed the manuscript at Merck’s request—for example, they changed
“systemic biosynthesis of prostacyclin … was decreased by [rofecoxib]” to “Cox-2 may play a role in
the systematic biosynthesis of prostacyclin.”3 w2…………..

…….Matters were complicated by the existence of conflicts of interest among board members.
According to Merck policies, the board is supposed to be independent, without financial
or emotional stake in the trial being monitored.10 Yet, the head of the VIGOR board
was awarded a two year consulting contract two weeks before the trial ended and as the
trial was concluding disclosed family ownership interest in Merck shares worth $70 000
(£37 000; €55 000).11 12 Although it is not possible to tell whether this financial relationship
made any difference, the conflict of interest was not a matter of public record at the time
the trial was conducted or published and of itself calls into question the independence of
the safety board.

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a 'fair use' of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.



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