Merck Settles Another Vioxx Case

All the shenanigans that went on in the course of Merck's marketing of the now withdrawn Cox-2 inhibitor non-steroidal anti-inflammatory drug Vioxx have provided grist for the Health Care Renewal mill since 2005.  For example, see these posts:

- here about ghost-writing of a Vioxx research publication;
- here, and here about allegations that Merck executives tried to intimidate Vioxx critics;
- here about how advocates of an extreme laissez faire approach to regulation of health care corporations used illogical arguments about the Vioxx case;
- here about how an apparently major clinical trial of Vioxx turned out to be a "seeding trial," that is, a study really meant to recruit supposed physician-researchers as prescribers; and
- here about how one once prominent Vioxx researcher pleaded guilty to fraud in connection with his research on other drugs. 

Thus, the Vioxx case provides a good lesson about some of the tactics used to deceptively and unethically promote health care products (pharmaceuticals in this case).

Merck just announced just the latest settlement of Vioxx related legal actions, as reported by Business Week:

Merck & Co. agreed to settle shareholder lawsuits over the withdrawn Vioxx painkiller by strengthening its drug-safety procedures, appointing a new chief medical officer and paying $12.2 million in legal fees.

Merck would appoint one committee to address risks that require immediate action and another to monitor the safety of drugs, the company said in a regulatory filing. Merck would also amend its code of conduct to promote scientific and academic integrity as well 'honest communication' with doctors.

'In all research endeavors that are sponsored by Merck, we will refrain from attempting to influence inappropriately the results and conclusions of such research,' according to the amended code. 'We strive for all communications with the medical community to be accurate, truthful and consistent with labeling.'

Also,

The company will be required to make corporate governance changes and “supplement existing policies and procedures,” ... [a Merck spokesperson] said.

Merck would submit results of clinical trials to a public registry, with its compliance overseen by an independent third party.

The chief medical officer will have an 'executive voice' on product safety issues independent of Merck Research Laboratories.

Note that this settlement is only of one type of lawsuit, as described in a Wall Street Journal article,

The pact, which is pending final court approval, would resolve state and federal shareholder 'derivative' complaints (which are brought by shareholders on behalf of a company) alleging that current and former Merck officers and directors breached their fiduciary duties in handling Vioxx.

Merck had already settled thousands of lawsuits,

Since the Vioxx controversy erupted, about 27,000 personal-injury lawsuits have been filed, the company says. Merck has been challenging all of the cases and settled many of them. Most notably, it agreed to a pay $4.85 billion to settle personal-injury claims of more than 40,000 people. In another settlement, the company will pay $80 million to resolve 190 claims filed by drug-benefit plans seeking to recover costs of paying for Vioxx use.

Merck has lots of other legal actions to go through,

The Vioxx litigation remains far from over. The U.S. Supreme Court is weighing a separate shareholder case, seeking billions of dollars in damages from the company. Merck disclosed last year the U.S. Attorney's office in Boston was conducting a grand-jury investigation of Merck's handling of Vioxx. The claims of some 310 plaintiff groups are outstanding in courts in the U.S., according to the securities filing. There are also cases overseas, including Australia and Turkey.

So the parade of legal actions and settlements thereof continues.  We believe that the scope of this parade provides some sort of index of bad behavior by the health care organizations needing to make such settlements.  Most of these legal results are reported on in the business media, and rarely appear in any medical, health care research, or health policy journals.  I submit that were health care professionals, health care researchers, and health policy makers more systematically aware of these cases, they might realize that unethical and sometimes illegal behavior, often generated by bad leadership unrestrained by poor organizational governance, is a major cause of the current, seemingly intractable health care crisis.

One notable attribute of the current Vioxx settlement is that it does mandate some changes in Merck's governance and leadership meant to prevent future cases similar to this one.  These include developing leadership structures and changing the company's code of conduct to emphasize the need for "truthful" communication, and the need to refrain from "inappropriately" influencing research. 

On Health Care Renewal we have discussed numerous examples of deceptive practices by health care organizations, often affecting marketing, and of manipulation and suppression of research.  It is a small step forward for one company to commit to honest communications and to not manipulate research.  A better code of conduct may at least be a start towards an organizational ethics policy, which in turn may have the potential to actually improve behavior. 

On the other hand, typical settlements that involve only monetary damages paid by the organization seem to have little deterrent effect on future bad behavior. Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts suffers any negative consequences. I submit once again that such fines are viewed merely as costs of doing business by the affected companies, and do not deter future bad behavior. Until the people who approve, direct, and perform unethical or illegal acts pay some penalties, expect such acts to continue, at best deterred only slightly by written policies that condemn them. I again suggest that to truly reform health care, we need rigorous regulation of health care organizations that has the power to deter unethical behavior that may risk patients' health

Physician Pleads Guilty to Fraud for Fabricating Celebrex (and Other) Study Data

As reported by the Springfield, MA, Republican:

A former chief of acute pain at Baystate Medical Center has agreed to plead guilty to falsifying medical research and must pay $420,000 in restitution to pharmaceutical companies, federal court records show.

Dr. Scott S. Reuben, of Longmeadow, was charged on Thursday with health care fraud. He signed a plea agreement with prosecutors a week earlier.

Reuben prompted a furor in the medical community in March, when he was accused of making up research results in at least 21 published studies and inventing patients in certain instances.

In one notable instance,

In 2005, Reuben received a $74,000 research grant from pharmaceutical giant Pfizer, agreeing to test Celebrex as a component of the multimodal therapy. He claimed to have treated 200 patients, 100 with Pfizer's product and 100 with a placebo.

'In fact, Reuben had not enrolled any patients into that study and the results reported both to Pfizer and to the Anesthesia and Analgesia Journal and in turn to the public were wholly made up by Reuben,' the charge states.

Albert said the fabrications were discovered by medical staff within the hospital during a routine review at the hospital's 'research week,' when clinicians design poster displays of their studies.

A report in the New London, CT, Day indicated the scope of Reuben's fake research:

Anesthesia & Analgesia later had to retract 10 papers authored by Reuben, and medical experts at the time said at least 21 journal articles by the anesthesiologist appeared to have been fabricated.

The agreement calls for Reuben to pay restitution of $296,557 to Pfizer and $16,000 to Wyeth Pharmaceuticals, two companies that merged last fall. Merck & Co. would receive $49,375 from the agreement, according to documents.

In addition to his fabricated Celebrex studies, Reuben had pretended to do research that backed the effectiveness of other pain drugs, including Pfizer's Bextra and Merck's Vioxx, according to prosecutors. Bextra and Vioxx later were pulled from the market because studies showed they increased the risk of death from heart attacks and strokes.

In addition, Reuben published data showing that Pfizer's antidepressant Effexor had exhibited painkilling properties.

Reuben's studies had been considered pioneering at the time they were published. His data had supported the use of two of Pfizer's major products - Celebrex and Lyrica - in combination to treat certain types of post-operative pain.

Reuben 'was a regular on the medical lecturing circuit,' according to court documents, and 'had become a well known figure in the anesthesia and pain management medical communities.'

Pfizer said previously that it had supported five of Reuben's research initiatives. Pfizer, which declined at the time to reveal how much it paid Reuben over the years to be part of its speakers' bureau, said the company played no part in the fraud.

Asked for a comment Friday, Pfizer was not able to provide a timely response.

Note that we usually do not post about stories of individual's clinical research misconduct, not because it is unimportant, but because individual misconduct may be related more to an individual's motives and character than to concentration and abuse of power in health care.

However, in this case it appears that Dr Reubens was enabled, at least in the psychological and logistical senses, by pharmaceutical companies happy to sponsor research which suggested the effectiveness of their products.  Since Dr Reubens apparently fabricated most of his data, notice that he apparently deliberately fabricated data that made Pfizer's Celebrex, Bextra, Lyrica, and Effexor, and Merck's Vioxx look good.  Perhaps there was careerism here.  Positive studies about "innovative" effective drugs are more likely to get published than negative studies or studies of old drugs.  However, we have noted before that pharmaceutical (and biotechnology and device) companies like to sponsor studies with results that make their products look good. 

One bit of good news in this story is that Reuben's colleagues at the hospital apparently were able to uncover the fabrications when they had an opportunity to critically look at data from several of his studies.

Certainly some Pfizer employees had easy access to the same data.  But perhaps they would not have thought to look at it critically as long as it was so unrelentingly positive about their company's products. 

As we have said before, health care professionals, policy makers and patients ought to be extremely skeptical of clinical studies sponsored (and often deeply influenced) by those with vested interests in the studies' turning out in certain ways.  We ought to reconsider national research policies that have turned over sponsorship of the majority of clinical research to those with such vested interests.

Hat tip to Prof Margaret Soltan on the University Diaries blog.

ADDENDUM (19 January, 2010) - see also comments on the Alison Bass Blog.

BLOGSCAN - Merck Hired Elsevier to Create Fake Peer-Reviewed Medical Journal

You just can't make this stuff up. On the Respectful Insolence blog, Orac recounted how pharmaceutical giant Merck hired medical publishing giant Elsevier to create what appeared to be a peer-reviewed journal, but theAustralasian Journal of Bone and Joint Medicine really was just a marketing outlet. The goal was to market Fosamax and Vioxx. This is another bizarre variant on the stealth marketing theme, taken to quite an extreme. And the pharmaceutical companies wonder why people don't trust them?

ADDENDUM (4 May, 2009) - Dr Aubrey Blumsohn is back online on his Scientific Misconduct Blog, and noted the academic luminaries who were willing to serve on the editorial board of this fake peer-reviewed journal.

ADDENDUM (11 May, 2009) - See also comments on Laika's MedLibBlog.

Response from author of "The ADVANTAGE Seeding Trial"

In response to my earlier post "Merck scientific debate hits bottom" I received the following from one of the authors of the VIOXX seeding trial paper The ADVANTAGE Seeding Trial: A Review Of Internal Documents, Ann Intern Med 2008", Dr. David Egilman, MD, MPH.

I posted Dr. Egilman's opinions below at his request. My own thoughts follow.

Dr. Egilman also posted numerous documents to and from Merck's lawyer at this link. (The tone of some of those documents towards Dr. Egilman is particularly disturbing, such as the one here.)

------------------------------------------------------

From: David Egilman, MD, MPH
To: Healthcare Renewal

I am one of the authors of the "Seeding" paper.

Merck executive Dr. Jonathan M. Edelman, Executive director, Global Center for Scientific Affairs wrote:

There's no doubt that the ADVANTAGE clinical trial had a legitimate scientific purpose. That purpose was to assess the gastrointestinal tolerability of VIOXX compared to naproxen – a commonly used arthritis medicine with known tolerability problems – in the treatment of patients with osteoarthritis in a primary care setting, and for the first time allowed patients taking concomitant aspirin to participate.

Dr. Edelman's claim that ADVANTAGE was the first trial that permitted aspirin use with Vioxx is incorrect. Study 058, which was part of Merck's application for new drug approval submitted in November 1998, permitted the use of up to 325 mg of aspirin per day. ADVANTAGE only permitted up to 100 mg per day. Study 058 was a 30 week trial. ADVANTAGE was only a 12 week trial. Study 058 involved patients older than 80, comparing Vioxx to namebutone (another NSAID) and was completed in April 1998, about 10 months before ADVANTAGE enrolled a single patient. Study 078, the ghost-written Alzheimer’s trial also permitted aspirin, began in April 1998 and was scheduled to be completed by April 2000 before the end of the ADVANTAGE trial. More patients took low dose aspirin in the Vigor trial than the Advantage trial.

Further, ADVANTAGE was not designed to test the effect of aspirin on anything. Although aspirin was permitted, the examination of aspirin effects was not included as part of the study objective which Merck described: "[t]o assess the tolerability of rofecoxib (VIOXX) compared with naproxen for treatment of osteoarthritis." On the other hand, Merck Study 136 was designed to test the effects of concomitant aspirin and NSAID use. This study revealed that Vioxx offered no GI protection to low dose aspirin users who constituted the majority of potential Vioxx users.

By November 1998, when Merck sought FDA approval for an OA indication and three months before the ADVANTAGE trial enrolled any patients, Merck had already informed the FDA it had sufficient studies to prove Vioxx was efficacious for osteoarthritis patients. Merck's osteoarthritis trials (that it used to get FDA approval for use of VIOXX in osteoarthritis patients) had compared Vioxx to 3 other NSAIDS. The VIGOR trial, which tested Vioxx and naproxen in rheumatoid arthritis patients, started at the same time as ADAVANTAGE and used twice the dose of Vioxx than was used in ADVANTAGE. VIGOR was, therefore, a more valid scientific trial to determine relative safety of the two drugs.

This request for and subsequent approval meant that Merck could claim VIOXX was as effective for pain as naproxen. Beginning long before the Advantage trial Merck claimed Vioxx was safer than all NSIADS including naproxen.

While ADVANTAGE was the first study that compared Vioxx to naproxen in OA patients, Merck had completed trials comparing the two drugs in other pain patients.

It is for these reasons that the President of Merck Research Laboratories (MRL) Dr. Scolnick characterized ADVANTAGE as "intellectually redundant."

Merck wrote:

ADVANTAGE was a double-blind, randomized, controlled clinical trial with a legitimate scientific purpose designed to answer previously unanswered questions about the use of VIOXX in osteoarthritis in a primary care setting. It was not a seeding study.

Merck’s personnel called it a seeding trial internally but in an apparent effort to hide its true purpose wrote:

“I eliminated the reference to seeding. It may be a seeding study, but let’s not call it that in our internal documents.”

Merck apparently tried to make it look like a typical science-based clinical trial to mislead IRBs and journals. All seeding trials make some claim to some usually trivial scientific purpose. For example the question of whether or not Vioxx works better on people as a function of height is a scientific question. It is of course a trivial question. In this case Merck had studies that compared Vioxx to naproxen for pain control before the Advantage trial had started. Merck also had a larger trial that tested GI toxicity.

Merck wrote:

ADVANTAGE was important because although the earlier VIOXX clinical trial program provided extensive data on efficacy and safety, it did not include naproxen as a comparison Medication.

This is not correct. Merck had a study that compared Vioxx to naproxen for pain control before the Advantage trial started. This was presented to the FDA in the original New Drug Application and was published in October 1999.

Merck wrote:

The ADVANTAGE clinical trial was designed, conducted, analyzed, interpreted and published by the scientific department of Merck's U.S. Human Health (USHH) organization, Clinical Development (CDP), in conjunction with participating investigators. CDP was part of the Medical and Scientific Affairs department of USHH and was separate from the marketing department within USHH.

A more complete picture is:

USHH was the marketing division of Merck. It included sub-divisions including sales, marketing and a medical/scientific group called CDP. CDP performed “medical” studies that could be used by marketing to increase product sales. These studies were only conducted if favorable results could increase sales. They were not done to obtain new indications for drug use and Merck did not publish or provide the FDA with some of these studies (example 106).

Mr. David Anstice, a marketing executive with no apparent scientific training or background was the President of Merck's USHH division. In contrast Dr. Edward Scolnick, a physician/scientist of international renown, was the President of Merck’s research division which was called Merck Research Laboratories. Mr. Anstice the person ultimately responsible for the Advantage trial testified:

Q. I understand that. All I'm saying is, this is the study [Advantage trial] that was initiated and conducted by marketing, right?
A. Yes, by doctors in marketing.

A picture being worth a 1000 words I provide the Merck graphic for the organization of the Advantage trial:



Here is the power point description of marketing’s role in the Advantage trial:



While the marketing division of USHH set the study “objectives” CDP was in charge of the technical aspects of study implementation.

Further proof that ADVANTAGE served little scientific purpose is the fact that Merck had already claimed that Vioxx was safer than and as effective as all NSAIDS including naproxen prior to the initiation of the ADVANTAGE.

Merck did not rely on any ADVANTAGE results to make any claim about Vioxx efficacy or safety to the FDA. The lack of scientific purpose behind ADVANTAGE is demonstrated by the fact that Merck had withheld the ADVANTAGE results from its application to the FDA that requested a label change that would allow them to claim Vioxx was safer than naproxen. Merck only produced the results after the FDA made numerous oral and written requests for the safety data discovered during the trial.

Merck claims Advantage produced important scientific information:

In the end, ADVANTAGE showed a different gastrointestinal profile between VIOXX and naproxen that was unaffected by concomitant use of aspirin. This was an important medical result for physicians. In addition to measuring the GI tolerability of VIOXX, investigators also monitored patients for adverse events, which were required to be submitted to the FDA. Therefore, in ADVANTAGE, Merck was further evaluating any potential risks of VIOXX.

In fact the trial that Merck performed to test the effect of concomitant aspirin and Vioxx use (136) showed that aspirin use thwarted Vioxx’s GI advantage. (Gastroenterology. 2004 Aug;127(2):395-402.) The conclusion Merck reached based on the Advantage result was wrong precisely because Advantage was not designed to test this question. This conclusion was based on data mining.

Merck wrote:

We also want to underscore that the scientific purpose of ADVANTAGE was properly disclosed to physicians-investigators, participants, and institutional review boards, and Merck's business interests were clearly understood.

Merck never disclosed the marketing purpose of the trial which included the fact that Marketing “set objectives.”

Merck accuses the authors of "bias.”

In this open letter to the editors of The Annals of Internal Medicine, Merck would like to put in perspective the latest article by four authors who served as paid consultants to plaintiffs' lawyers in the VIOXX litigation against Merck. We are troubled by the biased article, which contains numerous inaccuracies, and wonder about the motivation behind this attack on Merck's scientific excellence and integrity.

Merck writes that the authors were “plaintiff witnesses” and “cherry picked” documents. As far as I know, all litigation ended about a year ago. None of the authors were paid on a contingency basis, the authors received no compensation from plaintiffs to work on the papers we have written and none of the authors are working on any Vioxx litigation at this time.

If money motivation equates to bias then it is Merck and its representatives who suffer from this problem. The same cannot be said of Merck or its representatives because while the authors have nothing to gain Merck’s future earnings depend, in some measure, on its reputation for honesty.

Merck does not explain how any theoretical bias impacted on the paper. They have not come forward with contradictory documents or testimony.

The authors agree that all the documents should be made public so readers can decide for themselves if we “cherry picked.” Merck, and Merck alone, continues to block the release of the documents.

Merck would not allow us to cite documents that showed that Advantage investigators were accused of fraud and at least one was convicted. Some of this data was deleted from the published paper but readers and editors were never informed of these problems.

It should be noted that eight Vioxx patients had heart attacks during the ADVANTAGE trial compared to one patient on naproxen. Merck never informed any of these patient volunteers of the cardiovascular risks of Vioxx before or after the trial although the informed consent stated that Merck would pay for treatment of drug related side effects. Unfortunately for some, this would have been funeral costs.

Merck wrote:

It is unfortunate that the authors and journal editors chose not to contact Merck before finalizing these publications. Had any of these individuals contacted Merck, factual errors could have been avoided.

I contacted Merck's main trial lawyer Ted Mayer and provided Merck an opportunity to comment on another paper related to the Advantage trial before it was submitted for publication. I did not send a pre-publication copy to plaintiff lawyers. Mr. Mayer provided comments and i included his comments in the final version.

Merck then complained about my contact to Mr. Mayer to Judge Higbee and requested that she sanction me for contacting their lawyer and then insisted that I make no further contact with them.

-- David Egilman

-----------------------------------------

My own thoughts on all of this are as follows:

The lessons of the Annals article are clear. The scientific community and the public are simply fed up with cavalier practices in the biomedical industry. While the article may affect remaining VIOXX litigation as pointed out here, it also should have an necessary "cleansing effect" on drug R&D.

It was not clinicians and scientists outside the industry who earned it the public's animosity. It was, and continues to be, the industry itself. As Roy Poses observed, there cannot be evidence based medicine if the evidence is distorted by commercial zealotry. I think the public recognizes this.

Further, marketing personnel have no place in pre-approval, pre-marketing scientific studies such as clinical trials. If they have a scientific role, it is perhaps in post-marketing studies, especially post-marketing surveillance for adverse effects. The latter is a function the pharma industry performs poorly.

Even in that latter domain, there must be honesty and transparency, characteristics with which the biases of marketing and its leaders (e.g., towards maximizing sales) may interfere.

Merck's responses to this new Annals article seem the antithesis of science. Instead, the responses appear to be right out of the political and legal warfare playbook (where logical argument prevails - except when presenting logical fallacy is to the advantage of the protagonists) ...

The response has been this:

• ignore the arguments and evidence [in this case, emails and documents from Merck itself],
  
• issue an ad hominem attack,
  
• issue slogans ("litigation in the name of science"),
  
• present a Red Herring as a distraction,
  
• issue accusations of bias,
  
• issue accusations of cherry picking,
  
• issue accusations of the authors taking evidence "out of context", etc.

and finally:

• produce no context or new evidence of your own, hoping the above tactics will make that unnecessary.
  

All that's seemingly missing are ... puppets.

Merck seems to expect the "courtesy" of being allowed to be a participant in any issues written about its conduct, as if the authors of this paper are its employees who under employment policies must permit any pubs they produce to be reviewed internally for approval. I believe the company's executives forget that their authority ends at the front gate.

It is also an odd and even arrogant request, especially considering the way the authors' evidence (Merck's own emails and documents) was essentially ignored in the responses, and the insinuations promulgated against the authors as serving plaintiff's lawyers -- which also implies that scientific integrity and the interest of patients is not their motivation.

As I mentioned in my earlier post, this is classic ad hominem and is insulting to authors in my opinion, as well as insulting to any clinician or scientist. Why would anyone want to provide a company that acts in this manner the courtesy of pre-publication involvement in investigative journalism?

Another issue I find interesting is noted in the limitations section of the paper where it is stated that:

... we did not identify, despite an exhaustive and systematic search strategy, documents detailing discussions between the marketing and research divisions, nor could we identify documents describing contracts between Merck and collaborating companies.

As well as the Annals editor's obervations that:

... despite the large body of documents searched by the authors, they discovered few details about exactly how Merck's marketing division carried out ADVANTAGE.

This is surprising. From an information science standpoint, it would not be unreasonable to believe there might be more related to this trial of a major drug in emails or powerpoints or other documents. This document sparsity could mean that the documents did not exist, but it also raises a speculative question about the document corpus produced in Discovery.

Could "inconvenient documents" have selectively been eliminated from the corpus of documents before it was released, and therefore not be present in the corpus of documents the authors searched? Could the documents the authors did find represent ones that were "missed" by some weeding out effort?

Finally, I believe the entire tenor of Merck's responses - ignoring evidence, stating the trial was "published in a peer reviewed journal" as a Red Herring and a justification of its legitimacy while ignoring Sox & Rennie's (the Annals editors) accompanying commentary Seeding Trials: Just Say "No" , belitting the authors, etc. - is very disturbing.

From "Seeding Trials: Just Say No":

No one told Annals the true purpose of ADVANTAGE. We learned about it when we received a letter to the editor from Dr. David Egilman, who was a consultant to the plaintiffs' attorneys in the civil suits against Merck. He had access to publicly accessible trial documents, which included Merck employees' e-mail messages that disclosed the true intent of the ADVANTAGE trial ... The article provides clear evidence that the intent of ADVANTAGE was to increase prescriptions of Vioxx (the study outcome of greatest interest to Merck seems to have been Vioxx prescribing rates) ... The documents do tell us that deception is the key to a successful seeding trial.

When I review NIH grant applications, if I suspect deception I will mention it to the study section leaders, and I can assure that if deception is verified higher up the chain, that application will not get funded (at the very least). I can also assure that legitimate medical journals do not willingly publish studies involving deception.

Merck's responses to the Annals article seem to represent a belief that the public (laypeople and physicians) are stupid and gullible.

This is not science, and is not a path to a return to the corporate greatness and respect that Merck once enjoyed and had earned.

Finally, a Red Herring of my own:



-- SS

BLOGSCAN - "Be the Power," Never Mind the Data

Available in 3 parts on the Clinical Psychology and Psychiatry Blog (here, here, and here), and in one part on PharmaLot, is a video apparently used for training Merck pharmaceutical sales representatives to sell Vioxx (rofecoxib) to doubtful physicians. The strategy seemed to be to use flash and bluster to avoid dealing with concerns that Vioxx was no more effective a pain reliever than generic non-steroidal anti-inflammatory medications (NSAIDs) like ibuprofen and that Vioxx caused adverse effects, including myocardial infarction. Although waving around graphically fancy sales brochures was advised, dealing with the shaky data for clinical research (some of which later turned out to be gimmicked in favor of Vioxx) was not. Tell me again that story that pharma sales reps serve an educational function.

Merck scientific debate hits bottom, keeps digging?

I find Merck Scientific Affairs executive Jonathan Edelman's op ed in today's Philadelphia Inquirer on the Vioxx "ADVANTAGE seeding trial" controversy to be mediocre spin control at best, if not deliberately misleading through selective omission of critical facts:

Taking Exception
Great value in clinical studies
Philadelphia Inquirer, Sept. 26, 2008

Your articles "Merck faces more criticism" (Inquirer, Aug. 19) and "Journal vs. the bad seed" (Aug. 20) drew the wrong conclusion.

The Advantage study was published by the Annals of Internal Medicine in 2003 after passing the journal's editorial and peer-review process that determined the study to be important new information for physicians. Dr. Harold Sox recently wrote in Annals that the way to identify a good clinical trial is to look at the importance of the scientific question it tries to answer.

This is the very same criterion that Annals and other medical journals use to select the studies that they publish and that Annals correctly applied in accepting the Advantage study five years ago.

Advantage was a randomized, controlled trial designed to address the scientific concerns of physicians, namely: the need to study Vioxx in osteoarthritis patients in the primary-care setting, in real-world conditions, and against a commonly used arthritis medicine, naproxen.

We are troubled by how easily the journal editors were persuaded by the conclusions of authors who were paid consultants to trial lawyers standing to profit from litigation.

[i.e., Hill et al, authors of the article "The ADVANTAGE Seeding Trial: A Review Of Internal Documents." Ann Intern Med 2008; 149:251-258 - ed.]

There is great value in conducting scientifically based clinical studies to address unanswered questions. We believe we acted appropriately in the Advantage trial, and stand behind our unwavering commitment to ethical conduct and scientific integrity.

Dr. Jonathan M. Edelman
Executive director
Global Center for Scientific Affairs
Merck Research Laboratories
Upper Gwynedd

The bulk of this op-ed, in fact, consists of a Red Herring and an Ad Hominem attack.

First, the Red Herring. The controversy is not about what the Annals published in 2003, it is not whether the science in the ADVANTAGE study was itself "good" in isolation of contextual (e.g., ethics and social policy) issues.

It is about what was written in the Annals in 2008, and the controversy over performing ADVANTAGE and other seeding trials, period -- which David Gorski at Science-Based Medicine so aptly describes as suffering from (at least) one major flaw, inherent deception:

... To boil it all down, here’s my perspective on why seeding trials such as this are inherently unethical, regardless of whether the clinical scientific question under study is worthy or the design of the trial can produce an answer to that scientific question. It all comes down to one issue: Deception. There is no way to carry out a seeding trial without deceiving virtually everyone involved below the level of study designers.

But I digress. Deception aside, it was not the words or the interpretations of the Annals 2008 authors that the ADVANTAGE trials were of questionable scientific value ...

Those words came from the head of Merck's own R&D division himself. The 2008 Annals authors are reporting the words of Merck's erstwhile head of R&D. Yet, Dr. Edelman failed to mention that highly important issue, as if it was irrelevant or immaterial. Politicians and biased journalists do this all the time - omit critical details to spin a story. It's one of the principles of effective propaganda.

From a physician/scientist, however, we expect better.

(I also note that Merck and other pharmas generally require careful vetting of materials released for publication. I assume the Edelman Inquirer op ed underwent internal peer review.)

From the New York Times:

In e-mail messages on April 7, 2001, to ... an executive vice president at Merck Research Laboratories, [President of Merck Research Labs] Dr. [Edward] Scolnick wrote that he was especially angry because the Advantage trial had no scientific purpose. In theory, Merck set up the trial to show that Vioxx caused fewer stomach problems than naproxen. But Merck had already demonstrated that with the Vigor trial, which tracked more than 8,000 patients for a year.

In pharma, the president of the research labs is usually considered "god" as far as new drugs are concerned. It was pointed out that Dr. Scolnick, largely seen as the #2 official in the company, worried that the ADVANTAGE study risked disclosing data to the Food and Drug Administration that could cause problems for Vioxx.

... [T]he reason we have resisted doing large marketing clinical studies is just this. It opens a lot of data to FDA that compromises the large clinically meaningful trials." Small marketing studies which are intellectually redundant are extremely dangerous," Scolnick wrote.

I find these statements by Merck's former head of R&D quite remarkable for many reasons, some stated in my earlier post here. In fact I completed several assignments for Dr. Scolnick and can state emphaically he was not someone easily challenged on scientific matters. He knew his stuff.

Dr. Edelman also omitted the following salient fact seen in the Annals editorial by Harold C. Sox, MD, Editor of Annals of Internal Medicine, and Drummond Rennie, MD:

No one told Annals the true purpose of ADVANTAGE. We learned about it when we received a letter to the editor from Dr. David Egilman, who was a consultant to the plaintiffs’ attorneys in the civil suits against Merck. He had access to publicly accessible trial documents, which included Merck employees’ e-mail messages that disclosed the true intent of the ADVANTAGE trial.

I note that it's unfortunate the Annals editors in 2003 did not have access to these remarkable statements and documents. This information, in fact, only saw the light of day due to the VIOXX litigation. I doubt Annals would have published in 2003 with such knowledge.

Now to the Ad Hominem in Dr. Edelman's op ed.

I find the Ad Hominem attack ("against the person") on the 2008 Annals authors, Drs. Hill, Ross, Egilman & Krumholz, disappointing (they were "paid consultants to trial lawyers standing to profit").

So what?

That is useless information in the context of their current article.

In an ad hominem attack, the character or circumstances of a person making a claim, or their actions, are impugned. This attack is taken to be evidence against the claim or argument the person in question is making or presenting.

This is an exceptionally poor form of argumentation, especially considering the current Annals article was based on an "informational infrastructure" consisting of plain-English emails and documents written by Merck officials themselves. They are available for examination at this link.

These documents, provided by the company itself under rules of legal discovery, do not appear to be taken "out of context" in any way. They appear to stand on their own merits.

The reason why an Ad Hominem (of any kind) is a fallacy is that the character, circumstances, or actions of a person do not in most cases have a bearing on the truth or falsity of the claim being made or the quality of the argument being made.

(The above explanation is from the Nizkor Project page on ad hominem attack, link. In the final example of ad hominem on the Nizkor page, substitute "lackey to the trial lawyers" for "lackey to the Pope" to better visualize just how outrageous the attack on the Annals authors is.)

Is this is the state of the art for Merck scientific debate, I ask?

If so, the company's leadership is in its ripe old age, dementia fast approaching.

If pharma wants to re-establish its credibility with physicians and patients, among others, it needs to start acting more like a concerned physician than a furiously spinning politician trying to "control the narrative."

Finally, as numerous examples on Healthcare Renewal demonstrate, there are those in prominent leadership positions in healthcare who never learned basic rules of logical thought or argumentation yet claim to proffer scientific or ethical truths, or selectively "forget" logic to advance their own agendas. At this point, I have no qualms about calling such people scoundrels.

Addendum:

I note the statement by Dr. Edelman in the Annals comments site at this link ("Merck does say no") that the 2008 Annals article by Hill et al constitutes "litigation in the name of science."

I'd opine that the article more resembles a rather straightforward exposé of probable smoking-gun internal emails and documents in the defense of science. "Investigative journalism" is an apt description.

As Roy Poses pointed out in the comments, evidence based medicine is impossible when the science is tainted in the name of commerce.

-- SS

No Denying the Haunting of the Medical Literature

There was a remarkable series of letters in the latest JAMA(1). They, in turn, were responses to an article by Ross et al about ghost and guest authorship of articles about rofecoxib [Vioxx, by Merck](2). (See our post about that article here.)

Two of the letters were notable because they came from the lead authors of articles that Ross et al described as ghost-written.

First was a letter by Hawkey, which said in part,

From my own publications, I was surprised to see references 79, 94, 96 and 108 as having been in a Merck publication status report since these were reviews independently invited by Lancet, Balliere, Gastroenterology Clinics of North America, and Gut respectively, and involved no contact with Merck beyond usual request for all relevant sources for information.

Second was a letter by Ferris, Galasko, and Kirby, which said in part, (referring to an article by Thal et al discussed by Ross et al)

The 3 alleged guests in fact played substantial roles: conceiving and designing the study (Thal), confirming accuracy of the primary study end point as a member of the end point adjudication committee (Ferris), and enrolling 109 patient (Kirby). The paper was initially drafted by Merck coauthors in August 2003, after discussion of the results had previously taken place with Dr Thal and Dr Ferris in June and July of 2003. Drs Thal, Ferris, and Kirby were formally approached about being coauthors on the paper and an associated abstract in September 2003. Each critically reviewed the complete statistical report and contributed to the revising the final manuscript.

Before I go further, let me say a little about how scholarly articles are customarily written when no guest and ghost authors are involved. For all the articles I have authored, the first author was the researcher who was in charge of the overall study, or at least was substantially in charge of the study component reported by the article. The first author always wrote the first draft of the manuscript, possibly getting help from other authors or medical writers, but always being overall in charge. The first author always took responsibility for the final draft and published version of the manuscript. The second and third authors were generally those most involved with the relevant project, and with rewriting the manuscript.

This process seems very different than that used to write the articles discussed above.

Note that neither Hawkey nor Ferris, Galasko and Kirby claimed to be the principal investigators of the relevant projects, to have written the first drafts of the manuscripts, or to be those with the final say on the final drafts or published versions of the manuscript. Furthermore, none denied that Merck authors wrote the first drafts of the relevant manuscripts or that Merck authors had substantial responsibility for the content of the published papers. Hawkey claimed to have had "little contact" with Merck, but that did not preclude Merck authors from writing the first draft, or taking substantial responsibility for the content of the manuscript. Ferris, Galasko and Kirby claimed to have had some roles within the research project, but did not individually or collectively claim to be the project's principal investigator or to be substantially iin charge of the project, and did not deny that Merck authors wrote the first draft and took substantial responsibility for the content of the manuscript.

Thus, these letter writers did not deny that they had failed to do the work and take the responsibilities normally entailed by first authorship of scholarly manuscripts. Nor did they provide any evidence that the claims made by Ross et al about the ghost authorship of their papers were incorrect.

On the other hand, Hawkey and Ferris, Galasko and Kirby did take the opportunity to fulminate about the original JAMA article. Hawkey criticized Ross et al for failing to "systematically evaluate" all the articles in their Table. Ferris, Galasko and Kirby decried "this unsubstantiated allegation of guest authorship" which raised "questions about the flawed methodology in the study by Ross et al."

It is ironic that the financial disclosures for the letters by Hawkey, and by Ferris, Galasko and Kirby used 24 lines of type. Dr Ferris alone disclosed being a former or current consultant to 32 pharmaceutical, biotechnology or similar corporations.

What is most troubling, in my humble opinion, about the letters discussed above is that their authors could not bring themselves to directly address the core issue raised by Ross et al: evidence that they used their good names and academic reputations to cloak articles generated for commercial purposes in the guise of scholarship.

The larger questions are: how much of the clinical research database and the body of scholarship on which physicians and patients base their decisions was commercially generated, but deceptively promoted as produced by academics only interested in the discovery and dissemination of the truth? Furthermore, how many respected academics have built their careers and reputations on the work of unnamed employees of commercial health care firms, and thus what should we make of their supposed scholarship? And finally, on a personal note, how many honest academics have been crowded out of the competition for the support and dissemination of their work by faux scholars who claimed as theirs work done by others for commercial purposes?

As was said on the PharmGossip blog, it may be time for a truth and reconciliation committee that will allow us to put these deceptive ways behind us. To better care for patients and better advance science, we need medical scientists who put allegiance to the truth ahead of allegiance to their personal financial gain.

ADDENDUM (27 August, 2008) - See also comments on Science-Based Medicine blog.

ADDENDUM (2 September, 2008) - See also comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

References

1. Guest authorship, mortality reporting, and integrity in rofecoxib studies. JAMA 2008; 300: 900-906. [Link here.]

2. Ross JS, Hill KP, Egilman DS, Krumholz HM. Ghost authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008; 299: 1800-1812. [Link here.]

ADVANTAGE: Who was actually in charge of R&D? And other questions...

Roy Poses addresses many of the controversial issues raised by the Annals of Internal Medicine article "The ADVANTAGE seeding trial: a review of internal documents" in "Bad Seed: the ADVANTAGE Trial of Vioxx."

I wish to raise a few additional questions:

The Wall Street Journal and others pointed out that Edward Scolnick, MD, President of Merck Research Labs and largely seen as the #2 official in the company, worried that the ADVANTAGE study risked disclosing data to the Food and Drug Administration that could cause problems for Vioxx.

"Small marketing studies which are intellectually redundant are extremely dangerous," Scolnick said. [i.e., they pose a danger of non-meaningful adverse results due to chance - ed.]

I find this statement by Merck's head of R&D quite remarkable.

I believe Dr. Scolnick was, as I've written before at this HCRENEWAL post, the quintessential clinician/scientist of excellence. He apparently held the following titles:

(a) Merck’s Executive Vice President, Science and Technology, (b) President, Merck Research Laboratories (“MRL”), (c) member of Merck’s Management Committee, (d) member of MRL’s Research Management Committee, (e) member of the board of directors of Merck.

This raises the following questions:

• If the President of the Research Labs, ostensibly the head of R&D at the company, could not stop such a "seeding trial" study of a drug not yet released and/or its publication, then who was actually in charge of R&D?
• Was the go-ahead for the study approved by erstwhile CEO Gilmartin? The Board?
• Was there internal conflict at high levels over this and similar issues of control?
  
• Why did Roger Perlmutter, MD, PhD, former Merck Executive Vice President of Worldwide Basic and Preclinical Research -- who was believed to be Merck Research Labs (MRL) leadership heir apparent -- suddenly leave Merck in 2001? Could it have something to do with perceived lack of control of the MRL President's office over pre-release drug studies?
• What other such "seeding studies" on other drugs were conducted, and who authorized them?
  

Several corollary questions also arise:

Merck rationed access to tools essential for R&D and new drug discovery to its R&D scientists on the order of several million dollars annually. Tools the science heads themselves wrote were essential to R&D were being denied them despite my best efforts as Director of the MRL Science Libraries to end the rationing through a comprehensive and (I thought) compelling gaps analysis. As an example of one site head's beliefs, a VP of Medicinal Chemistry wrote a note about substantially increasing desktop access to cheminformatics tools such as CrossFire and SciFinder as well as other specialty databases (as did other R&D leaders):

"These applications are invaluable to the productivity of medicinal chemists in my department. CrossFire, in particular, is highly useful as the primary source for chemical information. Most new Ph.D. chemists whom we recruit are accustomed to using these tools to facilitate their research, and in fact, it is embarrassing that I have eight new Ph.D.'s who have arrived beginning last August who still do not have desktop access to CrossFire or SciFinder. I cannot overemphasize the value of having these tools accessible to chemists at their desktop, and I would urge you to expedite their deployment as quickly as possible."

This raises the questions:

• Why were "seeding studies" that the head of R&D himself called "intellectually redundant" and "extremely dangerous" being funded, while the needs of R&D and new drug discovery in particular were being underfunded?
• The budgetary decisions for these tools, I believed, were ostensibly being made by the VP of Research Computing in MRL, an IT person lacking a science or biomedical background (an issue for another time). What pressures was that person being put under from other departments - e.g., those running "seeding studies" - to cut essential R&D budgets?
• Was the budget decision not to end rationing of advanced informatics tools necessary for new drug discovery actually made by the VP of Research Computing? Or was the decision made by someone else to siphon money for other purposes, who had a different agenda?
• Is Merck's pipeline thin due to such decision making? Did the company sacrifice its future for immediate gratification, not realizing the whole scenario would implode when the drug, VIOXX, was found to have "previously unknown" harmful side effects, an issue which itself has been the topic of much controversy and billions in litigation?

Related to VIOXX, other questions that arise relative to rationing of informatics tools are:

• Could the rationing of tools essential to drug scientists in any way have been related to a desire by someone to hobble their ability to explore the issues related to drug side effects?
• Why were many in the company who previously had live access to the webcasted, periodic R&D Research Council meetings suddenly cut off from access in late 2002 or early 2003? What, exactly, did the company fear from dissemination of such discussions about R&D?

Finally, the last questions that arise are:

• Does all the above represent mismanagement?
  
• Do the issues represent shareholder deception? (i.e., how can funding of "seeding trials" while simultaneously denying discovery scientist access to critical R&D tools be construed as the acts of a truly "research-driven" company? Indeed, Merck itself advertises itself to shareholders as a "global research-driven pharmaceutical company dedicated to putting patients first.")

Of course, the answers to all of these questions could be quite banal and ordinary. However, I merely report and raise questions. Perhaps someone needs to explore further, and decide.

-- SS

Bad Seed: the ADVANTAGE Trial of Vioxx

An article in the Annals of Internal Medicine by Hill et al(1), and the accompanying editorial by Sox and Rennie(2) have created quite a stir in the media and blogsphere. Even so, it seems worth reviewing the main points, and adding some comments.

Hill et al address the ADVANTAGE trial, published in the Annals in 2003.(3) This was a randomized controlled trial that compared rofecoxib (Vioxx, by Merck) to naproxen for patients with osteoarthritis. 600 investigators each enrolled a few (target 6) patients. The trial failed to show that rofecoxib had any advantage of naproxen in terms of pain relief (see our discussion here). Long after the trial report was published, it turned out that its first author had no involvement in the study until Merck presented him with a copy of the manuscript written by company authors describing it, making it one of the more prominent recent examples of ghost-writing (see post here).

Hill et al obtained access to numerous internal Merck documents that only came to light in response to discovery requests filed in litigation. They appear to show that the ADVANTAGE trial was actually a "seeding" trial, designed to market the drug by putting "its product in the hands of practicing physicians, hoping that the experience of treating patients with the study drug and a pleasant, even profitable interaction with the company will result in more loyal physicians who prescribe the drug." In support of that, they found these themes in the documents they examined.

- "The trial emerged from the marketing division with a marketing objective;"
- "Merck's marketing division collected, analyzed, and disseminated both the scientific and the marketing data; and"
- "Merck did not reveal the marketing purposes of the trial to participants, physician-investigators, and institutional review board members."

Remarkably, an internal Merck memo made these further points:

First, the trial was targeted to a select group of critical customers.

[These were] primary care physicians. The ADVANTAGE trial utilized this important group as investigators.

Second, the design of the trial focused on demonstrating the value of VIOXX to this important audience

So, the study was designed primarily not to answer a clinical or scientific question, but to target certain physicians as "customers."

Third, execution of the trial ... [involved] integration of the field, marketing, and CDP [Clinical Development Program].

Thus, the study was really run by marketers, not scientists of clinicians.

Also,

Finally, the results of the trial are being carefully tracked. An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers....

Thus, the primary subjects of the trial were really not the patients, but the "investigators." Really, this was a trial that showed that involving primary care physicians as "investigators" in a seeding trial caused them to prescribe the supposed study drug more often than physicians not involved in the trial.

Nonetheless, informed consent forms for the trial did not inform subjects of its underlying marketing objectives.

This article appears to be the first to provide evidence that pharmaceutical companies may deliberately disguise marketing efforts as clinical research. This is a real achievement, since obviously the companies involved make every effort to hide what they are doing, and it only through discovery during litigation did the facts come out.

The authors conclude that

At least 3 elements of seeding trials are harmful to science and society. First, full informed consent is not possible without disclosing the full purpose of the trial. Physicians and patients participating in ADVANTAGE were informed of the scientific objectives of the study, but the research protocol and informed consent templates indicate that they were not told about the key role of Merck's marketing division in the trial or the true purpose of the trial. Second, good research practice is at risk when the marketing division designs and conducts a study. In a seeding trial, in order to fulfill strong marketing objectives, the recruitment of several research sites with fewer patients per site may result in less quality control from investigators and use of sites that have less research experience than academic centers or community physicians' offices, which may be more accustomed to hosting clinical trials. Quality control and rigorous research conduct may not receive adequate attention when marketing is the primary purpose of the study. Third, the study may have little scientific merit. Around the same time as ADVANTAGE, Merck launched the VIGOR (Vioxx Gastrointestinal Outcomes Research) trial to be the definitive study of gastrointestinal toxicity. The FDA required Merck to conduct VIGOR before putting claims of improved gastrointestinal safety on the Vioxx label. Thus, the purpose of ADVANTAGE was neither to seek a new indication nor to perform postmarketing surveillance.

Additionally,

Failure to disclose the primary purpose of a trial has ethical ramifications for patients, physicians, and the design of clinical trials. Seeding trials like ADVANTAGE, in which the study medication has yet to receive FDA approval, may cause patient injury for marketing purposes.

The primary marketing objectives of seeding trials are hidden from the public, the medical profession, and institutional review board members, preventing them from making a fully informed decision about the balance of benefits and harms to themselves and society.

The importance of the article by Hill et al, in my humble opinion, goes beyond its clear demonstration that seeding trials do exist. The article demonstrates how clinical research may be twisted into marketing. The article demonstrates how an ostensibly scientific endeavor may be based on deception, when science is supposed to be about the pursuit of truth. The article demonstrates how the ethos of the huckster has replaced that of the physician in large organizations once regarded as ethical.

Once again, this is a reminder that patients, physicians and policy makers must be extremely skeptical of clinical research sponsored by organizations which have something to gain if the research turns out a certain way. Furthermore, it is a reminder to physicians that generous offers from organizations selling products, services or ideologies do not arise from altruism.

As Sox and Rennie suggest, physicians should "just say no" to seeding trials. Maybe it is time for society to "just say no" to letting those with products to sell run experiments on humans to test them.

See also comments on Alison Bass' blog, Clinical Psychology and Psychiatry, GoozNews, PharmaLot, Retired Docs Thoughts, See interviews with authors of the Annals article on the Carlat Psychiatry Blog and PharmaLot.

ADDENDUM (25 August, 2008) - See also comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

References

1. Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med 2008; 149:251-258. Link here.

2. Sox H, Rennie D. Seeding trials: just say "no." Ann Intern Med 2008; 149: 279-280. Link here.

3. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, et al. ADVANTAGE Study Group. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003;139:539-46. [Abstract/Free Full Text]

Another Example of Manipulation of Clinical Research (Vioxx Department)

We have posted frequently about manipulation of clinical research by those with vested interests in having the research turn out a certain way. (Try clicking on the label "manipulating clinical research" below.) A recent JAMA article, companion to the article on ghost writing and guest authorship which we have already discussed, provided another vivid example of the manipulation of clinical research. [Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA 2008; 299: 1813-1817. Link here.]

Basically, the article was a case-study of how mortality results of trials of rofecoxib (Vioxx, by Merck, now off the market) were reported. The article focused on two clinical trials, 078 and 091, and compared results reported in publications, reported to the FDA, from the commercial sponsor's own analysis, and from an independent analysis of the original data done by an author of the JAMA article.

Our major interest is the manipulation of research as reported in the clinical literature (because published results are what are most available to physicians, other health professionals, and patients to provide evidence used in clinical decision making). So we will focus on these results.

Here is how the published reports of these trials discussed mortality (quoting from the JAMA article), first for study 078:

'A total of 39 deaths occurred in patients who were taking study treatment or from fatal adverse events that started within 14 days of the last dose (24 or 3.3% for rofecoxib and 15 or 2.1% for placebo). . . . There were an additional 22 deaths in the off-drug period (17 in patients assigned to rofecoxib and five in patients assigned to placebo); 12 of these (11 in the rofecoxib group and one in the placebo group) occurred more than 48 weeks after treatment discontinuation.' The report also states: 'In addition to evaluating efficacy, the present study provided important placebo-controlled data on the safety of rofecoxib 25 mg over periods of up to 4 years in an elderly population. . . . Rofecoxib was generally well tolerated by the elderly patients in the study, consistent with results from prior clinical studies in osteoarthritis (Langman et al, 1999; Reicin et al, 2002) and AD (Reines et al, 2004). The overall incidence of adverse experiences, serious adverse experiences, and discontinuations due to adverse experiences were [sic] similar or only slightly increased for rofecoxib vs placebo.' The overall impression created by this report, for which 8 of 11 authors are employees of the sponsor, is that rofecoxib was 'generally well tolerated.'

And for trial 091:

'There were no drug-related deaths during the study. Non-drug related deaths occurred in 11 patients (9 in the rofecoxib group and 2 in the placebo group) while taking study treatment or within 14 days of the last dose.' Deaths that may have occurred more than 14 days after the last dose were not reported. Regarding safety, the authors conclude that 'Rofecoxib was generally well tolerated by the elderly patients in our study, which is consistent with results from previous clinical trials in patients with osteoarthritis.'

Note that the reports both mentioned that there were more deaths in the group of patients who took rofecoxib, but did not analyze these results for statistical significance, and found no importance in these results.

Here are the results of the sponsor's own intention to treat analysis, which was done in 2001, and not sent to the FDA until 2003.

Study Rofecoxib Mortality Placebo Mortality Hazard Ratio (95% CI)
091 13/346 3/346 4.43 (1.26-15.53)
078 21/723 9/732 2.55 (1.17-5.56)

Note that in both trials the death rates were statistically significantly higher for patients taking rofecoxib compared to placebo.

And the JAMA author's independent analysis of data combined from both trials showed a total mortality of 57/1069 for patients treated with rofecoxib, 29/1074 for those on placebo, and a hazard ratio of 2.13 (1.36-3.33).

Thus, it appears that the two published trial reports minimized the drug's apparent relationship to mortality by failing to do an intention-to-treat analysis, and in fact failing to do any analysis of the mortality data.

This is just the latest (but certainly one of the better publicized) examples of how commercial sponsors of clinical research may manipulate the design, implementation, analysis, and/or dissemination of results of studies to further their vested interests.

This is bad for patients because clinical decisions supposedly based on apparently the best data from clinical research may be distorted by such manipulation.

This manipulation also betrays the trust of research subjects who volunteered to participate thinking that the results of the research were meant to further science and patient care. Instead, the manipulation of clinical research means that its results may really mainly further the marketing of the sponsors' products or services.

As the JAMA authors concluded,

The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary. A clinical trials system in which sponsors fund the trials that are conducted by independent investigators would provide additional protections.

In my humble opinion, continuing revelations about suppression and manipulation of clinical research suggest that all such research ought to be done by truly independent investigators who have no financial or other entanglements with organizations with vested interests in the research turning out a certain way.

Ghosts Come Home to Roost

We posted quite a bit starting in 2005 about ghost-writing (see post here with links backward).

Back then it became evident that a particularly pernicious type of ghost-writing was much more prevalent than anyone seemed to realize.This sort of ghost-writing has several important elements.

• Commissioned by Those With Vested Interests - The writing is commissioned by an organization with a vested, usually commercial interest, e.g., a pharmaceutical company.
• Directed to Support Vested Interests - The ghost-writer, perhaps a free-lancing medical writer or employee of a medical communication company, writes an article meant to support that organization's interest, often by setting the stage for the organization's new products. For example, a pharmaceutical company about to market a new drug may commission articles that makes the condition for which the drug is used seem particularly common or important, or which emphasizes the negative aspects of current treatments.
• Fronted by an "Expert" - Finally, an expert, often a well-known academic, agrees to become the article's ostensible first author.

In 2007, we posted to summarize an article on ghost writing which appeared in respected, but not widely circulated journals. Moffatt and Elliott made two clear points:

• Ghost writing is common.
• Ghost writing is wrong.

They also suggested some important things that ought to be done.

• Universities need to treat the practice of signing on to ghostwritten journal articles as a case of academic misconduct.
• Lawyers should start naming ghostwriters and sham authors as defendants in litigation against the pharmaceutical industry.
• There needs to be a standing committee, task force, or office with an established institutional home whose job is to gather information about potential cases of ghostwriting, to sanction authors who have been determined to participate in ghostwriting, and to disseminate information about ghostwritten papers to the public.
• There needs to be an effective strategy for identifying and discouraging ghostwriting.

Of course, this issue got little attention, and none of the measures noted above were implemented. Until yesterday....

Yesterday, a major article appeared in JAMA which described a case-study of ghost authorship and ghost writing of publications related to the drug rofecoxib (Vioxx, Merck, now withdrawn from the market) that used internal company documents made public in the course of litigation about alleged injuries due to Vioxx. [Ross JS, Hill KP, Egilman DS, Krumholz HM. Ghost authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 2008; 299: 1800-1812. Link here.]

This article should be required reading not just for anyone interested in ghost writing, but for anyone concerned about what has gone wrong with health care. The main points of the paper were:

Merck used a systematic strategy to facilitate the publication of guest authored and ghost written medical literature. Articles related to rofecoxib were frequently authored by Merck employees but attributed first authorship to external, academically affiliated investigators who did not always disclose financial support from Merck, although financial support of the study was nearly always provided. Similarly, review articles related to rofecoxib were frequently prepared by unacknowledged authors employed by medical publishing companies and attributed authorship to investigators who often did not disclose financial support from Merck.

The authorship pattern observed within these documents suggests there was a widespread practice of inappropriately attributing authorship to academic authors and a failure to disclose relevant financial relationships.

Unlike the stories of ghost authorship we discussed in 2005, the JAMA article got a tremendous amount of press coverage. I should note that this included some rebuttals from Merck and some of those identified as "front" authors by the JAMA article. Here is a sampling, first of the authors:

The fact that the draft was written by a Merck employee for later discussion by all the authors does not in of itself constitute ghostwriting [Dr Louis Kirby, identified as an added academic author of one article, quoted by Stephanie Saul in the NY Times.]

But Steven H. Ferris, a neuropsychologist at New York University School of Medicine who is listed as the second author, said [the charges of ghost authorship were] ... not true. He said he was on a committee that reviewed the clinical records of 195 patients who received diagnoses of Alzheimer's during the study -- a task that took many hours, and for which he was paid.

'I was directly involved in a very substantive way,' he said this week. 'If an entity like JAMA is going to make an effort to expose a problem, they better get their facts straight. It is harmful if they don't.' [per the Washington Post.]

Having had a 20 plus year previous career in academic medicine, I can state with conviction that first, second, and third authors of major research papers published in important journals are expected to have been the people who conceived, designed, and implemented the study, analyzed its results, and were primarily responsible for the interpretation of thse results. Note that neither "author" above described his role in the trial in such terms.

Most of Merck's initial response seemed to come from its lawyers, for example,

A spokesman for Merck's legal team dismissed the JAMA authors as 'people in the pay of trial lawyers.' [per the Washington Post]

[James] Fitzpatrick, Merck's attorney, said: 'It is correct that Merck would sometimes use an outside company to compile the literature in a field and do the first draft, much the way a professor would use a research assistant to do the same thing.' [Per the Washington Post.]

Jim Fitzpatrick, a Merck outside lawyer, said the company agrees that authorship and financial relationships should be properly disclosed. The company adopted guidelines in 2003 to commit to further transparency in its publications, he added. Merck acknowledged that it sometimes worked with outside medical writers 'to facilitate the publication' of the studies, but said academic researchers 'were involved with the drafting and review of the papers that bear their name.'

Merck research chief Peter Kim said, 'We are disappointed that such false and misleading statements about Merck from trial lawyers have made their way into a medical journal.' [per the Wall Street Journal.]

A Merck legal spokesman said the company sometimes uses outside companies to draft articles that summarize research on its drugs. 'That's a common evolving practice in the industry,' said spokesman Kent Jarrell.

'We do not consider that ghostwriting,' added Jim Fitzpatrick, lead counsel in Merck's defense against numerous lawsuits over Vioxx. He said the company expects that the person recruited to sign the article 'would carefully review and make sure that the paper accurately reflected his or her scientific opinion.' [per the Boston Globe.]

Note that none of these responses provided anything concrete to refute the major points of the article, that Merck or MECCs in its pay found "front" authors for the clinical trial report articles who were not, in fact, the people who conceived, designed, and implemented the trial, and analyzed its results and crafted their interpretation. Doing minor edits of a draft someone else writes does not an author make.

The Ross et al article was accompanied by an editorial by the Editor in Chief and Executive Deputy Editor of JAMA [DeAngelis CD, Fontanorosa PB. Impugning the integrity of medical science: the adverse effect of industry influence. JAMA 2008; 299: 1833-1835. Link here.]

Its main conclusions were:

The profession of medicine, in every aspect—clinical, education, and research—has been inundated with profound influence from the pharmaceutical and medical device industries. This has occurred because physicians have allowed it to happen, and it is time to stop.

What are the lessons from the 2 articles in this issue of JAMA, from other publications that have examined related issues, and from extensive experience with how clinical research has been manipulated by for-profit companies? First, manipulation of studies and misrepresentation of study results could not occur without the cooperation (active and tacit) of clinical researchers, other authors, journal editors, peer reviewers, and the FDA. Second, public trust for clinical research is in great jeopardy especially when the extent of how widespread such practices have become is unknown. Although we truly believe that the vast majority of researchers and other authors are honest and have the highest scientific integrity, manipulation of studies and publications by the pharmaceutical and medical device industries is either increasing or there has been more exposure of these practices. Third, in addition to clinical research, clinical practice and medical education also are greatly influenced by for-profit companies. Drastic action is essential, and cooperation of everyone involved in medical research, medical editing, medical education, and clinical practice is required for meaningful change to occur.

Some of the press coverage included more vivid comments by DeAngelis.

I consider that being scammed. [Referring to ghost written article in JAMA, per article by Stephanie Saul in the New York Times.]

The manipulation is disgusting. I just didn't realize the extent. We're the ones who have allowed this to happen. Now we've got to make it stop. [per the AP.]

[Ghostwriting is] a terrible form of prostitution. We've given up the profession. We've got to get it back. [Per the Philadelphia Inquirer.]

DeAngelis and Fontanarosa had a list of 11 detailed action items, many of which were relevant to those suggested by Moffatt and Elliott above. However, item 11 was radical.

Individual physicians must be free of financial influences of pharmaceutical and medical device companies including serving on speaker's bureaus or accepting gifts.

Maybe this time someone will be listening.

We on Health Care Renewal have been talking for years now about how clinical research and medical education have been influenced and manipulated to promote vested interests. It now appears that a substantial portion of the clinical evidence base and a substantial amount of medical education have been so undermined.

Dr DeAngelis is right. We have given up medicine and now we have got to get it back. If we don't, we will be left with unimaginably expensive health care that does little good except to the pocket books of the well connected.

ADDENDUM (16 April, 2008) - On the PharmaLot blog, Ed Silverman noted that Dr Ferris (see above) seemed to have trouble recalling his actual role in the Vioxx trial. Also on that blog, Ed Silverman noted that Senator Grassley is looking into the role of one of the MECCs mentioned in the Ross et al article.