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All the shenanigans that went on in the course of Merck's marketing of the now withdrawn Cox-2 inhibitor non-steroidal anti-inflammatory drug Vioxx have provided grist for the Health Care Renewal mill since 2005.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Merck & Co. agreed to settle shareholder lawsuits over the withdrawn Vioxx painkiller by strengthening its drug-safety procedures, appointing a new chief medical officer and paying $12.2 million in legal fees.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

Boston Scientific (Again) Settles - This Time, Charges of Kickbacks Disguised as Clinical Studies

One would think that the stories about bad behavior by health care organizations would quiet down just before Christmas, but no...

As reported by the AP:

U.S. attorneys in Boston said Wednesday heart device maker Boston Scientific will pay $22 million to resolve allegations its Guidant division paid kickbacks to doctors to get them to use its heart devices.

The U.S. Department of Justice said Guidant paid physicians $1,000 to $1,500 each in 2003 and 2004 to participate in four studies, called RaCE, RaCE II, RaCE III, and MERITS. It said the studies were designed to increase sales of pacemakers and defibrillators.

Federal officials said the company targeted doctors who favored products made by other companies, hoping the payments would induce them to use Guidant devices more often. They said Guidant submitted claims for payment on the devices to Medicare.

Boston Scientific did not admit wrongdoing as part of the civil settlement. Under the agreement, its cardiac rhythm management division will have to publicly disclose payments to physicians on a Web site. Boston Scientific also entered into a corporate integrity agreement.

So here we have an example of a "seeding study," that is, a marketing effort to persuade physicians to prescribe a product disguised as a clinical research study, but for medical devices, not drugs.  Seeding studies seem to combine multiple kinds of unethical behavior, deceptive marketing and manipulated research.  There had been some question in the past whether seeding studies exist, but this is the second recent example to come to light, suggesting that not only do they exist, but that they are used by device as well as pharmaceutical companies.

Note that, as Bloomberg reports, this is the third major settlement of allegations of bad behavior made by Boston Scientific,

The company agreed last month to pay $296 million to settle a Justice Department probe into Guidant’s handling of heart devices and restated third-quarter results. [See post here.] In 2007, Boston Scientific agreed to pay $240 million to settle more than 8,000 lawsuits claiming Guidant hid defects in defibrillators, which are devices that shock the heart back into regular rhythm.

Cataloging legal settlements seems to be a useful way to assess the sorts of bad behavior manifested by large health care organizations (see some posts here). However, as we have said frequently, such settlements, including the "corporate integrity agreements" now frequently attached to them, seem to have done little to deter bad behavior.  Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts will suffer 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.

I submit that would-be health care reformers who want to improve care, reduce costs and improve access should advocate for real negative consequences for people who implement, direct or approve the various versions of fraud, kickbacks, and miscellaneous corruption and malfeasance we have discussed on Health Care Renewal.

By the way, the board of directors of Boston Scientific includes two noted academics with leadership roles in academic health care.  Marye Anne Fox is the Chancellor of the University of California - San Diego, and hence the leader of a major medical school and academic medical center.  The university's mission statement, alongside which sits her picture, proclaims it "strives to maintain a climate of fairness, cooperation, and professionalism." Uwe Reinhardt, Professor at Princeton, is a noted health care economist, and blogger on the Economix blog for the New York Times.  Perhaps such august academic personages could tell  us how they are assuring that the company they are paid well to oversee upholds, rather than undermines professionalism and fairness.

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

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

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]