Ethics: April 2008 Archives

Damn, kids. Just say "no" to free tuna hoagies.

That's the recommendation from a task force created by the Association of American Medical Colleges. The report proposes that any gifts from pharma—including food, medical instruments, or ghostwriting services*—should be banned from all US medical schools. And because a large chunk of medical-school education takes place within affiliated hospitals, the proposal would logically extend to these training sites as well.

The task force included representatives from medical academia and organizations concerned with medial education (the AMA and ACCME), but pharma input was also represented by Pfizer CEO Jeff Kindler, Amgen CEO Kevin Sharer, and former Lilly CEO Sidney Taurel. The task force was chaired by P. Roy Vagelos, MD, a former Merck exec.

While seemingly happy agreements were achieved on most of the task force's recommendations, Kindler and Taurel specifically objected to the report's proposal that faculty be discouraged from participating in industry-sponsored speakers' bureaus. These programs typically involve the "training" of scores of key opinion leaders (a term often loosely applied) to give talks to their regional collegues by using industry-supplied slide decks. Robert Alpern, MD, dean at Yale, likened the practice (and the Pathophilia blog agrees with him) to "ghost talking," according to today's NYT. The practice creates a conflict of interest much more egregious than whatever comes with hoovering a free sandwich on the fly.

*Gifts thoroughly enjoyed by preceding generations of medical trainees and/or their faculty.

Photo: iStockphoto.

The contaminant identified in recalled lots of heparin, an oversulfated chrondroitin sulfate with a tetrasulfated disaccharide repeat, has not been isolated to date from animal tissues, according to data published online yesterday in Nature Biotechnology. Investigators suggest that the contaminant was, therefore, intentionally introduced into the product.

Other important information from the article:

• Synthetic tetrasulfated disaccaride repeat units of chondroitin sulfate exhibit antithrombin activity, which probably explains how the contaminated heparin passed an activity screen, such as a whole-blood coagulation test.
• The contaminant is structurally identical to Arteparon,* an intramuscular drug that was marketed in Europe for the treatment of individuals with degenerative joint disease. Arteparon has been shown to induce an allergic-type response and was withdrawn from the market because of patient deaths, most likely due to thromboembolic complications.

*As far as I can tell, Arteparon is identical to Adequon, which is marketed by Novartis for canine arthritis and by Luitpold for equine joint disease.

The contaminant in recalled heparin lots appears to trigger hypotension and other adverse reactions by activating the kinin-kallikrein pathway and generating anaphylactoid complement proteins. Testing of the isolated contaminant, oversulfated chondroitin sulfate, and a synthetically generated version on human plasma and in pigs was reported in today's NEJM.

Among the most intriguing findings was the fact that not all animals treated with the contaminated heparin developed adverse clinical signs; however, all treated animals demonstrated activation of kallikrein. On the basis of this observation, the authors speculate that some patients who received the tainted heparin, such as those undergoing dialysis, may have been more vulnerable to the contaminant's contact-system-induced hypotensive effects, because of concurrent exposure to the dialysis membrane (which also activates the contact system) or treatment with ACE inhibitors (which block bradykinin degradation).

The authors conclude that a simple in vitro bioassay that assesses kallikrein activity, in addition to more sophisticated analytic tests, will aid the screening of heparin lots for oversulfated chondroitin sulfate and other polysulfated contaminants.*

*Dermatan sulfate, a known heparin impurity, was found in most of the contaminated lots; however, the compound's presence was not associated with kallikrein activity.

From the AP by way of the WSJ: A junior high school student in Kentucky was arrested and charged with felony wanton endangerment after planting crumbs from a peanut-butter cookie in an allergic classmate's lunchbox.

The Pathophilia blog believes that this kind of bullying would happen less often if "peanut" didn't sound so funny.

According to the AP, the FDA said yesterday that there is a "solid link" between the hundreds of allergic reactions and now 81 deaths associated with Baxter's recalled heparin and a contaminant, identified as oversulfated chondroitin sulfate. The FDA statement is a response to a Chinese official's claim that the contaminant could not be the source of the adverse reactions, because some batches of the implicated heparin did not contain it. The FDA also responded that this claim is based on false assumptions.

Baxter's heparin supplier, Wisconsin-based Scientific Protein Labs, said in related news, "It is now clear that the suspect contaminant was introduced earlier in the supply chain in China and was widespread throughout the unrelated Chinese supply chains of many companies." SPL owns a Changzhou plant, which buys its crude material from Chinese heparin "workshops." The plant was cited by the FDA in February for a number of "significant deviations" from good manufacturing processes.

The FDA publicly released its warning letter to SPL's Changzhou facility yesterday, which included the following admonishments:

• There is no assurance that processing steps used to manufacture heparin sodium, USP are capable of effectively removing impurities.
• You fail to have adequate systems for evaluating the suppliers of heparin crude materials, and the crude materials, themselves, to ensure that these materials are acceptable for use.
• Equipment used to manufacture heparin sodium USP is unsuitable for its intended use.

A Chinese health official* said today that the oversulfated chondroitin sulfate found in batches of Baxter's recalled heparin could not have caused the reported allergic reactions and deaths, because only some of the implicated batches contained the contaminant. In a weird turnaround, Chinese health officials state that they will visit Baxter's plant in New Jersey, presumably for inspection purposes. Baxter has numerous manufacturing facilities worldwide, including one in Cherry Hill, NJ.

Source: Reuters

Update: The Philly Inquirer reports that, in February, the FDA inspected Baxter's 372,000-square-foot facility in Cherry Hill, NJ, and observed no infractions.

*Jin Shaohong, deputy director-general of the China National Institute for the Control of Pharmaceutical and Biological Products.

The president of the American Medical Writers Association (to which I belong) has written to its members (below) regarding the practice of medical ghostwriting, and AMWA's response to the NYT article about Merck's use of guest authoring and ghostwriting has been printed. I agree with AMWA's assessment.

Hello, AMWA colleagues,

As many of you have been discussing, the articles in this week's JAMA about alleged misuse of medical writing resources by Merck in publications about Vioxx garnered a lot of press coverage. As is often the case, the JAMA articles and the associated press coverage tend to blur the distinction between "guest authorship" (putting an author's name on an article he/she did not help to write) and the unacknowledged use of medical writers (ghostwriting, a term AMWA tries to avoid). A number of people have asked whether AMWA should do something.

Several of us saw this as an opportunity to assert AMWA's leadership in promoting ethical practices in medical writing. Accordingly, we have submitted letters to the editors of the NY Times, Philadelphia Inquirer, and Chronicle of Higher Education, all of which carried stories about the JAMA articles. All letters are signed by me as AMWA president.

Key points in all the letters:

• While ghostwriting (the undisclosed contribution of a medical writer) is unethical in scientific publications, the use of professional medical writers may be appropriate and ethical.
• Using their skills in communicating complex data, professional writers help researchers report their findings effectively, making contributions comparable to those of professional statisticians who analyze data or artists who create illustrations.
• The 5500-member American Medical Writers Association promotes ethical practices in scientific publication, including acknowledgment of medical writers' roles, adherence to applicable guidelines (eg, authorship rules of the International Committee of Medical Journal Editors), and full disclosure of potential conflicts of interest, including financial support.
• Transparent disclosure of the roles of all contributors avoids ghostwriting and allows readers to evaluate the credibility of research reports.

We're also drafting a response to JAMA. We'll keep you posted to let you know if these letters are published. In addition, Lori Alexander will include an editorial in the summer issue of the [AMWA] Journal, bringing these issues to members' attention.

Best regards,
Sue Hudson

The NIH's National Institute of Child Health and Human Development is offering a calculator to estimate the outcomes for very preterm infants, reports the NYT. The calculated outcomes are based on gestational age (22-25 weeks), birth weight (401-1000 g), sex (girls inexplicably fare better than boys), singleton or multiple birth status, and the mother's receipt of antenatal corticosteroids within 7 days of delivery (to boost infant-lung development). Outcomes are provided for all infants and those who receive mechanical ventilation and include chances of survival with various grades of anticipated neurologic impairment.

The calculator is based on a study of nearly 4500 very preterm infants at a network of hospitals and is intended to aid the decisions of healthcare workers and families regarding levels of care.

Thanking God and Catherine DeAngelis (and trying not to confuse the two), the Pathophilia blog embraces the opportunity to post about something other than the ENHANCE study.

I'm referring to the already-heavily-blogged-about case study in today's issue of JAMA, which examined Merck's use of academic guest authors or contract ghostwriters. The study's authors were consultants for the personal-injury attorneys in the Vioxx-related litigation against Merck and therefore had access to the drugmaker's internal documents (which are now publicly available here).*

A primary conclusion of the case study is that Vioxx clinical-trial manuscripts were initially authored by Merck scientists, but that first authorship was later attributed to recruited, university-affiliated physicians—presumably to lend academic credibility or cache to the published studies. The numbers are difficult to pin down, but the JAMA case study identified 24 clinical-trial articles from 1999 on (which are referenced in a detailed table) and highlighted a few studies in the text, including an Alzheimer's trial that was not listed in the table (Thal LJ et al. Neuropsychopharmacology. 2005;30:1204-1215). Elsewhere, the authors identify 16 of 20 clinical-trial articles that were initially drafted by a Merck employee but were then published with an academically affiliated first author. In these cases, the Merck author was typically bumped to an anchor position.

The study authors also described documents revealing the outside contracting of a ghostwriter for one Merck study, "A randomized, placebo-controlled, parallel-group, double-blind study to evaluate the safety and efficacy of rofecoxib 25 mg and celecoxib 200 mg in patients with osteoarthritis of the knee or hip." However, a citation for the published article is not found. (The JAMA case study suggests that medical ghostwriting is, not surprising, more prevalent when creating review pieces.)

Although the intentions of the case-study authors may be well placed, it is troubling that they did not seek direct responses from Merck scientists or the cited academic authors before JAMA's publication of the piece—which is really more of a journalistic-type exposé than any report of scientific merit. (A few of the implicated academics have taken their umbrage to the NYT and other press outlets.) Also, in the full spirit of disclosure, the authors should have revealed their compensation as a result of the Vioxx litigation. If financial relationships with relevant drug manufacturers should be disclosed, then so should financial relationships with relevant plaintiffs' firms. 

*Evidently at the insistence of JAMA's chief editors, if DeAngelis and Fontanarosa are to be believed.

Forehead-slapping insights like these explain why Andrew von Eschenbach's head of the FDA and you're not.

From an April 11 report at Connecticut's TheDay.com:

• Hesketh is currently being held at a Rhode Island detention center after being arrested by Federal agents on March 26 for possessing, receiving, and distributing child pornography. According to Federal agents, Hesketh and a Buffalo, NY, deli worker exchanged 85 pictures, which included infant molestation, during at least one "chat" session. Hesketh reportedly told Federal authorities that he conducted his child-porn activities, under the female persona of "Suzibibaby," at his New London home, at work, and on business trips. During travel, Hesketh allegedly carried more than 1000 child-porn images on 3 compact flash drives.
• Hesketh was hired by Pfizer 6 years ago and was fired as patent director from the company on March 28. Without commenting specifically on Hesketh's case, Pfizer spokesperson, Liz Power, was reported to say that "the company does not allow employees to use computer resources or systems that contain or promote abusive or objectionable language or information that is illegal or obscene." "[A] number of technical controls block objectionable web sites, prevent peer-to-peer file sharing, and remove unapproved software," according to Power, and she indicated that "systems" are scanned several times a year.
• Hesketh, a British citizen, was denied bond after the judge learned that he owned multimillion-dollar properties throughout the world.
• A motion filed April 4 indicates that Hesketh's attorney and the US Attorney's office are negotiating a plea deal. A probable cause hearing that was scheduled for April 10 did not take place.
• According to a spokesperson for the US Attorney's office, most of those convicted in child-porn cases are sent to prisons that have medical hospitals with sex-offender programs; the 2 named were Devens in Ayer, MA, and Butner in North Carolina.
• Hesketh, 61, has been married for 39 years and has 4 adult children and 5 grandchildren. According to Hesketh's wife, the couple are "on the verge of divorce." Reports indicate that she has known little-to-nothing of their finances.
• Before working for Pfizer, Hesketh was an executive at then Glaxo Wellcome in England.

This afternoon's WSJ Health Blog provides access to drafts of after-the-fact "minutes" from the November 2007 meeting of independent reviewers of the ENHANCE study data. The draft documents, which include inserted comments from imaging expert James H. Stein, MD, were originally obtained by a Congressional subcommittee, according to the WSJ blog. Many of Stein's comments relate to the integrity and quality of ENHANCE's image database, which he concluded was "not acceptable." The image database resided at Amsterdam's Core Echo Laboratories (CEL), which is directed by ENHANCE's primary investigator John Kastelein, MD, PhD.

A few excerpted comments from Stein:

The imaging and reading protocols in ENHANCE were suboptimal even relative to methodologies employed at the time the study commenced and relative to procedures in clinical and epidemiological studies conducted in the 1990s.

We did not state the data and analysis "are reportable."

When we looked at images and considered the CIMT [carotid intima-media thickness] values of individual subjects over time, almost all the examples we saw showed measurement errors, biologically implausible measurements, biologically implausible changes in CIMT measurements, and/or failure to adhere to the protocol.

Great concern was expressed that the aggregate values may look reasonable, but that they may not reflect reality.

The concerns about unreported and later updated file segments were serious. I recall that I and other panel member[s] specifically stated that we could not determine if the database was "clean and credible" based on the information presented.

It is my recollection that there also were concerns about data management, such as the existence of data files with measurements that either were not entered into the official measurement database or that reflected more "recent" measurements than those in the measurement database. A statement should be inserted here that reflects concerns about the integrity of the data [which] was part of the reason for convening the expert panel. 

It is also revealed in the documents that data for 485 of 640 (~76%) subjects in ENHANCE were missing, and that data for 75 (~12%) subjects were biologically implausible (defined as >0.1-mm CIMT change between baseline and endpoint).* Because the missing data for the common carotid artery were considerably less, either 3% or 8% (depending on which source you take), it was suggested that the primary endpoint might be changed to the CCA measurement.

*The Pathophilia blog has repeatedly expressed its frustration that the volume of missing or implausible data, which would certainly undermine the integrity of and conclusions from the ENHANCE study, had not been revealed. 

Moving through this morning's pharma blogosphere is an AP story describing the responses of some drug or medical-device companies to Senator Chuck Grassley's request that they disclose their CME funding to outside groups. The current industry model is that of Eli Lilly, which provides a highly itemized (and therefore, very difficult-to-synthesize) online grants registry report for each financial quarter of 2007.

Among the companies' soup-to-nuts replies to Grassley:

• Medtronic will post payments for professional meetings and patient groups on May 1 (no mention of funds to medical communications companies);
• AstraZeneca will do the same on August 1;
• Merck is "currently in the process of developing an action plan";
• Amgen and Abbott have formed "working groups"; and
• nose-thumbing Schering-Plough reports that it has no plans "at the moment" to publish the requested information.

Today's WSJ Health Blog notes that Grassley's also sponsoring the Physician Payments Sunshine* Act of 2007, which will require quarterly reports from drug or medical-device companies to the DHHS regarding payments made to individual physicians or their employers.

CME = continuing medical education.

*As in, blow sunshine up my...?

The FDA reports today that more than $100,000 worth of nonprescription Chinese "natural supplements" for erectile dysfunction were seized because they contain sildenafil, the active ingredient in Viagra, or a sildenafil analog. The seized products—Shangai Regular, Shangai Ultra, Super Shangai, Naturalë Super Plus, and Lady Shangai—originated in China and were packaged and distributed by a company in Puerto Rico.

Prompted by a consumer complaint, the FDA conducted an inspection of the Puerto Rico distributor in November 2007, at which time the products' active ingredients were discovered; however, the products' labels did not list sildenafil or the sildenafil analog. An FDA press release in December advised consumers not to purchase the drugs, which were embargoed by the Puerto Rico Department of Health before the seizure.

On February 15, The Netherlands Health Care Inspectorate reported its identification of large doses of tadalafil (Cialis), vardenafil (Levitra) and acetildenafil (an analog of sildenafil) in imported Chinese "herbal" impotence pills. Since 2003, the FDA has recalled a number of nonprescription sex-enhancement pills because they contained undeclared tadalafil, vardenafil, sildenafil, or chemical analogs.

Physicians in Leipzig, Germany, identified lead intoxication in 29 regular smokers of marijuana, according to correspondence in the latest issue of the NEJM. Elemental lead was discovered by means of atomic absorptiometry or plain-old eyeball (left) in partially used weed samples from 3 of the affected users. It is believed by authorities that the lead was deliberately cut into the marijuana to increase its weight and therefore the profits from a street product that is sold by the gram. The lead is thought to be easily absorbed through the respiratory tract, once the tainted marijuana is smoked.

Photo: Close-up of partially used dime (euro) bag of marijuana with visible, grayish lead particles from the NEJM.

In response to criticism (mainly in the WSJ) that Harlan Krumholz, MD, unfairly monopolized Sunday's ACC panel discussion of the ENHANCE study, which recommended that Vytorin be relegated to last-resort cholesterol management, the Yale cardiologist fired back yesterday in a blog post to Pharmalot.

"We [the 4-physician panel] were asked to comment on the ENHANCE study and discovered over the course of several weeks of discussion that we had a clear consensus about the recommendations for practice. My comments reflected that consensus," reads an excerpt.

Others on the ACC panel, who have not yet chimed in publicly one way or the other, were Joseph Messer, MD, Rick Nishimura, MD, and Patrick O’Gara, MD, whose selection for discussion of the ENHANCE study at the ACC was questioned by Schering-Plough CEO Fred Hassan. However, criticism of the panel generally and that of Krumholz specifically are not limited to SP insiders like Hassan or chief medical officer Robert Spiegel. A Sanford Bernstein analyst reported to the WSJ that the panel discussion "was essentially not a panel discussion at all, but rather a monologue by Dr. Harlan Krumholz, who was very negative on Vytorin."

Another legitimate criticism from Hassan, a criticism which has nevertheless been cast in a negative light by Pharmalot's Ed Silverman, is the lack of allowed participation by the ACC audience to specifically question the ENHANCE results and the panel. Such an open forum would have (or, at least, should have) raised the issue of the missing or implausible data in the ENHANCE study and their effect on the trial's validity.

Image: The SNL Archives.

Today, the WSJ Health Blog provides access to an entire thread of e-mails sent during July 2007 (~3 months after Carrie Smith Cox sold $28 million worth of SP stock) between the ENHANCE study's primary investigator John Kastelein, MD, PhD, and SP's John Strony, MD (IMPROVE-IT study director), and Enrico Veltri, MD (ENHANCE study director)—all of whom express their various frustrations with the protracted examination of the ENHANCE study data. The thread is the original courtesy of SP, in its attempt to provide balance to the excerpted Kastelein e-mails provided by Senator Grassley. The Pathophilia blog, given its love of chronology (chronophilia?), provides an abridged, interpretive version of the e-mail exchange in temporal sequence. One lesson from the publication of the thread: Be careful who you dis in professional e-mails.

 

07/06/07, Kastelein to Strony: While on vacation, Kastelein is awfully pissed to learn (presumably from an e-mail sent by Strony) that SP has decided not to present the ENHANCE study results at the upcoming scientific sessions of the AHA in November—especially without consulting Kastelein first. (The deadline for abstract submission was June 1, and that for late-breaking clinical trials was June 29.) Kastelein threatens to terminate his collaboration with the company and to "take appropriate steps" to contact the editors of "major journals" and the FDA—the ultimate, but vague, "Dear John" letter (hey, literally and figuratively) of any academic PI.

 

07/06/07: Strony responds to Kastelein with a somewhat conciliatory e-mail, indicating his best efforts to contact Kastelein by other means and explaining the decision by SP and Merck execs to hold on the submission of the ENHANCE study results to the AHA. Strony itemizes a number of problems with the processing of the ENHANCE data: The primary, carotid data are undergoing a "query process," and the consolidation of the data into a "commercially available, validated system" from scattered sources (eg, various computers, laptops) chewed up weeks. In addition, the auditing of the image database was stalled, when 150 "extraneous image values" were identified in a particular batch. Strony also advises that SP's standard operating procedures forbid the "locking and relocking" (presumably the unblinding and reblinding) of any database. He concedes that ENHANCE is the "trial from hell."

 

07/07/07: Still miffed and frustrated, Kastelein responds to Strony and cc's Veltri (aka Rick), indicating that Merck had cleared Kastelein to say publicly that the ENHANCE results would be presented at the AHA. Fearing the perception of colluding with SP to hide or manipulate the ENHANCE data with dilatory tactics, Kastelein writes, "[Y]ou will be seen as a company that tries to hide something and I will be perceived as being in bed with you."

 

07/09/07: Veltri now writes back, explaining to Kastelein that the decision to delay the presentation of the ENHANCE study results was essentially his (and that of his Merck counterpart, Elizabeth Stoner, MD [who has since left Merck]), so that the quality of the data could be ensured. Veltri reminds Kastelein that they've had a discussion about data-quality issues before and chastises, "I do not see what you are raging about," with respect to Kastelein's threat to contact journal editors and the FDA. Veltri also essentially reinforces Strony's explanation for the delayed processing of the ENHANCE data to ensure integrity: "[W]e must work together to complete the outstanding database cleanup and readings in a rigorous manner and not short cut for the sake of presentation." However, Veltri doesn't discount the possibility of submitting the ENHANCE data, if available, for the AHA meeting, even after the "late-breaker" deadline.

 

07/13/07: Not entirely appeased, Kastelein responds to Veltri (and cc's Strony) by reiterating his frustration and lack of control over the ENHANCE study. He also expresses dissatisfaction with several study consultants, including Gene Bond (presumably M. Gene Bond, PhD), and adds that he is "constantly under pressure" from Merck (not SP, notably) to plan activities before, during, and after the AHA meeting.

Prompted by continuing coverage of the controversial ENHANCE study—including a recent letter fired off by Senator Chuck Grassley to the CEOs of the study's sponsors, Merck and Schering-Plough—the Pathophilia blog engages in another exercise that illustrates the chronology of SP's stock price, insider transactions, and important events in the ENHANCE study timeline.*

The years preceding 2006 are shown primarily to illustrate what may have been normative insider trading, during a time when the quality of the ENHANCE study data had not been realized. The most intriguing event revealed from this investigation (which may only be news to me, but at least I'm providing semi-colorful graphs) is the inordinately large sale or exercise of stock options taken by 3 SP officers from April 20, 2007, to May 21, 2007—at a time when SP's share price was at an all-time high since 2003, but also when independent contractors were wrestling with the now-recognized data-quality problems of ENHANCE.

According to these insider-transaction data, Carrie Smith Cox, Brent Saunders, and Ron Cheeley sold a little more than $32 million and exercised stock options to the tune of $19 million during this time period. Carrie Smith Cox sold the lion's share of stock for $28 million (as has been previously reported) and exercised $16.5 million in stock options.

2003

2004

2005

2006

2007

CDC = Cholesterol Development Committee, a joint venture of the study sponsors.

*Basic graphs for SP's stock prices were obtained from MSN Money, and insider transactions were obtained from AOL Stock & Finance.