Ethics: November 2009 Archives

Investigating medical ghostwriting, Senator Chuck Grassley (IA-R), ranking minority member of the Senate Finance Committee, sent a letter to the deans of 10 medical schools, reported the NYT on Wednesday. The text of the 2-page, single-spaced letter was chosen carefully by one or more members of Grassley's staff and then signed by Grassley.

In the Grassley-signed letter (which can be found here), the medical deans are asked to respond to 6 essay-type questions regarding their schools' policies on ghostwriting and plagiarism. The deans will, no doubt, delegate the writing of the responses to administrative minions and then sign their names to the responses no later than December 8th, as requested.

Photo of Senator Grassley from grassley.senate.gov.

On July 6, 2009, for reasons that remain unclear, the Senate Special Committee on Aging sent a letter to Thomas Sullivan, president of Rockpointe Corporation, a private, 18-employee company that produces continuing medical education (CME) programs for physicians. The letter requested "an accounting of funding received by Rockpointe Corporation from pharmaceutical, medical device and biologics companies for three and one-half years from January 1, 2006 to the present."

In his July 20 response to the Committee, Sullivan voluntarily provided the financial information, while requesting that the Committee use "reasonable protection against this information becoming publicly available." Sullivan clarified, "[A]s we have discussed with your Chief of Investigations, Jack Mitchell, the business information provided is proprietary."

Later in his letter, Sullivan expressed confusion about the Senate Committee's specific interest in his private CME company:

It is a concern to us that this letter has been directed to Rockpointe as a result of a group meeting that we initiated with the Aging Committee staff. That initiative was intended to provide information, understanding and insight concerning CME and the proposed Physician Payment[s] Sunshine Act. The meeting, and the required time and preparation, constituted a good faith effort to bring relevant information to the Committee. Our intent was to differentiate accredited CME from promotional marketing. Under the credo of "no good deed goes unpunished," this initiative led directly to your singling us out among the hundreds of similar CME providers to submit confidential business records. We have expended considerable time, expense and professional fees identifying, locating, reviewing and organizing nearly 4 years of business records in order to digest and prepare the accurate summary you requested. An inquiry of his nature will likely discourage other "good Samaritans" from exercising their rights as involved citizens to bring issues of concern to the attention of the committee.

Rockpointe's financial data (and Sullivan's letter) were recently made publicly available through UCSF's Drug Industry Document Archive and reported last week by Alicia Mundy in the WSJ. It is certainly reasonable to conclude that the data were provided to the archive through the Committee (either directly or indirectly), despite Sullivan's request that the confidential information remain confidential.

But I contend that the suspected behavior of the Committee toward Sullivan's company could have been predicted by examining its powerful chief investigator, Jack Mitchell (whom Sullivan mentions in his letter).

John Howard "Jack" Mitchell (who, ironically enough, was a presenter along with Sullivan at the recent National Disclosure Summit in March) is mostly a career government staffer—although he served as an investigative reporter under syndicated columnist Jack Anderson in the late 70s/early 80s and was evidently a CNN correspondent sometime in the mid-90s. But the role that appears to have primarily informed Mitchell's "purpose" (for lack of a better word) is that of Special Assistant for Investigation in the office of FDA commissioner David Kessler. There, during the late 90s, Mitchell worked closely with Kessler on his unsuccessful effort to bring the tobacco industry under FDA control. Mitchell is specifically credited with bringing Jeffrey Wigand, the notorious industry whistleblower and tobacco insider, to the attention of Kessler.* At a symposium of the Association for Medical Ethics in March 2008 at the University of California at Irvine, Mitchell said of his FDA stint, "[T]o some respects, that was one of the best jobs I ever had."

Mitchell's work with Kessler against Big Tobacco can reasonably be expected to inform whatever righteousness he may feel when investigating other industries, including the drug and medical-device industries—which are presently in the sights of the Senate Committee on Aging. (And Mitchell's righteousness as a government reformer could only have been fortified by the recent passage of legislation that now puts tobacco under FDA control.)

However, caution is warranted in dealing with the righteous, particularly crusaders who hold powerful, non-elected government positions. Generally everything's fine if you completely agree with the crusader; however, you're no more likely to convince him that there's more than one side to an issue than you are of persuading Joel Osteen that Jesus was merely a nice Jewish boy. Moreover, if you reveal sufficient differences of opinion to a crusader, and specifically one who happens to be a senior Congressional staffer, you may find yourself the subject of a Senate Committee investigation—as Sullivan discovered.

In language that supports this contention, Mitchell himself displays an authoritarian mindset that merits caution, if not outright distrust. To illustrate, the following are excerpts from Mitchell's speech at the ethics symposium (which can also be viewed here).

When you've done the kind of work I do for so long—as an investigative reporter, a Senate investigator on 2 different occasions, and I've run government investigative offices like Dr. Kessler's—I see that frankly as part of the same thing. Just in different jobs, in different roles. When you do that, you realize that, to some degree, that whether you like it or not, whether you care to admit it to yourself or not, that there's a strong reformist streak within you. And so I tend to seek out people who are like that or see that, and I see that characteristic in them.

And so the most important thing you bring to the table when you try to do effective oversight, you try to change public policy, is you find, you ferret out the people who are capable or who have the courage to do something like that. That's how I found Dr. Jeffrey Wigand and made myself close enough to him that he was willing to come forward to the FDA.

In some cases, Mitchell's language suggests that he thinks he runs the Senate Committee on Aging and is a legislator. For instance, notice his use of "I," "my," and "we," instead of language that would more accurately refer to the Committee or Senator Kohl.

When I did a, when I began our year-long series of hearings last year on conflicts of interest and consultant payments in the medical-device and pharmaceutical industries...

And

So these are all parts of the same things the committee continues to explore as we continue our series of 5 or 6 hearings on these type of conflicts, both in the medical-device and pharmaceutical industries. And we hope to do some more hearings in the fall and into next year in support of a number of pieces of legislation. We're gonna be looking at continuing medical education. We've done a hearing on academic detailing by the pharmaceutical companies. We're going to do some hearings on free drug samples that are given to physicians and medical students and ways to combat that type of influence peddling. And we're going to do some more hearings as necessary on these continuing conflicts in order to deal with them.

And most of that is in support of some legislation you've heard about here...called the Physicians Payment[s] Sunshine Act, which is coauthored by my boss, Senator Herb Kohl of Wisconsin—who is chairman of my committee, the Senate Special Committee on Aging.

And

Now at this point, while we've negotiated this bill very closely with industry and with other parties, it's not clear to me what the fate of the bill will be for this year. We've tried to put it into the Senate Medicare package. We haven't been successful with that to date, and it doesn't appear that's going to happen. We may introduce it as a stand-alone bill with an advisement to industry...

And

One thing you may wonder, for those of you not very familiar with Congressional oversight is, the question of why would we—why would Congress be interested or why would it be any of Congress's business—the type of ethics issues that we're discussing in the medical-device and orthopedic and, as well, pharmaceutical industries. Well the reason is that my committee has jurisdiction over Medicare, and most of the medical-device companies receive a majority of their income from Medicare and Medicaid in many instances—not in all—but many. In fact, many medical-device companies receive the bulk of their income from Medicare reimbursement and Medicaid reimbursement payments. So that provides my committee, at least, with the direct jurisdiction—since we have control of the centers for Medicare and Medicaid in order to make sure and try to be vigilant that our taxpayer dollars, which go into this system—the billions of dollars—are well spent and well protected.

And

We fully intend any legislative efforts that we undertake to include all of those players, not just the large companies. And while it's pretty difficult to establish what I might call a level playing field that is our ultimate goal—we want to establish a regulatory framework that's fair to everybody and includes limits that are not unreasonable for the small companies or for the large companies. And that takes a lot of back and forth and push and shove. And I'm not sure that even the language we have in the legislation now is final or is the final answer to the problems. 

What is also concerning is that Mitchell conveys not-so-veiled threats to companies or organizations that don't cooperate with the Committee.

...[S]hould anyone block the bill's progress...we will come back next year with more oversight hearings and a much more toughly worded bill that we will be much less willing to compromise over or negotiate.

And

I must say that we invited some of the more established surgical professional associations to participate or submit written testimony to our hearing, and they declined. So hopefully, I'm hopeful they will see that the train is leaving the station, and that some of these groups really need to get on board or at least offer some comment and cooperation in terms of the legislative and other proposals which we put forward on the table.

Finally Mitchell discloses that his (or really, the) Senate Committee on Aging is not averse to going after small companies.

The large companies aren't the only players. There are a lot of entrepreneurial small companies who are out there spending a lot of money trying to influence physicians and surgeons and draw them into their sphere of influence. 

* Mitchell is featured prominently in Kessler's book about his anti-tobacco crusade, The Question of Intent.

Thumbnail image of Jack Mitchell from disclosuresummit.com.

Here's something any perpetrator should catch hell for: changing the primary outcome of a trial.*

In studies of gabapentin (funded by Parke-Davis and later by Pfizer) for neuropathic pain, bipolar disorder, or migraine prevention (all off-label uses), the protocol-defined primary outcome was often changed in the published report. This is just one observation of Johns Hopkins investigators after their analysis of internal documents from 20 industry-sponsored gabapentin studies. Their full report is available in the latest issue of the NEJM.

Among the 20 trials assessed, only 12 (60%) were published (see Table); the results of 9 trials were reported as full-length articles. In 8 (67%) of the 12 trials, the protocol-defined primary outcome differed from the primary outcome in the final report. In 6 (50%) studies, a completely new primary outcome was introduced; and in 5 studies, the new primary outcome favored gabapentin treatment.

Article	Statistical Significance Favoring Gabapentin?
Primary outcomes agreed with protocol
Backonja M et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836.	Yes
Backonja M, Mutisya EM. Review of gabapentin dosing in five placebo-controlled clinical trials for neuropathic pain. Eur J Neurol. 2002;9(suppl 2):191.	No
Serpell MG, Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99:557-566.	Yes
Gomez-Perez FJ et al. Gabapentin for the treatment of painful diabetic neuropathy: dosing to achieve optimal clinical response. Br J Diabetes Vasc Dis. 2004;4:173-178.	Yes
Primary outcomes did not agree with protocol
Mathew NT et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-128.	Yes
Wang PW et al. Gabapentin augmentation therapy in bipolar depression. Bipolar Disord. 2002;4:296-301.	Yes
Vieta E et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry. 2006;67:473-477.	Yes
Caraceni A et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol. 2004;22:2909-2917.	Yes
Gorson KC et al. Gabapentin in the treatment of painful diabetic neuropathy: a placebo-controlled, double-blind, cross-over trial. Neurology. 1998;50(suppl 4):A103.	Yes
Wessely P et al. Preliminary results of a double-blind study with the new migraine prophylactic drug gabapentin. Cephalalgia. 1987;7(suppl 6):477-478.	No
Pande AC et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord. 2000;2:249-255.	No
Gordh TE et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain. 2008;138:255-266.	No

Other scientifically unsound behavior included the failure to differentiate between primary and secondary outcomes (2 trials), the relegation of primary outcomes to secondary outcomes (2 trials), and the failure to report 1 or more protocol-defined primary outcomes (5 trials). The Hopkins investigators found that trials with statistically insignificant primary outcomes were more likely to be partially reported or reported with a changed primary outcome.

The internal documents were made available to the Hopkins researchers as a result of ongoing litigation regarding the improper marketing of gabapentin. The anchor author of the analysis (Kay Dickersin, PhD) has served as a paid expert witness in litigation related to gabapentin clinical trials, and the lead author (S. Swaroop Vedula, MD) has received fees from plaintiffs' lawyers.

A study published earlier this week, in the Annals of Family Medicine, revealed that the primary outcomes of randomized studies published in 5 highly regarded journals (including the NEJM), were often changed from those defined in the trials' registry listings. The original primary outcomes of the gabapentin trials were only known through access to internal documents. Dickersin argued to MedPage Today that public registration of industry-sponsored trials should be mandatory to aid the transparency of these clinical studies.

N.B.--In 2004, Pfizer paid a $430-million fine to the government for the off-label marketing of gabapentin (ie, Neurontin).

* Without a darned-good reason.

Earlier this week, the WSJ Health Blog reported on a newly published study by Boston researchers Zinner et al (Participation of academic scientists in relationships with industry. Health Aff (Millwood). 2009;28:1814-1825), who assessed the extent to which academic physicians and other scientists have financial ties with the drug or device industry. The story was also predictably picked up by Ed Silverman at Pharmalot.

The blogs' respective ledes highlighted the finding that about 53% of academic researchers have some kind of financial relationship with industry—an observation plucked from the article's abstract. But if one reads the article, the most face-slapping result, IMNSHO, was the horrifying uniformity of the surveyed respondents: 72% were male, and 77% were white. The ethnic/racial diversity, or obvious lack thereof, is flabbergasting. The only minority represented to any notable extent was "Asian."* Among the 2168 respondents** from clinical or nonclinical "life-science" departments, 22 described themselves as black or African American. That's one percent.

Ethnicity/Race	No.	%
White	1705	77
Asian	314	14
Hispanic, any race	56	3
Declined to report	57	3
Other	47	2
Black or African American	22	1
Total	2201*	100

And it's not as if the survey candidates were cherry picked. The authors selected a random sample of faculty from the life-science departments at the 50 US universities that received the most NIH funding in 2004. Survey responses were collected between December 2006 and March 2007. The findings are, therefore, one hell of an indictment of those making contemporary academic appointments in the life sciences at our top programs.

Unfortunately the authors (who include my favorite, sociologist Eric Campbell) did not address the homogeneity of their survey population; perhaps they believed it to be off point. But such a stunning revelation demands examination.

* The ethnic/race breakdown was similar for clinical and nonclinical faculty. The authors did not break down race by professorship level (full, associate, and assistant). The findings are probably even more disheartening.

* It's assumed, although not clarified by the authors, that 34 respondents selected more than one ethnicity/race in the survey.

IMNSHO = in my not-so-humble opinion.