Tuesday, July 24, 2007

Could This Be What's Wrong with Company-Sponsored Clinical Trials?

The website ClinPage recently carried a story about a presentation made by Robert Ruffolo, president of R&D for Wyeth:


ClinPage ooh'd and aah'd about the fantastic results Ruffolo has had at Wyeth--discovery productivity up 500 percent, preclinical productivity up 600 percent, enrolling subjects in trials at 100 percent (vs. 60 percent a year earlier). The author made it clear that any competing company that did not sniff around to see how Ruffolo and Wyeth did all this would be crazy.

The story went on:

And his rivals, Ruffolo says, often express disbelief at the change that Wyeth has imposed on its scientific staff. Said Ruffolo: “I am often shocked by what I hear from our counterparts: ‘Our scientists would never agree to that.’ It’s not a democracy. You want democracy? Go to Russia.” The more profound issue, it would seem, is whether rigid scientific mindsets will be a barrier to further productivity gains at drug companies less interested in top-to-bottom transformation than Wyeth.

Now, isn't this exactly the problem? How far can you shoehorn science into a business-productivity model, before science has been turned on its head completely into marketing and PR? Isn't this at the very heart of what we see that's wrong with commercially-sponsored pharmaceutical research these days? Ruffolo says it's all the fault of FDA and Congress--those wusses are insisting that drugs be super-squeaky-safe, and ignore the bigger question of whether the drugs offer benefit. But when the benefit is so tiny that you need a multicenter trial with tens of thousands of patients enrolled to find any sign of it, maybe Congress and the FDA have it right and it's Ruffolo and his cronies who are the problem.

The article states that Wyeth is now so big on productivity measures that "missing a patient recruitment goal by a single patient might mean missing your bonus." Somehow I have a hard time imaging that any Wyeth worker would be a stickler for the ethics of research and for careful informed consent, when having the patient say no may mean you lose your bonus.

Thursday, July 19, 2007

Mandatory Trials Registry--Two Years In

The International Committee of Medical Journal Editors, made up of the editors of some of the most prestigious medical journals in the world, began to require in 2005 that anyone submitting a manuscript regarding a clinical trial should previously have registered that trial in a public registry meeting certain strict criteria for disclosure. The Editors have now issued an interim report two years later. They claim that the effort has been a marked success. Before their requirement became effective, the largest existing registry, ClinicalTrials.gov, contained 13,153 trials. A month later there were 22,714 trials listed, and this past April, the site listed over 40,000 trials. Moreover, a World Health Organization site that was not very well developed in 2005 has now been much more fully implemented, and promises to become a useful, international one-stop entry point into all trial registries. Many journals whose editors are not part of the International Committee have joined in the requirement.

In HOOKED, I recommend mandatory clinical trials registration as a very useful interim step but not as the final answer to the many problems with industry-sponsored clinical trials, and the conflicts of interest created when academic investigators are funded by the drug industry. While more needs to be done it is nonetheless encouraging that the registry step has so far been successful.

Laine C, Horton R, DeAngelis CD, et al. Clinical trials registration--looking back and moving ahead. N Engl J Med 356:2734-35, June 28, 2007.

Unexpected Consequences of an Arms-Length Research Relationship

The New England Journal of Medicine recently published an analysis of a court decision that raises some interesting implications for the relationship between a pharmaceutical company and an academic medical center (AMC) with regard to conduct of drug trials and rights of patients.

Briefly, in Abney v. Amgen, March 2006, the US Court of Appeals upheld a ruling that Amgen had no contractual obligation to provide an experimental drug to research subjects after completion of the study, even though the consent form indicated that that would be possible. The drug, glial-cell-line-derived neurotrophic factor (GDNF), was instilled via catheter into the brains of patients with Parkinson's disease. The study concluded that GDNF was not effective. However, individual patients who believed that they had been benefited demanded that the drug be provided for an additional 2 years, as the consent form had promised. The court ruled that the consent form was an implied contract with the institution doing the research (in this case, University of Kentucky) but not with Amgen since Amgen did not directly control the research process.

Mello and Joffe, in their commentary, address the legal vs. the ethical issues. Legally, a drug company can avoid some accountability by keeping this sort of arms-length relationship with the AMC. But ethically, it seems that if patients were promised the drug after a trial is over, somebody owes them that drug, unless the study has showed that the drug is actually dangerous. (They argue that the mere demonstration of lack of efficacy is not a sufficient reason to deny the drug to a patient who is fully informed but who requests it.) They advise AMC's to assure that if they enter into a contract with a drug company, then the contract contains provisions that will allow the AMC to keep relevant promises with the research subjects.

I mention all this because, in HOOKED, I argue for even more than the usual arms-length contractual relationship between drug company and AMC; I urge instead a real firewall through the creation of an NIH-type research body that can take drug industry funds, and offer competitive grants to do the desired research, without money changing hands directly between the company and the academic investigators. If this idea of the neutral research institute were to become reality, then it would be even easier to assure that any promises of this sort could be kept, as a condition for the company getting the research done in the first place. (We would still need to ask--is it wise to promise this to research subjects, in the event that the research demonstrates that the drug is ineffective overall? Or should any such promise be contingent upon demonstrating efficacy as well as safety? Or is it more respective of individual variability among subjects to promise the drug in any case?)

Mello MM, Joffe S. Compact versus contract--industry sponsors' obligations to their research subjects. N Engl J Med 356:2737-43, June 28, 2007.

Abney v. Amgen, Inc. 443 F.3d 540 (6th Cir. 2006).

Tuesday, July 17, 2007

Are Nurses Embracing Pharma Marketing?

I am not a regular reader of Dermatology Nursing, the journal of the Dermatology Nurses' Association--since I am not a dermatology nurse. So perhaps you'll forgive me for only now learning about an article that appeared in their August, 2006 issue.

Entitled, "They Are More than Just Pretty People Handing Out Cool Pens," this paper by Melodie Young, MSN, RN, A/GNP-C, President of the Association, seems at one level to be trying to lay out some of the ethical concerns about getting one's information about pharmaceuticals from commercially biased sources. The article notes that there are concerns about pharmaceutical marketing and that some offices and clinics have elected to ban drug reps.

But the clear message of the article is that the nurse should welcome the rep as an ally and fellow professional. Here are some samples: "most of the people in these sales positions are pleasant, bright, highly educated and ethical, very polished people who truly care about patients"... "The Dermatology Nurses' Association would be unable to host the number and magnitude of educational programs currently available without the financial support of industry."... "the next time a sales rep enters your office, remember to say thank you, and not just for the cool pen."

Ms. Young appears to believe that the present system of oversight works just fine. The PhRMA code of ethics prohibits companies from doing anything over the top in marketing or gift-giving. She even believes, "To keep educational events unbiased, many pharmaceutical companies employ independent medical education companies or professional groups to develop the content and curriculum for these events." Pardon the fact that some of the rest of us doubt the "independence" of companies that rely on the industry for 80-90 percent of their revenues.

It is widely known among those with some familiarity with drug marketing that the nurses and receptionists are often the way the rep can gain entry into the ofice of a skeptical or unwilling physician. One would think that a professional nursing organization would want to warn its members against being used and manipulated for these ends. Instead at least one nursing association seems to be eagerly doing the bidding of the industry--and happily pocketing the industry revenues it takes in. (Not that the nurses are any less ethically pure than the many physicians' organizations that do the same thing--even if they are not so blatant about singing the praises of the "highly ethical" reps.)

Is Pharmageddon Coming? Write and Earn 1,000 Euros

An organization in the UK called Social Audit is worried about "Pharmageddon," which they define as: "the prospect of a world in which medicines and medicine produce more ill-health than health, and when medical progress does more harm than good". They are concerned about what they see as the twin problems of the over-medication of the wealthy world and the under-medication of the developing world. They attribute this state of affairs to a "conspiracy of goodwill"--various parties all want to do good, but are driven by a highly competitive marketplace into behavior that ultimately undermines their good intentions.

Social Audit hopes to have a conference on "Pharmageddon" in the future and with that in mind is inviting writings on this topic, and offering prizes of 1,000 euros for the best material submitted. See:


Sunday, July 15, 2007

DTC Ads: Coming to a Europe Near You?

The BMJ (formerly British Medical Journal) has been tracking in its news columns the efforts of the pharmaceutical industry and some of its supporters within the European Union to bring direct-to-consumer drug advertising to Europe. Currently only the U.S. and New Zealand allow such advertising, and I understand that New Zealand is seriously considering a ban.

In 2002, the European enterprise and health commissioners proposed to the EU parliament an expansion of the allowable health information that can be disseminated to the public from the industry. The parliament overwhelmingly rejected the proposal. The commissioners made no bones about their disappointment and apparently bided their time until they could reintroduce similar proposals. Some commentators believe that they chose this spring for two reasons--first, that only 25% of the current membership of the parliament is left from the previous vote in 2002; and second, that the members of parliament are about to stand for election and so appearing to be "pro-health" will stand them in good stead. By contrast, consumers organizations in Europe are lining up in opposition.

It is a sad commentary on the state of advertising in the U.S. that the rallying cry behind this effort to loosen the limitations in Europe is a solemn promise that the end result would not be the anything-goes frenzy now characterizing the American airwaves. The commissioners insist that all they want is more readily available health information for the consumer/patient. Their critics point out that this is basically a stealth campaign, as nowhere in the proposals are there any regulations that have sufficient teeth to prevent blatantly commercial messages from going out.

For their part, the enterprise commissioners make no secret of the reason that they support loosening the rules. They believe that the pharmaceutical industry in Europe is falling behind their U.S. and Japanese counterparts in profits, and they want their part of the world to be more competitive. It is hard to see why they believe that allowing more information on pharmaceuticals to reach the public will improve the competitiveness of the local industry, unless they envision messages that will have increased drug sales as a direct consequence.

Incidentally, you might wonder, if the U.S. and Japan are held up as the "ideally" profitable drug industry nations, but only the U.S. allows DTC advertising, then how does Japan come in? I understand through one report that Japan has some interesting loopholes that allow advertising practices that in some instances nearly mimic the U.S. For example, you cannot directly advertise prescription drugs in Japan, but if you are conducting a research trial, you are allowed to advertise for volunteers. Drug companies sponsoring studies of their products put out full page ads in popular newspapers and magazines that purport to be a call for research subjects, but where about 9/10 of the advertising copy actually extols the virtues of the drug.

In April, the commissioners reported their proposals for more liberal advertising policies, and the consumers' organizations bellowed back. It was not clear from the reports when a final vote can be expected.

Brown H. Sweetening the pill. Can big pharma be trusted to provide independent health information to patients? BMJ 334:664-6, 31 March 2007.

Moynihan R. Direct to consumer advertising should not come to Europe. BMJ 334:1025, 19 May 2007.

More Academic Centers Becoming Pharm-Free Zones

Thanks to the weekly update from the Prescription Project (see Links), I learned that a couple more university medical centers have joined the movement to adopt strict policies limiting the access of pharmaceutical industry marketing people and methods to their campuses. Stanford probably got the most publicity when it adopted such a policy a year or so ago.

The recent moves have ocurred at the University of Pittsburgh and UC-Davis. At Davis, the policy was actually an expansion of an earlier policy, adding device and other manufacturers to a policy that previous dealt mostly with drug companies.

The articles listed other campuses (besides Stanford) that had already taken similar steps to ban most industry marketing activities--Yale, UCLA, Michigan, Penn, Vermont, Henry Ford (Detroit), and Kaiser Permanente of Northern California. I believe that Wisconsin was actually one of the first campuses to go this way.

Griffith D. UCD expands its ban on medical freebies: in addition to drug industry, any other vendor doing business with health system is now included. Sacramento Bee, July 3, 2007.

Fahy J. UPMC draws up severe code on freebies. Pittsburgh Post-Gazette, July 2, 2007.

Monday, July 2, 2007

Gifts to Physicians and Prescription Data--the Unwelcome Light of Publicity

Both state legislatures and Congress are getting riled up about the excesses of the pharamceutical gravy train for physicians, and the company's ability to manipulate physicians to do their bidding through clever marketing. Today's New York Times editorial addresses interest in the U.S. Senate on creating a mandatory registry of all payments from pharmaceutical companies to physicians. (Several states, notably VT and MN, already have laws to require such reporting, and the Times has been having a field day mining those reports in recent weeks.) Several state legislatures are considering outlawing the selling of physicians' prescribing data. (The NH law to ban such sales has been challenged in court.)

What I find interesting about this is that it is flushing the industry out into the open with regard to some of its key rationalizations. The defense of the drug rep arriving at the physician's office with a complete listing of all prescriptions the doc has written for the company's drug and for its competitor drugs? It allows the company to fine-tune its educational message to the physician, addressing the physician's particular needs for drug information. The defense of payments to physicians generally? It is all about education, and physicians are independent scientists who make up their own minds and who cannot be swayed by few free coffee mugs or sandwiches.

To which the New York Times responds, addressing a mandatory payment registry: "If there is nothing wrong with such payments, neither the doctors nor the industry should object to public disclosure." On the matter of the sales of data to drug companies, it is well known that the reps are instructed by the companies to go to considerable lengths to hide the fact that they have these data from the physicians. So the same argument applies there as well--if this is all about education, and the more effective targeting of drug information, why go to such lengths to conceal from physicians the fact that your detail rep has these data?

Is your doctor tied to drug makers? [editorial] New York Times, July 2, 2007, p. A18.