Should Detectives, Not Just Academics, Review Drug Research?

The different reports I intend to comment on may seem a bit disconnected as you read this; however, I think you will see the common thread.

A little while ago I wrote Money, Medications and Motives, related to this report of a corrupt doctor who strongly promoted prescription of powerful antipsychotic medicines to children while receiving un-declared income of over $1.6 million from drug-makers. That New York Times article goes on to describe other doctors acting similarly and implies a systemic problem in the relationship between practicing physicians, academia and the massive medical industry.

This perspective was published in the New England Journal Of Medicine today (Volume 362:669-671 February 25, 2010 Number 8): Serving Two Masters — Conflicts of Interest in Academic Medicine, by Bernard Lo, M.D.

He comments on the recent introduction by Boston-based Partners HealthCare, which includes some of the nation's leading teaching hospitals, of strict limitations on the level of compensation appropriate for their officials for serving on boards of directors of biomedical companies or similar situations. I must admit, from my perspective, a limit of "$5,000 per day for the time spent at board meetings" seems a trifle loose; it certainly causes one to wonder what the unlimited compensation has been. He includes this comment in his conclusions:

The public grants the medical profession considerable discretion in setting its own standards because it trusts that physicians will place patients' interests ahead of their own or those of third parties. To maintain this trust, AHCs (academic health centers ) should take the lead in addressing conflicts of interest in medicine, rather than merely responding to government requirements and adverse publicity about troubling cases. Taking the initiative will promote a culture of accountability and a commitment to professionalism.

I could not agree more. Unfortunately, I think the gate has been left open too long and the horse has well and truly bolted. It is now time for agencies beyond academia and the medical profession to take a keener interest.

A couple of days ago an article was reported in TheHeart.org about an analysis performed by Dr Mohammed Hassan Murad (Mayo Clinic, Rochester, MN) and colleagues of 202 papers or articles authored by medical professionals concerning Avandia. Coincidentally, an article in the UK Guardian newspaper reports that, after a two-year inquiry, the US Senate finance committee concluded that Glaxo Smith Kline knew of the link between Avandia and heart problems in 2004 but intimidated scientists to ensure favourable reports. You might note in that Guardian report "Glaxo firmly rejected the committee's findings, saying that 164 independent clinical trials have failed to find an association between Avandia and heart attacks."

Coincidence is a strange thing. Independently, as far as I can determine, Dr Murad and his colleagues examined the links some authors of papers and reports had with antihyperglycemic agent manufacturers and with rosiglitazone's manufacturer which may have conflicted with an unbiased report on the medication. Please read the full article; I don't wish to infringe copyright so I'll just mention the bare facts.

The analysts found that 107 of 202 papers or reports included a conflict-of-interest statement and 90 (45%) indicated a conflict existed.

Of the authors who concluded that no risk of heart problems are posed by rosiglitazone, 91% had financial relationships with antihyperglycemic agent manufacturers and 86% had relationships with rosiglitazone's manufacturer.

On the other hand, of authors who stated unfavourable opinions, only 25% had financial relationships with antihyperglycemic agent manufacturers and only 18% had relationships with rosiglitazone's manufacturer.

I don't think it takes a statistician to realise those numbers are significant. Who pays the piper calls the tune.

Earlier this month this brief statement appeared in the FDA news Drug Daily BulletinFeb. 2, 2010 Vol. 7 No. 22

Researcher Reaches Plea Agreement on Charge of Fabricating Data

A former influential pain drug researcher has reached a plea agreement with the Justice Department on a charge that he fabricated patient data. Federal prosecutors accused Scott Reuben, former chief of acute pain at Baystate Medical Center in Springfield, Mass., of falsifying patient data in trials of painkillers, including Merck’s Vioxx (rofecoxib) and Pfizer’s Celebrex (celecoxib). Reuben agreed to plead guilty to one count of healthcare fraud.

News reports on that appeared in several places, this is a brief extract from Medpage Today:

A Massachusetts anesthesiologist accused of fabricating data in studies of pain drugs will plead guilty to federal criminal charges under an agreement with prosecutors.

Scott Reuben, MD, a well-known pain researcher at Baystate Medical Center in Springfield, Mass., was charged with one count of healthcare fraud.

Early last year, the hospital announced that an internal audit had revealed that Reuben had made up research data out of whole cloth, affecting at least 21 published studies over a 15-year period. (See Special Report: Few Gaps in Analgesic Practice After Reuben Retractions) The criminal charge arose from one of those studies, funded by Pfizer and published in Anesthesia & Analgesia in 2007.

If you refer back to that article of mine on Money, Medications and Motives you will find that Celebrex was not Pfizer's big money maker. This is from 2007 figures:

"Pharmaceutical revenue from Pfizer’s U.S. operations decreased last year as competition in the cholesterol market contributed to an 8 percent decline in revenues for the firm’s flagship product Lipitor. The company’s $48.6 billion 2007 total revenue was 1 percent better than its 2006 revenue of $48.4 billion.

Overall, the company’s domestic revenue dropped 11 percent to $21.74 billion in 2007. Lipitor (atorvastatin calcium) had revenue of approximately $7.2 billion in the U.S. last year compared with approximately $7.85 billion in 2006. Worldwide Lipitor revenues were approximately $12.7 billion, a 2 percent decrease from 2006."

There are many countries in the UN that don't have a gross revenue like that. In 2007, if Pfizer was a country and not a manufacturer of pharmaceuticals, $48.4 billion would have positioned Pfizer 72nd out of 190 countries on the world rankings, just below Belarus and just above Luxembourg.

Until the FDA, TGA and other regulatory agencies can be absolutely confident that research studies are not only scientifically sound but are also not fraudulent, it appears to me that there is a case for agencies such as the FBI in the USA and equivalents in other countries to be involved in following the money trail during the process of approval of a medication for prescription by physicians.

There is the possibility that drugs like Lipitor and Celebrex save lives. But there is also the possibility that they kill people. All medications have side effects. Medications scientifically and honestly researched and trialled which provide detailed advice to regulators, physicians and patients of both the benefits and the risks can be a boon to mankind. For example, the risk of type 2 diabetes from Prednisone is well known, but the benefits for patients undergoing chemo are also significant. If a phsyician and patient decide to use that medication when fully aware of the risk, that is acceptable.

However, in my opinion, if a person deliberately falsifies or distorts influential reports on medications which lead to killing people who would not otherwise have died, and if others become aware of that consequence but deliberately falsify or suppress that information to profit from the sales of that medication, that person and those people should be charged with homicide, not just fraud.

Big fines will not cause a blip in the balance sheet of companies with resources like Pfizer. However, the possibility of being charged with murder may cause some second thoughts before repeating or facilitating actions such as the Celebrex scandal.

Resources such as the FBI are limited so their allocation needs to be targeted. An obvious starting point, in my opinion, would be to review ALL of the papers used by the FDA when making their decisions on statins, including Lipitor, Crestor, Zocor and all of othes presently approved.

Follow the money trail...

Cheers, Alan

Everything in Moderation - Except Laughter