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Friday, February 26, 2010

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

Tuesday, February 16, 2010

SMBG Research, Or The Lack Of It

Nearly three years ago I challenged the authors of a particularly poor paper titled "Impact of self monitoring of blood glucose (SMBG) in the management of patients with non-insulin treated diabetes: open parallel group randomised trial" in the British Medical Journal to conduct a study based on Test, Review, Adjust.

When I first read Jennifer's Test, Test, Test I used to wonder why a study of that method had never been performed.

Of course now, with a little more experience, the reasons are fairly obvious to me. To start with, no researchers are even vaguely aware of the technique. That is apart from the fact that the results are unlikely to lead to increases in medication sales. Over five years ago, back when I naively thought someone would listen, I rang the Australian offices of Roche and Lilly to suggest it. They were polite and totally uninterested. I thought that at least the major test-strip manufacturers may have a vested interest. Apparently not.

My response to that paper was another small attempt to interest somebody in the appropriate field in the concept. But I have to be realistic; not many researchers read the "Rapid Responses" and Farmer et al certainly were not going make any attempt to prove themselves wrong.

The idea surfaced again today when Stuart, a Type 1 diabetic on the dLife forum, posted this very interesting question:

"If you wanted someone to explore something, to do a STUDY on a subject(s) about our diabetes, what do you want them to research? What areas do YOU want to know far more about that don't seem to be being done??? "

He had some very interesting replies. You can read them here. I would like to expand slightly on my answer there.

There are so many areas of diabetes crying out for research. There are some that have never been studied at all, including those dealing with diet modified by structured testing or similar methods which can lead to minimal medication or insulin needs. At the moment research tends to be focused on finding new medications or new ways to use old medications. In the real world "who pays the piper calls the tune".

No researchers are asking us, the diabetics, "what should we be researching?"

My own area of interest is just one of many possibilities. Despite understanding the reasons I still find it hard to believe that after more than three decades of home self-testing of blood glucose by diabetics no medical researcher, anywhere, has researched the use of structured self-testing for dietary modification to reduce blood glucose excursions.

Thousands of type 2 diabetics like myself have been "researching" the method personally and reporting their individual successes on many different forums since before I was diagnosed eight years ago, but we don't count in professional medical and research terms. We are diabetics, not scientists and our reports are anecdotes, not data.

I will offer the basic idea. Who knows, maybe there is a bright scientist out there looking for a PhD subject who has the ability to find a grant or research funds.

I propose a study comparing two groups of type 2 diabetics, all within their first 12 months of diagnosis. The only exclusion criteria would be that none should be using insulin or an insulin-stimulating medication such as a sulfonylurea at the commencement of the study.

Group 1, control, would be treated as individuals by their physicians and other specialists in exactly the same way as the present guidelines for their country. For example that would be the ADA or AACE and American Dietetic Association guidelines in the USA, Diabetes Australia here, or the NICE/NHS guidelines in the UK.

Group 2 would would also be treated as individuals by their physicians and other specialists in exactly the same way as the present guidelines for their country with the exception of dietary and testing guidelines. Instead, they would be given basic dietary guidelines to understand the differences between carbohydrates, fats and protein and their effect on blood glucose levels, and would also receive training and support in using feedback from peak post-prandial blood glucose testing to modify diet and lifestyle. The method taught would be based on the technique described in Test, Review, Adjust. If that needs clarification I am available as a consultant :)

The period of study would be three months initially, with weekly support and review to record indicators for both groups for the first four weeks, then monthly for the next two months with a preliminary report prepared after three months. Periodic follow-up review and reports would be performed at 12 months, five years and ten years. Indicators recorded would include A1c, fasting and peak post-prandial blood glucose levels, lipids, weight, blood pressure and any others the researchers felt valuable.

The five year and ten year reports would follow up all the earlier results and also include morbidity and mortality and any differences in progression to, or of, diabetes complications.

An inexpensive pilot study would not need very large populations and could be restricted to the first three months. The results of that could support further study over the longer period with a larger population.

I can also see other possible studies. For example, the possibility of combining Gannon and Nuttall's LoBAG20 or LoBAG30 diet with the above study as the starting diet for Group 2 is one that intrigues me. But it may be unwise to put too many variables in the mix. One thing at a time.

My area of interest may be quite different to yours. If you were the person asked by the researchers "what do you want us to study?" what would your answer be?

Cheers, Alan

Everything in Moderation - Except Laughter

Wednesday, February 03, 2010

Good Targets, Bad Methods

There has been a lot of discussion in the media and the blogosphere about an Early Online Publication in the Lancet on 27 January 2010.

Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study

Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly



Low and high mean HbA1c values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value."

What has saddened but not surprised me is that the reaction in on-line medical discussions has been much the same as that when the ACCORD and ADVANCE studies appeared. No-one has questioned the methods used to attain targets, all appear to accept that there may be a problem with attempting to aim for tight targets for type 2 diabetics. Thus, the targets are bad and should be eased.

I was not going to write about it because so many others have, but eventually I responded in Present where a doctor posed the following question based on this study: "Are we treating our patients to death?"

This was my response to the doctors.

The answer depends, of course, on the method of treatment and the individual nature of your patient's diabetes.

All of these studies, including ACCORD, ADVANCE and these recent ones have a common thread. They presume that the only way the physician can reach lower A1c and blood glucose goals in a patient is by medication. None of them consider using lifestyle – diet and exercise - changes to complement minimal medication or insulin to achieve those goals.

You all presume that a patient would not use diet and exercise. And, of course, to some degree you are correct, especially when the most generally prescribed diet is directly counter-productive for achieving better A1cs and blood glucose levels.

So you prescribe diet and exercise, the numbers go up, you presume non-compliance and prescribe metformin or a sulf or add insulin, they keep going up so you increase those and add more meds. But you also stress that the patient should eat more carbohydrates – and less fat - to be absolutely sure there are no hypoglycemic episodes as a result of the sulfs or the insulin and so the cycle continues, chasing it's tail.

Lower blood glucose and A1c targets do not cause higher mortality and morbidity. I have read success stories from many thousands of pro-active diabetics of all types on many forums since I was diagnosed eight years ago who have clearly demonstrated the opposite is true.

On the other hand, over-medication to attempt to counter poor dietary advice DOES cause higher mortality and morbidity; that is the consequence these studies are showing.

The solution? First, stop promoting the terrible “heart-healthy” high-carbohydrate AHA diet to your patients, or allowing the dieticians you send your patients to to do so. Instead, suggest that the patient use their meter at their post-prandial peak blood glucose timing to find out what foods are killing them and they will quickly reduce those foods, and their levels, and substitute others. The technique is described here:

Some patients will do that and succeed; some will need further medication, but much less than you usually prescribe. And others will be non-compliant whatever you prescribe. They are the ones to prescribe higher medication to – but they are also the ones you should set easier targets for. Because they are the ones dying from over-medication.

Cheers, Alan.

Everything in Moderation - Except Laughter.