Thursday, February 28, 2008

US FDA sets standards for medical journals and peer review

Photo Credit vaneska~tHOmz's
In seeking to define standards for ‘good reprint practices’ by pharmaceutical companies seeking to provide copies of journal articles to doctors the FDA has had to grapple with the quality of articles and of journals. That they have failed is hardly a surprise, but that they even tried is quite astonishing given their intimate knowledge of the hundreds (if not thousands) of flimsy and misleading research reports submitted to the agency from these same companies seeking drug approvals, most of which are published in these same journals.

The FDA has a legislated role not only to approve new pharmaceuticals, but to do so quickly. The agency is under pressure from all sides except the ranks of the cautious and skeptical to approve drugs and new usages with minimal delay and minimum of assurance they are effective and safe. Once approved, pharmaceutical companies market these drugs to physicians and patients for use.

Pharmaceutical companies (and some physicians and sick patients) are anxious to see if drugs approved for one indication - say epilepsy in adults - might just work for other health problems - say Parkinson’s disease or among groups of individuals (such as children and pregnant women) where there are often few clinical trials.

These ‘off-label’ (non-FDA approved) uses are the target of this FDA Guidance for Industry on Good Reprint Practices for the Distribution of Journal Articles.... The guidance on good reprint practices is a set of suggestions that pharmaceutical companies should use when they are promoting drugs for unapproved uses. The FDA claims that:

“public health may be advanced by healthcare professionals’ receipt of medical journal articles ... on unapproved or new uses of approved or cleared medical products that are truthful and not misleading.”

This is ludicrous. That pharmaceutical companies would select journal articles that are “truthful and not misleading” is irrational from the companies point of view - they will select articles that support use of the product, that emphasize benefit and minimize harm - and naive or blind from the FDA point of view.

There is a wealth of evidence that the published literature looks like a shipwreck of clinical trials that have been shown to be wrong. First of all it is clear even from the perspective of the FDA that published studies sponsored by pharmaceutical companies show a terrific bias towards benefit and against harm. Studies showing benefit of a product are published, those showing no benefit or harm are not. The astonishing thing is that the FDA is intimately aware of this sham evidence base, for it has the only complete record of all clinical trials done to explore new uses of existing products.

For example of 74 clinical trials of antidepressants (involving 12 drugs for which companies sought approval 31% were never published. Published clinical trials show that the drugs are on average 31% better than the comparison drugs or placebos; however, when all the evidence is examined - published and unpublished - the 12 drugs on average showed no benefit over the comparison group.<1> Ludicrous is not too extreme an adjective to describe a belief that pharmaceutical companies will show doctors the complete evidence, on anything.

In its disconnect from reality the FDA goes further by listing a set of criteria that pharmaceutical companies can use (are not required to use) when choosing articles to flog to doctors and their patients. Under the rubric “Good Reprint Practices” we find that:

The Journal should:
1. Have an editorial board that uses experts.
2. Have an editor and board independent of the journal owners
3. Have a policy of full disclosure of conflict of interest or biases.
4. Be peer reviewed

The Journal article should not:
1. Be false or misleading
2. Be a drug company funded special supplement.
3. Have been withdrawn by the journal
4. (Promote a product) that poses a significant risk

I know of few journals that would; a) not have these policies in place; b) publish articles known to be false or misleading and; c) not know and understand that they regularly violate them all, despite their best intentions.

Even well funded journals like the New England Journal of Medicine and JAMA get duped and make mistakes. And they know that they are publishing but part of the evidence, mostly the part showing benefit.

The vast vast majority of journals, however, are small, employ a part-time editor and have but limited time and resources to provide effective oversight of the material they are publishing. They can't guarantee to effectively sort the excellent science from the sloppy, and even less to detect purposeful deceit by funding sponsors with embedded conflicts of interest. Yet, the FDA criteria render virtually all medical journals eligible for cherry picking of articles by company marketing departments and peddling of it to practicing physicians and their patients.

This is not an effective or safe way to improve the health of the public. It is a an effective and now legally protected way ("the FDA said we should") for pharmaceutical and device manufacturing companies to expand markets for unapproved uses.

Further there is no need to promote selected research publications on specific drugs to physicians. Although individual practitioners ought to be able to recognize the conflict of interest of the pharmaceutical company salesperson, they don’t. The majority continue to accept visits and advice form various peddlers. The average practitioner (and patient) has little training, experience or frankly interest in reading and understanding research articles.

In fact, individual practitioners should be encouraged to not read research articles involving randomized trials of a single drug, for there is a reasonable probability that any one study will be flawed or subsequently disproved by accumulating further evidence. Average practitioners are encouraged to stick to guidelines which while themselves are still susceptible to bias and influence by pharmaceutical companies are at least one-half degree of freedom removed from Wall Street.

The FDA criteria for choosing a journal and article do not reflect the very flawed reality of current medical publishing nor of the sad state of market driven medical research, nor of the abilities, availabilities and interests of practitioners to read an understand. The FDA does not have to cave to pressure from Wall Street to let pharmaceutical companies market directly to individual practitioners and their patients by flogging journal articles. Ethical pharmaceutical companies should act responsibly and urge the FDA to drop this guidance.

Reference

Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-60.

Thursday, February 21, 2008

Diabetes cured? - Rosiglitazone trials raise new questions.

What your doctor is reading, or should be.

Today, diabetes in adults is common. Yet, when Banting, Best and others in 1922 showed the effects of a crude extract of pancreatic tissue on the blood sugar of a 14 year old boy the disease was uncommon. <1> Only those who had extremely high blood sugars, usually discovered in childhood with what we would now call Type I diabetes, were diagnosed with diabetes. They were ill, had ketosis (acid in their blood), were extremely ill and usually did not survive long beyond adolescence. Insulin changed that dramatically.

Type II diabetes was obviously around, but was not diagnosed by physicians because it was asymptomatic unless the blood sugar levels were exceedingly high, in which case the patient had loss of sugar in the urine which was accompanied by water and produced symptoms of thirst and frequent urination, day and night. Thus, in the 1960’s and 70’s it was uncommon for physicians to diagnose diabetes unless the patient symptoms, in which case, either insulin or one of the oral agents could be prescribed - in addition to diet and weight loss, neither of which was effective (then and today).

Type II diabetes became a recognized disease when it was observed that individuals with high blood sugars had a higher risk of micro-vascular complications (peripheral small arterial disease in the legs, leading eventually to ulcers and amputations, and microvascular effects on the kidney and retina and associated renal failure and loss of vision) as well as macrovascular complications (atherosclerosis of larger arteries and associated heart attacks and strokes).

Epidemiologic studies revealed a clear association between high blood sugars and these bad outcomes. But it is a jump in logic to assume that the culprit is the blood sugar. Perhaps the blood sugar increases are due to some other cause, which is also causing disease in small and large arteries? In this counter explanation, the blood sugar is but a sign of the disease, not the cause. Reducing blood sugar may not prevent the bad outcomes.

The interest in the new oral agents, for the treatment of asymptomatic increases in blood sugar, and aggressive marketing by manufacturer’s of these agents, along with endorsements by then nascent patient advocacy groups such as national diabetes associations, led to an epidemic of Type II diabetes, later fueled by increasingly sedentary lifestyles and a glut of obesity.

What was needed to unravel this possible paradox - that we were diagnosing and treating a disease that did not exist (treating a blood test not a disease) was a randomized clinical trial tabulating outcomes that really mattered to people - fewer amputations, less renal and visual failure, fewer strokes and heart attacks and perhaps longer life.

Readers will understand the importance of RCTs for this type of question. We understand that such RCTs will be difficult to complete because the outcomes are relatively rare and occur but years later; thus the need for very large numbers of study subjects with Type II diabetes followed for long periods of time. Expensive trials, long durations, prone to missing information and loss to follow-up of many trial subjects makes this type of research unwieldy, unfriendly and open to variable interpretations, all of which has happened. .

There have been but a few such trials. Earliest was the University Group Diabetes Study about 30 years ago. The results were unclear and the trial is still being interpreted. Nonetheless the results form the basis of current therapeutic recommendations.

The other important outcome trial of type II diabetes is the United Kingdom Prospective Diabetes Study (UKPDS), involving over 4,000 patients randomized to receive an oral anti-diabetic agent and followed on average for about 10 years. <2> That study showed improved outcomes, but the trial was messy (patients often took multiple agents over this time frame including insulin, many were lost to follow-up etc.). The results are still discussed.

Since then, as newer oral pharmaceuticals were developed to lower blood sugar or increase insulin sensitivity, regulatory agencies have required RCT evidence only that they work: that they do lower blood sugar. Ignoring patient meaningful outcomes, only small RCTs of short duration are needed.

Recently, however, pharmaceutical companies have conducted larger RCTs to determine if use resulted in fewer serious complications among patients with Type II diabetes. Undoubtedly, the motivation for doing these trials is to develop data that would give their product a competitive edge in an increasingly crowded market of new compounds.

The ADOPT trial (A Diabtes Outcome Prevention Trial), <3>The DREAM trial (Diabetes Reduction Assessment with Rampril and Rosiglitazone Medication), <4> and the RECORD trial (Rosiglitazone Evalutaed for Cardiac Outcomes and Regulation of Glycemia in Diabetes) <5> trials were all sponsored by pharmaceutical companies anxious to show that their particular drugs were better than cheap generic versions of older drugs (sulphonyl ureas and metformin).

All 3 trials showed no benefit. And all 3 trials strongly suggest that the new medications are not only of no benefit, but are harmful to patients with Type II diabetes.

Suffice to look at Rosiglitazone.

In an extraordinary piece of research, Nisan and Wolski <6> found 26 reports of small clinical trials with rosiglitazone. Summarizing these in a meta-analysis they showed that patients randomized to receive this drug, often along with metformin or a sulfonyl urea were at a statistically significant higher risk (43%) of heart attacks and/or death than the control groups receiving just sulfonyl urea or metformin. [Relative risk 1.43, 95% CI 1.03 to 1.98]

In an effort to refute the Nisan Wolski paper, GalaxoSmithKlein hurriedly released an unplanned interim analysis of their ongoing trial (RECORD) that, unfortunately for the pharmaceutical company, not only failed to refute the previous results but rather confirmed them; although the company interpretation disparaged the seriousness of the harms (heart attacks, strokes and death).<4>

Pharmaceutical company sponsors generally attribute the unexpected bad-for-sales results (for their products) to unforeseen difficulties in carrying out the trials (for example lower than expected frequencies of outcome events) and, curiously, tend to attribute the unfavourable results - even if statistically significant, to chance.

But even a casual observer would interpret these studies as showing no benefit form these newer compounds. And with the potential for harm, cautious physicians and patients would conclude that is best to avoid prescribing and taking them.

Interpretation

These results are striking and deserve our attention. The evidence is clear that even within the company sponsored RCT, patients taking rosglitazone along with another agent suffered more heart attacks, strokes and/or death than those taking a single older agent such as metformin or a sulphonylurea.

These results are applicable to all drugs of this class - thiazolidinediones

Implications

For patients

Patients with type II diabetes should not be taking thiazolidinediones. Those receiving these compounds should be switched to sulphonylureas and or metformin or insulin.

Patients with type II diabetes, who are asymptomatic and have blood sugars lower than their renal threshold (no sugar in the urine), should be encouraged to lose weight and exercise. Often this will bring their blood sugars into more normal ranges.

Current guidelines <7> are less cautious than I am and continue to recommend aggressive lowering of blood sugar even in asymptomatic patients. There is some evidence from randomized trials of insulin and from animal experiments that maintaining blood sugars in near normal ranges is associated with reductions in micro-vascular disease and thus ought to reduce the risk of peripheral vascular disease, renal failure and loss of vision. Thus theoretically, a lower blood sugar is better. But there is little clinical evidence to support the guideline recommendations which are all financed by pharmaceutical companies with deeply vested interests.

For society

The epidemic of type II diabetes is the result of the hard work and clever execution of projects hatched by marketing divisions of pharmaceutical companies eager to expand markets for their products. The fact that all trials of treatments of type II diabetes have shown that treatment can cause harm (or might in the UKPDS trial), makes it imperative that we once again consider a large scale simple trial of these oral agents, and measure the simple but devastating outcomes that count for patients; amputations, renal failure, blindness, myocardial infarctions and stokes and deaths.

In the interim, patients with abnormal blood sugars as their only ‘abnormality’ might be best to avoid drugs.

References used - links to those that are free

1. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Preliminary report. CMAJ 1922;12:141-6

2, UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications
in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UDPKS) Group

3, Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43. [Erratum, N Engl J Med 2007;356:1387-8.]

4. Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose toleranceor impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-105. [Erratum, Lancet 2006;368:1770.]

5. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) Study: interim findings on cardiovascular hospitalizations and deaths. N Engl J Med 2007;357.
DOI: 10.1056/NEJMoa073394.

6. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular disease. N Engl J Med 2007;356:2457-2471. [Erratum, N Engl J Med 2007;357:100.]
online free

7. Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., Zinman, B. (2008). Management of Hyperglycemia in Type 2 Diabetes: A Consensus 8. Algorithm for the Initiation and Adjustment of Therapy: Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes . Diabetes Care 31: 173-175
online free

Monday, February 18, 2008

Chronic Knee pain from osteoarthritis and what to do about it - Topical ibuprophen.

About 1 in 3 adults over the age of 50 have chronic pains in the knees. Most are caused by osteoarthritis, essentially a wearing out of the joint, most likely due to age, prior injuries, obesity or other overuse (work or weight bearing), and in part to one’s genes. If you want to know if you have osteoarthritis a good source is the US National Institutes of Health. They have a patient friendly guide that is free. (Handout on Health Osteoarthritis) Figure is in the handout and shows the main joints that are affected by osteoarthritis.

Most people with more severe forms of pain, especially pain that limits walking, will try anti-inflammatory drugs like aspirin or ibuprofen. These drugs, collectively called NSAIDs (non-steroidal anti-inflammatory drugs), however, can cause side effects, the most serious of which is bleeding in the stomach. Minor side effects are also reported such as indigestion (gastritis or abdominal pains) and a few others such as increases in blood pressure or decreases in kidney function. They should be used with care in patients with pre-existing hypertension, heart, kidney or liver disease and in patients with known gastric bleeding and or taking drugs that might make bleeding easier (anti-coagulants, steroids).

Recently topical ibuprofen has become available.

This study is an RCT of 282 patients selected from general practices in the UK. They represent about 1% of the patients in these practices who were identified as possibly having osteoarthritis. Of these, 85% completed the study.

Primary Outcome Measure: Knee pain at 12 months in the topical and oral groups.

Result: There was no difference between the two groups in pain severity, joint stiffness or mobility.


Interpretation of study:

Topical and oral ibuprofen provided equivalent relief for osteoarthritis of the knees. The study was not designed to show that topical ibuprofen was less likely than oral ibuprophen to cause side effects, especially gastrointestinal bleeding, nor that other side effects were less or more frequent.

The study was not blinded at the patient level: subjectivity may have played a part in this result. Given the low statistical power obtained in this carefully planned study it is difficult to imagine that any other study could do much better. The we may never know the answer to the study question - are topical NSAIDs as good and safer and better tolerated than oral NSAIDs? It is likely however that oral ibuprophen would provide a larger effective dose, resulting in better pain relief and a higher incidence of side effects.

Implications:

For the patient

The rational patient could try topical ibuprofen and expect to find equivalent symptom relief to his or her oral pill: And judge for themselves if this occurred and was worth the additional cost of the topical drug.

The authors say that symptom relief generally did not change over the study, suggesting, perhaps that neither route of administration works - that a placebo or simple acetaminophen (Tylenol, Paracetamol), or no drug treatment might do just as well, and have with fewer side effects.

For Society

Given the higher costs (currently) of topical Ibuprofen, the equivalence of oral and topical ibuprophen for symptom relief and the paucity of data on serious adverse effects, health insurance plans should consider topical ibuprophen to be cost-ineffective compared to oral generic products and therefore not covered. Database studies of large numbers of users might be used to detect rate differences in serious adverse events and if this were so, then the topical agents might be cost-effective.

References:

Underwood M, Ashby D, Cross P et al. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomized controlled trial and patient preference study. BMJ 2008:336:138-42 doi:10.1136/bmj.39399.656331.25