FDA’s CDER Director: The problem of outsourced clinical trials

Janet Woodcock, MD, the Director of the FDA’s CDER, the division that approved pharmaceuticals, discusses the problem of more and more clinical trials being conducted in small countries around the globe that provide inadequate oversight.

 

Nortin Hadler, MD: lack of evidence for widespread statin use

Produced and interviewed by Steven Greer, MD

Nortin Hadler, MD, Professor of medicine and microbiology/immunology at The University of North Carolina School of Medicine, discusses the weakness in the body of literature to support the widespread usage of statins to lower cholesterol.

Limitations of The Lancet papers espousing the cancer risk reduction of daily aspirin

March 21, 2012 By Dr. Kausik Ray from St. George’s University in London

Here are my thoughts on The recent Lancet papers that uses meta-analysis to study whether daily aspiring reduces the risk of cancers. I think the editorial was very good and I concur with the conclusions. There were methodological limitations:

1) The meta analyses conducted included data on about 36 000 people and about 360,000 person years of follow-up (FU). However, they excluded the two largest trials which had cancer incidence as a prespecified endpoint (the Women’s Health study and the Physicians Health study). We included those in our paper and had data on 102,000 people and 700,000 person years of FU.

2) That being said, the present data provide mechanistic insights into the potential role of aspirin. The fact that benefit on cancer incidence with low dose appears after 3 years fits with what we understand about cancer neogensis and the fact that in the second paper there were favorable effects on cancer metastases provide supportive data for a potential role for aspirin.

3) The data do not tell us much about who to treat or the risk benefits, as you need to treat about 189 people for 10 years or 1890 people for 1 year to prevent 1 new cancer. In contrast for every 219 people treated for 5 years there’s one extra major non cerebral bleed, or 1095 people/year. So the risk benefit, on average, is 2 extra bleeds per incident cancer prevented. Remember these do not capture intracerebral bleeds, retinal bleeds hospital admissions etc as cancer incidence is collected in cancer registry and is more reliable than collecting bleeding data after trial follow up has finished. The data that bleeding declines and aspirin is protective against bleeds >5 years is biologically implausible. The implication is if you treat whole populations and more bleed especially early they come off drug so the NNT (i.e. those who stay on drug) to prevent one event will become even higher.

4) The studies published add considerably to our understanding, but guidelines should not change on the basis of these for general populations. We need the results of ongoing studies which accurately record cancer incidence and document non-trivial bleeds over extended follow up to determine net benefit. Beyond that we need at an individual level to determine who is at high absolute risk of bleeding and who is at high absolute risk of cancer to determine on a personalized level whether the treatment is suitable. (e.g. those with a high bleeding risk score versus a low risk score for cancer would not be individuals the medical community should perhaps offer this treatment to.)

Ongoing trials will help clarify matters, and what the present study adds is the possibility that in a few years time, if we correctly identify risk versus benefit, we might use aspirin for the primary prevention of cancer rather than vascular disease.

The following is or previous interview with Dr. Ray on the bleeding risks of aspirin.

Nortin Hadler, MD: inappropriate use of epidemiology data

Nortin Hadler, MD, Professor of medicine and microbiology/immunology at The University of North Carolina School of Medicine, discusses the inappropriate use of broad epidemiology studies to draw conclusions that guide actual clinical therapy.

Medical imaging is more dangerous than the Japan or Chernobyl accidents

Update April 20, 2011

The NEJM has a paper out about the clinical effects of radiation fallout from nuclear reactor accidents. Our previous work below is consistent with their findings. Our table, below, is similar to the NEJM table 2 on page 5. It required finding data from obscure Chernobyl reports and WW2 A-bomb studies.

The importance of those charts is that one can now judge how bad or not is the Japan crisis. Recently, reports from Japan were that one reactor was leaking more than 40 mSv per hour. People living near Chernobyl received less radiation than that, in total, over the entire period of exposure.

March 16, 2011

By Steven Greer, MD   The Healthcare Channel

The developing nuclear disaster in Japan is generating much press about radiation and cancer risks. CurrentMedicine.TV developed a condensed table comparing the radiation doses from Three Mile Island, Chernobyl, and common medical imaging studies. Astonishingly, many common medical imaging tests deliver doses of radiation far greater than doses received by populations around nuclear plant accidents.

If one were unfortunate enough to have been in the heavy fallout zones of the Russian Chernobyl accident in 1986, they would have received 17 to 31 mSv of radiation. However, if one undergoes a common cardiology procedure called PCI to unblock coronary arteries, they receive 15 mSv (see charts below). Even worse, a thallium “stress test”, a completely optional procedure, delivers 40 mSv: far more than the heaviest-hit areas of Chernobyl. Now, cardiology practices have purchased profit-generating “64-slice CT-scans” to be used as screening tests for coronary artery disease. These tests deliver up to 32 mSv.

Common chest CT-scans can also deliver 40 mSv, and patients often have repeat scans. At one New York Hospital, for example, it is routine on the cardiac surgery service to send a patient not awakening from CABG surgery to the head CT-scanner daily for medicolegal reasons. In the rare event that the patient had suffered a stroke, the hospital and doctor would be liable for not treating the hemorrhagic stroke. In fact, many CT-scans are performed for defensive medicine reasons, such as “rule out appendicitis” abdominal scans.

To determine the cancer risk from radiation exposure, scientists still have only the WW2 Hiroshima/Nagasaki survivor cohort data as the gold standard. The United Nations BEIR VII report is the bible of radiation risk. Most Japanese survivors of the atomic bombs received less than 100 mSv (or two cardiac stress tests). From the BEIR reports, we know that radiation doses of just 10mSv or more are now believed to be correlated with increased future cancer risks. Therefore, all of the medical imaging studies discussed above increase the risk of cancer down the road.

In addition to the dangerous nature of many medical imaging studies, this category of medical cost has ballooned to become one of the biggest costs to the Medicare/Medicaid and private insurance payers. MedPAC recently issued another report on this problem. These often-unnecessary procedures not only hurt your DNA but also your IRA (and federal deficit).

(Click on figures to enlarge.)

From the journal “Radiology”, Mahesh et al

Roger Chou, MD: How the AHRQ creates and grades a meta-analysis

Produced and interviewed by Steven Greer, MD

A meta-analysis is the most influential form of systematic review now, but are all meta-analysis worthy of the highest level of quality in the hierarchy of the AHRQ? Are some meta-analyses “garbage in, garbage out”? Are there standardized, widely accepted, methods for going about a meta-analysis, or are the drug and device industries manipulating this process to create marketing junk science? Are academic doctors doing more meta-analyses because they end up being referenced by more journals and boost their CV?

In Part 1, Dr. Roger Chou of Oregon, a researcher for the AHRQ via a contracted Evidence-based Practice Center, and also a contributor to the U.S. Preventive Services task Force, discusses the rulebooks used by the AHRQ to go about systematic reviews of medical literature.

In Part 2, Dr. Chou discusses how they spot a bad meta-analysis and exclude it from their systematic reviews. He lists as a specific example of a sloppy meta-analysis.

Gordon Guyatt, MD: Proper methods for meta-analyses

Produced and interviewed by Steven Greer, MD

Meta-analyses and other forms of systematic reviews of the medical literature to determining comparative effectiveness have grown in prevalence and prestige over the last decade. PCORI, AHRQ, The Cochrane Group, medical societies, and many other organizations have their own efforts to create reviews of clinical therapies. Not surprisingly, for-profit entities have also hijacked the process the create research to suit their needs.

In Part 1, Dr. Guyatt explains why this systematic reviews have grown, and discusses the major established guidelines for conducting such reviews. He mentions AMSTAR and The Cochrane Handbook as the best resources, in his opinion.

In Part 2, Dr. Guyatt mentions how the process for meta-analysis can be manipulated to create junk science data.

Joe Selby, MD, MPH: The newly formed PCORI

August 9, 2011

The newly appointed Executive Director of the still forming Patient Centered Outcomes Research Institute (PCORI), Joe Selby, MD gives an overview of the purpose and first deliverables of PCORI.

Nortin Hadler, MD: problems with combined endpoints

Nortin Hadler, MD, Professor of medicine and microbiology/immunology at The University of North Carolina School of Medicine, discusses the problems of using combined endpoints for clinical trials.

Gordon Guyatt, MD: Flaws of the JUPITER trial for Crestor

The HCC interviewed Dr. Gordon Guyatt to discuss the major flaws in the way the Crestor JUPITER trial was conducted and reported.