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Research Articles and Papers on:



Conjugated Equine Estrogen and Risk of Benign Proliferative Breast Disease:
A Randomized Controlled Trial

Thomas E. Rohan, Abdissa Negassa, Rowan T. Chlebowski, Laurel Habel, Anne McTiernan, Mindy Ginsberg, Sylvia Wassertheil-Smoller, David L. Page
JNCI Journal of the National Cancer Institute 2008 100(8):563-571;

The researchers of this paper explained that estrogens greatly increase the stimulation of breast tissue and may therefore increase the risk of benign breast disease, a condition that is associated with increased risk of breast cancer.

They tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. 10739 postmenopausal women were first tested and given annual breast examinations and mammograms before being randomly assigned to 0.625 mg/d of CEE or to placebo. They identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated sections and subjected them to standardised central review.

The results showed that a total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease.

The researchers concluded that the use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.
There was a Contents and Caveats section added to this study.  The Implications showed that the use of unopposed estrogens appears to increase risk of benign proliferative breast disease, but whether this would translate into an increase in breast cancer is not yet known.

The Limitations showed that the trial participants were treated with only one estrogen regime and dose, and the trial was stopped early.

Symptoms and signs induced by CEE might have increased the likelihood of suspected breast lesions and biopsy in the treatment arm.

This is extremely worrying and perhaps women should think twice before being given oestrogen using CCE - something that Dr Barry Durrant- Peatfield has been warning against for years.


A systematic review of randomised clinical trials of individualised herbal medicine in any indication

Postgraduate Medical Journal (Postgrad Med J 2007;83:633-637).

R Guo , P H Canter , E Ernst
Peninsula Medical School, Universities of Exeter & Plymouth, UK Correspondence to: Peter H Canter, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter, EX2 4NT, UK

The aim of this study was to “summarise and critically evaluate the evidence from randomised clinical trials for the effectiveness of individualised herbal medicine in any indication.”   They searched electronic databases and approached experts in the field to identify randomised, controlled clinical trials of individualised herbal medicine.

Two authors independently extracted data to find the final trials for use in the study. 
The Alliance for Natural Health state, “You would be forgiven for thinking that this was a review of dozens or even hundreds of studies. But just three? Yes, although Prof Ernst and colleagues started their review with a hopeful 1345 references in the peer reviewed literature, their particular and harsh inclusion criteria managed to whittle away some 98.8% of the references leaving just 0.2% - i.e. three! How the journal allowed this paper to be titled “A systematic review” and how they allowed the title to include its relevance to “any indication” is anyone’s guess.

Of the three papers, one ran for 16 weeks and involved IBS sufferers, another for just 10 weeks concerning patients with knee osteoarthritis and the final one covered durations between 12 weeks and 6 months, in the case of patients suffering breast or colon cancer. Can these three trials really be extrapolated to apply to “any condition” and all forms of individualised herbal medicine?”

The results of the systematic review showed that “Three randomised clinical trials of individualised herbal medicine were identified. Statistically non-significant trends favouring active over placebo treatment in osteoarthritis of the knee probably result from large baseline differences and regression to the mean. Individualised treatment was superior to placebo in four of five outcome measures in the treatment of irritable bowel syndrome, but was inferior to standardised herbal treatment in all outcomes. Individualised herbal treatment was no better than placebo in the prevention of chemotherapy-induced toxicity.”

ANH believe that the trials used are not scientifically meaningful as compared when they apply to just three types of condition and cover such short durations, when the real knowledge about these products is among practitioners who have benefited from thousands of years of clinical practice.

It is no surprise, then, that the conclusion of the review shows that   “There is a sparsity of evidence regarding the effectiveness of individualised herbal medicine and no convincing evidence to support the use of individualised herbal medicine in any indication.”

ANH state, “it is the authors’ choice of blatantly incorrect title and conclusion that appears to have been carefully selected to do damage to the herbal medicine sector. Strange as this might seem, regulators around the world are looking for excuses to medicalise herbal products. Wouldn’t this be just the ticket, or at least another nail in the coffin, to try to show that the evidence base is weak, that herbal medicines might be dangerous and that they, in any case, don’t work? Although the authors claim to have consulted herbal practitioner associations during the course of their work, judging by the reaction we’ve heard just today, on the day of release of the study’s findings, we are not convinced many herbal medicine practitioners will support the study’s conclusion.

Scientists like Prof Ernst have become so introspective over their worship of their reductionist methods that they fail to see how they do or don’t relate to the much, much bigger picture of how extremely complex and diverse, natural substances interplay with even more complex and diverse genomes. This truly is an abuse of science.”

ANH need all the help they can get to counter this systematic review and to fight for our right to use herbal medicine.



Most physicians have no confidence in their own ability to use medical statistics

Published in Journal Watch General Medicine August 29, 2007

A survey from the Mayo Clinic documents how insecure most doctors feel about using statistics in respect of evidenced based medicine.

301 medical students, internal medicine residents, and internal medicine faculty members completed a questionnaire (response rate 64%), and only a small minority agreed they had had adequate training in medical statistics (17%), could tell when the correct statistical methods were used in a study (23%), could conduct their own statistical analyses with confidence (15%), or could design their own research with confidence (28%).  The teaching staff were seldom confident using statistics independently and even among respondents with extensive self-reported research experience, only 55% were confident conducting their own statistical analyses. Almost 80% of respondents felt a biostatistician should be centrally involved in most research.

Abigail Zuger, MD commented,  “This study's results certainly ring true: It seems only the rare physician is truly fluent in statistics and in the language of medical research. Further, while researchers may collaborate with biostatisticians on their projects, clinicians struggling to explain new studies to patients are on their own and often make big mistakes. The authors suggest that evidence-based medicine become the vehicle for more-effective training in biostatistics for all.”


West CP and Ficalora RD. Clinician attitudes toward biostatistics. Mayo Clin Proc 2007 Aug; 82:939-43.


Mandatory Disclosure of Trial Results for Drugs and Devices

We have long considered the drug industry to be less than honest and recent trials have shown this to be true.

The study, “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy” by      Erick H. Turner, M.D., Annette M. Matthews, M.D., Eftihia Linardatos, B.S., Robert A. Tell, L.C.S.W., and Robert Rosenthal, PhD showed that  31% - 3449 study participants - were not published. The researchers found that “Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies).

According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.” They concluded that they could not determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. They felt that “selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

However, this may soon be a thing of the past as from September 2008, a new US law will mandate the public disclosure of results.  The FDA Amendments Act, states  that any ongoing clinical trial involving a drug, biological product, or device regulated by the US Food and Drug Administration (FDA) must be registered at

clinicaltrials.gov and that, from 27 September 2008, triallists must start to post in that same registry the results of those trials. This applies to all clinical trials of drugs and devices except phase I drug trials (preliminary safety studies for new products) and small feasibility studies of a device. Furthermore, it covers all trials—whether or not they are conducted and sponsored by industry and wherever they are conducted—if the products concerned need approval by the FDA.

There will be fines for anyone who fails to comply and they will be publicly named on clinicaltrials.gov.

The results must be published within one year of the date that "the last subject was examined or received intervention for purposes of final collection of data for the primary outcome.” The BMJ support this regulation and will no longer consider unregistered trials for publication.  Researchers must post on clinicaltrials.com two tables giving all the key results for the main outcomes and from 2009 they must post two tables of any harms.  More consultations may lead to further disclosures being mandatory.

There are challenges for journals. They may not want to publish results that have been published on clincaltrials.gov.  However, I feel this is a great leap forward. At least we will soon know of all trials and their outcomes and be able to make an informed choice about the drugs.