Blog entry by Meguid El Nahas

Picture of Meguid El Nahas
by Meguid El Nahas - Sunday, 14 July 2013, 10:28 AM
Anyone in the world

EXAMPLES OF FRAUD IN MEDICINE AND IN STUDIES INVOLVING RAS INHIBITION IN JAPAN:

July 12, 2013

Diovan Data Was Fabricated, Say Japanese Health Minister And University OfficialsReply

by Larry Husten • People, Places & EventsPolicy & Ethics • Tags: Hiroaki MatsubaraJapan,KyotoKyoto Prefectural University of MedicineNovartisscientific misconductvalsartan

 

Following a long series of accusations, retractions, and the resignation of a prominent professor, it now is clear that data from a large Japanese study of valsartan (Diovan, Novartis) was fabricated. On Thursday officials at Kyoto Prefectural University of Medicine said that “had patient records been used in their entirety,” the Kyoto Heart Study “would have had a different conclusion,” reported AFB.

In 2009 the Kyoto Heart Study investigators, including the chief investigator, Hiroaki Matsubara, reported that treatment with valsartan resulted in significant cardiovascular benefits independent of the drug’s blood-pressure lowering effect. Now officials at the university say the drug had no such effect.

On Friday Norihisa Tamura, Japan’s health minister, said data had been “fabricated and falsified.” Tamura said he would set up a committee to prevent episodes like this from happening again.

and in the past:
 

RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial

Dr Naoyuki Nakao MD a Corresponding AuthorEmail AddressAshio Yoshimura MD aHiroyuki Morita MD aMasyuki Takada MD bTsuguo Kayano MD bProfTerukuni Ideura MD a

Summary

Background

Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximumdose, in patients with non-diabetic renal disease.

Methods

336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat.

Findings

Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0·38, 95% CI 0·18—0·63, p=0·018) and 20 (23%) of 86 on losartan alone (0·40, 0·17—0·69, p=0·016). Covariates affecting renal survival were combination treatment (hazard ratio 0·38, 95% CI 0·18—0·63, p=0·011), age (1·30, 1·03—2·29, p=0·009), baseline renal function (1·80, 1·02—2·99, p=0·021), change in daily urinary protein excretion rate (0·58, 0·24—0·88, p=0·022), use of diuretics (0·80, 0·30—0·94, p=0·043), and antiproteinuric response to trandolapril (0·81, 0·21—0·91, p=0·039). Frequency of side-effects with combination treatment was the same as with trandolapril alone.

Interpretation

Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched.
 
Comments:
 
These are very disturbing reports of fraudulent publications in Japan relating to the efficacy and superiority of RAAS inhibitors whether Trandolapril in combination with Losartan on the progression of CKD (Nakao et al) or the Kyoto Heart Stduy on Valsartan cardioprotective effects independlently of changes in BP...so why is this taking place in Japan but undoubtedly elsewhere.
 
Back to Bad Pharma...and Bad Doctors....but alo Japan...
 
Most clinical traisl of new therapeutic agenst are sponsored by the Pharmaceutical Industry; Good Pharma, without it we wouldnt be treating many life threatening medical conditions.
 
But
1. Most clinical investigators in many emerging (and emerged as well...) countries are targeted by the Pharma industry; they are receiving remunarations for their involvement in such clinical trials; in the form of money, in the form of recognition, in the form of prominence and fame in their profession...doctors like all humans are responsive to such incentives...
Consequently, doctors and invetigators involved in clinical trials want to please their paymater...the Big Pharma who recruits them.
 
2. Pharma analyses the result of the RCTs they sponsor....statisticians and analysts employed by the Pharma company almost exclusively analyse the result and data of the study; they "clean" it..."process"...it and ultimately provide investigators with a sanitised version of the outcome of the trial...
This is dangerous as it invites manipulation of the data by the Pharma employees to please their paymaters....Bad Pharam!
This has come to light in the UK with a major Pharma company in a trial on osteoporosis where the raw data emanating of the trial were not shown or shared with the investigators but instead the sanitised version of the Pharma analysis leading to questions posed by the likes of Dr Aubrey Blumsohn (who wasnt paid by them) about the conduct of senior investigatores including Prof Richard Eastell (who was a senior consultant to the Pharma):
http://www.bmj.com/content/339/bmj.b5293
 
3. Next, why are these fradulent reports emanating repeatedly from Japan?
This brings to mind issues relating to Japanese culture, and the deferential approach to authority and seniority. 
Dont challenge, dont question...authority; If the Professor says that the trial is positive....who is the junior investigator or company employee to challenge him (seldom her...). Whistleblowing is not yet part of japanese culture. Whistelblowers are fired...marginalised or even prosecuted...this was highlighted in the report by Michael Woodford, who was the Olypmus camera company Chief Executive Office (CEO), who reported alarmingly bad and fraudulent practices in the Japanese company he was head of; he was fired and sued by the company! he wrote "EXPOSURE" counterattacked and got vindicated as bad and fraudulent practices were confirmed and the company found guilty of malpractices...
He wrote a book: "EXPOSURE" that puts the fraudulent practice of Olympus in the context of the Japanese society and its culture. he attributed malpractices in Japan industry to over-deferential attitude to authority and seniority. This may also be symptomatic of japanese healthcare companies and medical investigations.
 
WHISTELBLOWING IS HEALTHY AND OFTEN JUSTIFIABLE....BUT THE WHILSTLEBLOWER SHOULD BE WILLING TO PUT HIS JOB ON THE LINE AS DR AUBREY BLUMSOHN AND MR MICHAEL WOODFORD DID...they both rendered a huge service to probity and transparency in Pharma and Industry in general!
 
BIG PHARMA needs to think again the conduct of their clinical trials....BAD DOCTORS need to be checked and challenged by those working with them and collaborating in their clinical investigations worldwide...as Scientifc Fraud is not a Japanese Exclusive....it is prevalent worldwide:
This is very nciely reviewed in this BMJ paper,  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702092/?report=classic,
listing:
Lack of Ethics
Career Ambitions/Promotion
Financial Rewards
Academic and Professional Rewards
But also Lack of Institutional monitoring and vigilance
 
A Must read for all clinical investigators!
[ Modified: Thursday, 1 January 1970, 1:00 AM ]