Princess Health and Transparency International Reports on Massive Corruption in the Pharmaceutical Sector - Media Hardly Notices. Princessiccia

Princess Health and Transparency International Reports on Massive Corruption in the Pharmaceutical Sector - Media Hardly Notices. Princessiccia

anechoic effect deception health care corruption manipulating clinical research marketing pharmaceuticals suppression of medical research Transparency International

Gusty 07:28 Add Comment

Health Care Corruption as a Taboo Topic

Transparency International (TI) defines corruption as

Abuse of entrusted power for private gain

In 2006, TI published a report on health care corruption, which asserted that corruption is widespread throughout the world, serious, and causes severe harm to patients and society.

the scale of corruption is vast in both rich and poor countries.

Also,

Corruption might mean the difference between life and death for those in need of urgent care. It is invariably the poor in society who are affected most by corruption because they often cannot afford bribes or private health care. But corruption in the richest parts of the world also has its costs.

The report did not get much attention.  Since then, health care corruption has been nearly a taboo topic in the US.  When health care corruption is discussed in English speaking developed countries, it is almost always in terms of a problem that affects benighted less developed countries.  On Health Care Renewal, we have repeatedly asserted that health care corruption is a big problem in all countries, including the US, but the topic remains anechoic.

Yet somehow, a substantial minority of US citizens, 43%, seemed to believe that corruption is an important problem in US health care, according to a TI survey published in 2013 (look here).  But that survey was largely ignored in the media and health care and medical scholarly literature in the developed world, and when it was discussed, it was again in terms of results in less developed countries.  Health Care Renewal was practically the only source of coverage in the US of the survey's results.

Transparency International's New Report on Corruption in the Pharmaceutical Sector

Now Transparency International (TI) has tried, and Health Care Reenewal will try again.  In June, 2016 Transparency International published a new report entittled

Corruption in the Pharmaceutical Sector

The report's executive summary states:

Within the health sector, pharmaceuticals stands out as sub-sector that is particularly prone to corruption. There are abundant examples globally that display how corruption in the pharmaceutical sector endangers positive health outcomes.

In my humble opinion, the report is particularly significant in that it classifies as corrupt various kinds of activities that occur within the pharmaceutical sector (and also in other parts of health care) which are often discussed publicly as anything from standard operating procedure through unfortunate errors to unethical behavior. These include many activities which we have frequently discussed on Health Care Renewal. For example,

Manipulation of Clinical Research

We have frequently discussed how pharmaceutical companies, and biotechnology, medical device, and other health care companies and organizations, may manipulate clinical research to enhance the likelihood that is results will favor their products and marketing goals, even if the results are biased, inaccurate, could mislead physicians and patients, and ultimately harm patients.  The TI report included: 

As pharmaceutical companies rely on gaining market entry in order to recoup R&D costs, when there is a lack of oversight in clinical trial data publication a conflict of interest exists in which a pharmaceutical company may have an incentive to manipulate clinical trial data. When clinical trial data is manipulated medical literature can become biased with positive findings fabricated, positive findings exaggerated or negative results hidden. This can result in inadequate prescribing patterns because HCPs rely on clinical trial data to make decisions on which medicines to use to treat patients.

Suppression of Clinical Research

We have frequently discussed how health care organizations (as above) may outright suppress clinical research when the results fail to support their interests.  The TI report included:

Transparency and access to information through mandatory clinical trial registration, sanctions for not registering results or providing clinical trial information, and the publication of both positive and negative results are commonly discussed as helpful tools to curb corruption. With the European Medicines Agency (EMA) as a notable positive exception, public agencies and authorities do not require R&D-based pharmaceutical companies to make their raw data publicly available, making it impossible to verify whether the reported results are accurate. Based on laws and regulations clinical trial data is considered to be proprietary information, which allows pharmaceutical companies to conceal important data from the public domain.

Manipulation of the Dissemination of Clinical Research

We have frequently discussed how health care organizations may manipulate the dissemination of clinical research, through various forms of publications, presentations, courses, media summaries, etc, to favor their products and marketing goals, even if the results are misleading and could harm patients.  For example, a while back we discussed the problem of "ghost-written" articles appearing in scholarly journals. The TI report included:

The practice of ghostwriting is also a risk with clinical trials. Ghostwriting involves the writing of clinical trial publications by industry and then having a highly esteemed researcher pass these findings off as their own without disclosing their actual involvement with the authorship of the article. It is a common practice, particularly in industry led trials. Ghostwriting is done to increase the prestige and reputation of the findings, while simultaneously researchers are able to improve their reputation, which can lead to promotions. Clearly this practice can result in inaccurate results being published.

Deceptive Marketing

We have frequently discussed how marketing of pharmaceuticals (and nearly everything else in health care) may be deceptive, favoring companies' products and services, but again misleading health care professionals and patients, and ultimately risking patient harm.  In the extreme, pharmaceutical companies (and other health care organizations) may resort to bribes or kickbacks.  The TI report included:

There are several methods for a corrupt pharmaceutical company to unethically market its medicines. At its most simple a pharmaceutical company can bribe a HCP directly with payments so its medicines are more likely to be prescribed. More abstrusely individuals may include a pharmaceutical company�s medicine on the national list that is reimbursed by public funds, in return for an indirect bribe by being sent to inappropriate holiday destinations for lavish conferences.

Corrupt marketing practices also include pharmaceutical companies providing misleading information regarding the safety and efficacy of a medicine to influence doctors� prescribing habits and encouraging off-label, unlicensed use to increase sales.

Other Topics

Finally, the report mentions such issues as the revolving door, regulatory capture, etc, etc, etc

A Striking, and Strikingly Anechoic Report

Again, while the report summarizes information that is likely familiar to most Health Care Renewal readers, what is striking is that it describes manipulation of clinical research, suppression of clinical research, manipulation of dissemination of clinical research, and deceptive marketing as corruption.  That is a sentiment rarely heard in the US, and one that appears nearly taboo.  

Demonstrating the strength of the taboo, this striking report has gotten almost no attention in the media or scholarly medical and health care literature in the developed English-speaking countries.  Let me note the important exceptions, however.

I learned of the report from a brief news item from the BMJ, the prestigious UK journal that seems most at the forefront of championing the integrity of medical and health care research.(1)  The only substantial news article I could find on the report was also from the UK, in the Independent.  Its sub-title is worth repeating:

Transparency International says corruption is making a few rich and wrecking the health of some of the world's poorest people

Also, there were brief articles in Reuters, and in (web-only) FiercePharma.  That is about it so far.

The report itself suggests why it has been so anechoic, just like nearly every other attempt to expose health care corruption to public discussion.  Essentially, there is so much money to be made through pharmaceutical (and by implication, other health care corruption) that the corrupt have the money, power, and resources to protect their wealth accumulation by keeping it obscure.  In the TI Report itself,

However, strong control over key processes combined with huge resources and big profits to be made make the pharmaceutical industry particularly vulnerable to corruption. Pharmaceutical companies have the opportunity to use their influence and resources to exploit weak governance structures and divert policy and institutions away from public health objectives and towards their own profit maximising interests.

Keep in mind that the money made from corruption does not just go to innocent peoples' retirement funds that are invested in pharmaceutical stocks.  It predominantly goes to top corporate executives and managers, and their cronies who preside over the corrupt practices.


I might as well repeat myself once again.  As I wrote in 2015,

If we are not willing to even talk about health care corruption, how will we ever challenge it? 

So to repeat an ending to one of my previous posts on health care corruption....  if we really want to reform health care, in the little time we may have before our health care bubble bursts, we will need to take strong action against health care corruption.  Such action will really disturb the insiders within large health care organizations who have gotten rich from their organizations' misbehavior, and thus taking such action will require some courage.  Yet such action cannot begin until we acknowledge and freely discuss the problem.  The first step against health care corruption is to be able to say or write the words, health care corruption.

Reference

1.  Torjesen I.  Group calls for more to be done to tackle corruption in the pharmaceutical industry. BMJ 2016;353:i3099. Link here.

Princess Health and Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients. Princessiccia

Princess Health and Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients. Princessiccia

aliromucab evidence-based medicine health care prices manipulating clinical research PCSK9 inhibitor Praluent Regeneron Sanofi-Aventis

Gusty 14:34 Add Comment

Here we go again.  The same month that it approved Entresto (look here), the US Food and Drug Administration approved a new PCSK9 inhibitor cholesterol lowering agent, alirocumab, immediately marketed as the pricy Praluent by Sanofi and Regeneron, and heralded by a blast of media hype.  Yet the evidence that this drug benefits patients is lacking, and critical review of the one big published randomized controlled trial of it raises many concerns.

Media Hype

Let us first consider the media hype.  The TIME coverage started with this headline,

This New FDA-Approved Cholesterol Drug is a Game Changer

The New York Times article by Andrew Pollack quoted Katherine Wilemon, founder and president of the FH foundation, an advocacy group for patients with familial hypercholesterolemia, who have very high cholesterol values and increased risk of heart and vascular disease,

It represents a new era of hope for us.

The Washington Post article started with,

The Food and Drug Administration on Friday approved the first in a new class of cholesterol-busting drugs that many doctors believe will trigger a breakthrough in reducing the incidence of strokes and heart attacks, which kill hundreds of thousands of Americans each year.

USA Today reported,

The drugs are predicted to be blockbusters many times over, adding billions of dollars to prescription drug costs, said Steve Miller, senior vice president and chief medical officer at Express Scripts, a leading pharmacy benefit manager.

Another NY Times article by Gina Kolata directly described the drug as

powerful almost beyond belief.

Ms Colata also quoted a cardiologist who characterized the drug again as a "game changer."

To be fair, note that while the WaPo article, NYT article by Pollack and the USA Today article provided hype attributed to "doctors," or identified individuals, they also quoted some people who were very skeptical about the drug.  However, in most of the media coverage, the positivity seemed to be more prominent and extreme than the skepticism. 

The High Price

In general, the media coverage noted that the "breakthrough," "blockbuster," "powerful" new drug would not come cheap.  Praluent would cost about $14,600 a year.  Naturally, those selling it saw this as a bargain.  For example, Andrew Pollack wrote in the NYT,

Sanofi and Regeneron Pharmaceuticals, which developed the product, said the price was justified by the potential benefits to patients and savings to the health care system that the drug would provide by preventing heart attacks and strokes � though the ability of the drug to do that has not been proved.

'We came to a price that is reflective of value, not what the market will bear,' said Elias Zerhouni, head of research and development at Sanofi, who said his own brother had suffered three heart attacks and needed new options to control cholesterol.

Gina Kolata went farther,

The $14,600 yearly price of the drug, which is injected under the skin once every two weeks, is a stunner. Yet for some patients, that might actually be a bargain.

She justified this by comparing the cost to apheresis, a radical procedure to treat high cholesterol. She did not discuss whether it had any evidence of clinical benefit. Yet,

'Cost is in the eye of the beholder,' said Dr. Daniel Soffer, [Mr. DeRuchie�s cardiologist at the University of Pennsylvania.

Presumably, Dr Soffer was the one who had recommended the apheresis treatment.

Note that at best, the company that sells this drug can justify the price only in terms of potential, not actual value or results.  

No Evidence for Clinical Benefit

Praluent, generic name alirocumb, is certainly a breakthrough in that it seeks to lower cholesterol through a novel mechanism.  The drug is a biologic, a monoclonal antibody that inhibits the enzyme PCSK9.

Yet a close reading of the one large published randomized controlled trial of alirocumab(1) belays the hype beyond that.  The study by Robinson et al was a double blind randomized controlled trial of alirocumab injections every 2 weeks versus placebo.  The protocol called for patients to be treated for 78 weeks, and followed for 8 more weeks, a bit more than one and one-half years.

Loss to Follow Up and Missing Data

The study enrolled 1553 patients in the alirocumab group, and 788 in the placebo group.  However, many patients did not complete the study: a total of 437 (28.1%) in the alirocumab group, and 193 (24.5% in the placebo group).  Reasons for noncompletion were adverse events (113, 7.2% alirocumab vs 47, 6.0% placebo); "nonadherent" to treatment (60, 3.9% vs 38, 4.7%), and "other reason," (264, 17.0% vs 108, 13.7%).

So the drop out rate was fairly high.  It was particularly troubling that the reasons for most of the drop outs were vague "other reaons."  I could not find a clarification of this term in the main article or  supplemental materials.

Furthermore, it was not clear how the investigators intended to collect data from patients after they dropped out, and how complete data collection about clinical events was for patients who dropped out.  (Note that for patients that dropped out, the investigators simply imputed, that is estimated cholesterol values, but did not necessarily measure them.  So even this measure was "potential.")

Drop outs and missing data are classically problematic because patients may drop out after suffering  events that could be counted as study outcomes.  The rate of these events could differ according to treatment group.  If patients who dropped out of the alirocumab group had more adverse events than those who dropped out of the placebo group, and these events were not recorded, the high drop out rate could have concealed important harms of the drug.

Thus it is quite possible that the study by Robinson et al undercounted adverse events due to aliromucab.

Multiple Study Sites

The study enrolled patients at a remarkable number of sites, 320 in 27 countries, so that the average number of patients enrolled per site was only seven.    It seems improbable that a study involving so many investigators and centers, most of whom must have devoted little of their time and effort to this particular study, would have adequate quality control.  I could not find a discussion of implementation quality control in the published article.

Thus it is possible that poor quality of study implementation, which could have affected enrollment and data collection, may have challenged the validity of the Robinson et al study.

 Lack of Generalizability in the Patient Population

The complete list of exclusion criteria, only appearing in the supplementary material, was extensive.  Patients with many common problems were supposed to be excluded, and the definition of the some exclusion criteria were vague and subjective.

Common conditions leading to exclusion were:
- Recent heart and cardiovascular problems, i.e., "(within 3 months prior to the screening visit [Week -3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack, endovascular procedure or surgical intervention for peripheral vascular disease."
- "Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during the study"
-  Severe congestive heart failure, i.e., "New York Heart Association Class III or IV heart failure within the past 12 months"
- Poorly controlled hypertension, i.e., "Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at screening visit or randomization visit."
- "History of hemorrhagic stroke."
- "History of active optic nerve disease."
- Use of systemic corticosteroids, other than for replacement 
- "History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer."
- "History of HIV positivity."
-   "Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (confirmed by reflexive testing)."
- Kidney dysfunction, specifically, "eGFR <30 nbsp="" p="">- Poorly controlled diabetes, specifically, HbA1c >10%.
- Abnormal liver enzymes, specifically, ALT or AST > x ULN

Vaguely described exclusions were:

E 25. Conditions/situations such as:
A) Any clinically significant abnormality identified at the time of screening that in the
judgment of the Investigator or any sub-Investigator would preclude safe completion
of the study or constrain endpoints assessment such as major systemic diseases,
patients with short life expectancy.
B) Patients considered by the Investigator or any sub-Investigator as inappropriate
for this study for any reason, e.g.:
i) Those deemed unable to meet specific protocol requirements, such as scheduled
visits.
ii) Those deemed unable to administer or tolerate long-term injections as per the
patient or the investigator.

Also,

iv) Presence of any other conditions (eg, geographic, social�.) actual or anticipated,
that the Investigator feels would restrict or limit the patient�s participation for the
duration of the study.

Thus the study would have excluded patients with a variety of common conditions, and may have excluded many other patients based on rather poorly defined decisions by individual investigators.  Since patients in clinical practice commonly have common conditions, the generalizability of the results of this study to many practices and patients was not clear.

No Evidence of Clinical Benefit

Patients should not be subject to treatments whose benefits do not clearly outweigh their harms.  The Robinson et al article focused on reductions in measured cholesterol, particularly LDL cholesterol.  The new drug certainly did seem to clearl reduce cholesterol, particularly LDL cholesterol.  However, these are only the results of laboratory tests.

Although high cholesterol and high LDL cholesterol indicate increased risk of future cardiac events, many patients with abnormal values do not have such events.  Having a high cholesterol or LDL cholesterol does not directly cause symptoms, or dysfunction.  Thus simply lowering cholesterol does not immediately or directly benefit patients.  Furthermore, other drug have been shown to lower cholesterol, but ultimately they accomplished this without ever being shown to benefit patients, e.g., by preventing heart attacks, strokes, or premature death.

However, cholesterol values are considered intermediate or surrogate variables.  They are not directly related to what happens to patients, who they feel or function, whether they get new diseases, or when they die.  So only showing that the new drug lowers cholesterol does not prove clinical patient benefit.

Although the published trial did attempt to record cardiovascular events, it did not find that the drug prevented them.  The small difference in total cardiovascular events affecting patients given alirocumab (4.6%) versus placebo (5.1%) did not reach statistical significance, that is, could well have been due to chance alone.

Furthermore, while elevated cholesterol is a chronic problem, and the problems with which it is correlated occur over the long run, the study ran for less than 2 years.  It could not measure the effects of the new drug beyond that.

So the clinical benefit of the drug was not evident in this trial.

On the other hand, the drug was not without its own risks.  More patients who received aliromucab left the study due to adverse events (7.2%) thand did those who got placebo (5.8%),  as noted above.  Also, as noted above, it was possible that adverse events affecting dropouts were not fully recorded.  Given that there were higher rates of dropouts due to non adherence and "other" reasons among patients who received alirocumab, the study might still have missed important adverse effects of the new drug.

So the study did not prove that the new drug has any clinical benefits, showed it does have clinical harms, and could still have easily underestimated its harms.  So it certainly did not show it had benefits that outweighed its harms.

Summary and Conclusions

The NEJM study was accompanied by an editorial by Stone and Lloyd-Jones(2) which documented that drugs previously shown to lower cholesterol were never proved to do any good for patients, and concluded,

it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. 

After an FDA advisory committee recommended approval of aliromucab in June, 2015, John Mandrola entitled a Medscape article,

Dear FDA: Resist the Urge on PCSK9 Drugs

His reasons included lack of proof of clinical benefits, and concerns that harms may have been missed but mainly because of its inability to detect long-term outcomes.


Again, the current media articles also noted the concerns raised by Dr Mandrola and the NEJM editorial These concerns, however, did not dissuade the FDA from approving aliromucab.  These concerns did not apparently affect the pricing of Praluent.  These concerns will likely not deter the drug manufacturers from continuing an aggressive marketing campaign.  Whether these concerns will deter physicians from prescribing, or patients from asking for these drugs is unknown, but unlikely.

And I have not seen anything published so far that addressed how the problem with dropouts and missing data may have lead to further underestimation of aliromucab's harms, the multiplicity of study sites may have lead to quality control problems further challenging the study's validity, and the extensive exclusion criteria may have reduced the study's generalizability.

So here we go again.  Another new drug is put on the market accompanied by a mighty hoopla, yet in the absence of clear data that it does more good for patients than harm.

As we said last year about valsartan-sacubitril, also just (July, 2015) put on the market as Entresto, at a high price and with lots of hype,...

All the enthusiasm about this drug may be premature, and does not appear to be evidence-based.  That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors' products look better than they really are is now an old story.  We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised.  Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.  Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. 

Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.


How high must our health care costs go, and how many unproven treatments must eventually be exposed as such before we learn that lesson?

ADDENDUM (6 August, 2015) - Fixed minor errors: misspelling of Ms Kolata's name fixed, misstatement re apharesis fixed, erroneous reference to second approved PCSK9 inhibitor removed.  

ADDENDUM (9 August, 2015) - Note that his post was republished on the Naked Capitalism blog.  


References
1. Robinson JG, Farnier M, Krempf M et al.  Efficacy and safety of alirocumab in reduincg lipids and cardiovascular events.  N Engl J Med 2015; 372: 1489-1499.  Link here.
2.  Stone NJ, Lloyd-Jones DM.  Lowering LDL cholestero is good, but how in whom?  N Engl J Med 2015; 372: 1564-5.  Link here.  

Princess Health and Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year. Princessiccia

Princess Health and Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year. Princessiccia

CHF clinical trials Entresto evidence-based medicine manipulating clinical research Novartis sacubitril

Gusty 07:54 Add Comment

The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price.  Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.  


Questions Raised by the One Big Published Controlled Trial

Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.

Does Sacubitril Actually Work?

 The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril.  Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF.  However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day.  Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done.  So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril.  Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.

What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?

The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan.  Furthermore, the trial had an active run-in period which resulted in the exclusion of  patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period.  This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial.  Finally, the trial, while big, was not big enough to discover rare but severe adverse effects.  Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.

How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?

The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease.  CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.

Other Doubts and Questions

In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity.  These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.

As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions.  As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.

So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.

More Enthusiasm and Hype about Entresto

These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it.  As soon as it was approved, the hype machine started up in a big way.

Per the NY Times,

'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis�s pharmaceutical division, said in an interview.

Per the Wall Street Journal,

Clyde Yancy, chief of cardiology at Chicago�s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It�s clearly superior to what we have.'

Per a Medscape news post, Dr Clyde Yancy also said,

A year later, I continue to feel that this is, in fact, a reflection of a new day�for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.

And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,

I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.

The Medscape article did document some doubts.  Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem.  Finally, Dr Yancy allowed that the early termination might be a problem.   Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem.  Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,

Can we change the narrative?  I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.

Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis.  Is is possible these commercial relationships tempered any concerns that might have had about the study design. 

I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death.  So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer.  But is it crystal clear the latest innovation is that good?

Billions of Dollars in Play

But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap.  Per the NY Times,

Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....

Novartis wants to convince you that it's not really that expensive

Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.

He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice.  Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either. 

In the financial news, you could almost imagine the salivation.  Per the WSJ,

Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.

In Reuters,

Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.

Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.

'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'

Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year.  But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?

Summary

We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections.  Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.

Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.

 Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor.  It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better.  As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,

When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.

To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits.  The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here).   Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous.  This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.


The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism.  We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them.  The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.

True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care. 



References

1.   McMurray JJV, Packer M, Desai AS et al.  Angiotensin - neprilysin inhibition versus enalapril in heart failure.  N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077  Link here.

2.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.

Princess Health and Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen? . Princessiccia

Princess Health and Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen? . Princessiccia

anechoic effect AstraZeneca atypical anti-psychotics clinical trials conflicts of interest manipulating clinical research research subjects suppression of medical research University of Minnesota

Gusty 13:53 Add Comment

Years after his death, there is now a little more clarity about the clinical trial in which Dan Markingson was enrolled when he died.  Whether this clarity will have any impact remains to be seen.

We most recently posted about the aftermath of Mr Markingson's death here, (and see posts in 2013 here, and in 2011 here.)  Very briefly, Mr Markingson was an acutely psychotic patient enrolled in a drug trial sponsored by Astra Zeneca at the University of Minnesota.  His enrollment was said to be voluntary although at the time he enrolled he had been under a stayed order that could have involuntarily committed him to care.  Despite his mother's ongoing and vocal concerns that he was not doing well on the study drug and under the care of trial investigators, he continued in the trial until he died violently by his own hand.  After his death, his mother Mary Weiss, friend Mike Howard, and University of Minnesota bioethics professor Carl Elliott campaigned for a fair review of what actually happened.  University managers not only rebuffed their concerns, but harshly criticized Professor Elliott, and ended up reprimanding him for "unprofessional conduct."

Two New Reports

In the last few weeks, two new independent reports on the case appeared.  Both vindicated the concerns and questions raised by Mary Weiss, Mike Howard, and Prof Elliott.

Association for Accreditation of Human Research Protection

One, called for by the University of Minnesota faculty senate, was by the Association for Accreditation of Human Research Protection,  and said that the university left research subjects "susceptible to risks that otherwise would be avoidable" (see this Minneapolis Star-Tribune article.)  Furthermore, according to a post in the Science Insider blog from the American Association for the Advancement of Science, it said,

[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,

Also, it said the university has been

assuming a defensive posture. In other words, in the context of nearly continuous negative attention, the University has not persuaded its critics (from within and outside the University) that it is interested in more than protecting its reputation and that it is instead open to feedback, able to acknowledge its errors, and will take responsibility for deficiencies and their consequences.

Finally, it noted a "climate of fear" in the Department of Psychiatry.

Office of the Legislative Auditor for the State of Minnesota

The second report, available in full here,was from the Office of the Legislative Auditor for Minnesota.  If anything, it was more damning. Its summary included,

the Markingson case raises serious ethical issues and numerous conflicts of interest, which University leaders have been consistently unwilling to acknowledge. They have repeatedly claimed that clinical research at the University meets the highest ethical standards and dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews. This insular and inaccurate response has seriously harmed the University of Minnesota�s credibility and reputation.

It seemed to affirm in detail nearly all of Weiss', Howard's and Elliott's concerns.  It recommended that the University should suspend new psychiatric drug trials until the problems it identified were remedied (see Star-Tribune article here.)

Vindication, but Will It Lead to Progress?  

Taken together, these reports vindicate the work of Mr Markingson's mother, friend, and academic watchdog Professor Elliott and their supporters.  As the Star-Tribune reported,

'Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,' wrote Mike Howard, a close friend to Markingson�s mother, in a letter in the audit. 'This report is the first step toward accountability.'

The Minnesota Post added the response of Professor Elliott and a colleague,

'It�s nice to have an independent confirmation of what we�ve been telling the university for five years, but which they have refused to listen to,' he told MinnPost on Thursday.

Elliott said he is not convinced, however, that Kaler and other university leaders are going to take responsibility for what happened in the Markingson case � or take the necessary steps to fix the problem going forward.

'One of the most worrying findings in the report was the widespread belief on campus that the university leadership doesn�t care about human study subjects,' he said.

Leigh Turner, another U bioethicist who has also been outspoken about the issues raised by the Markingson case, expressed similar concerns. 'Can we expect reform from the very people who have done nothing for the past several years?' he said in a phone interview.

'I hope there�s some change,' he added. 'But the fact that [Markingson died in 2004] and it�s now 2015, I think hope has to be tempered with a dose of realism. There are some very powerful forces interested in minimizing the findings and suggesting that there are only minor things that need to be done.'

It appears there a several major remaining questions.

What Were the Underlying Causes?

Although both reports went into some detail about what happened to Mr Markingson, they seemed not to dwell on why it happened.  They did not seem to address relevant contextual factors, policies, and decisions.  For example, the report by the Office of the Legislative Auditor included,

We understand that the University of Minnesota has been and should continue to be an institution that delivers not only high quality medical care but also engages in cutting edge medical research� research that does pose risks to human subjects. In addition, we do not question the appropriateness of the University obtaining money from pharmaceutical and other medical companies to support that research. However, in every medical research study�whether supported with public or private money�the University must always make the protection of human subjects its paramount responsibility.

However, as we and many others more erudite have discussed frequently, clinical research that evaluates products or services made by the commercial sponsors of the research has proven to be highly susceptible to manipulation by these sponsors to increase the likelihood that the results will serve marketing purposes, and suppression if the manipulation fails to produce the wanted results.  Commercial sponsors often strongly influence the design, implementation, analysis and dissemination of clinical research.  Often their influence is mediated by financial relationships with individual researchers and with academic institutions who seem more and more beholden to outside sponsors, that is, by conflicts of interest.  The report by the Auditor noted pressures, including financial pressures on the physician who ran the study in which Mr Markingson was a subject to enroll more patients and keep them enrolled.  To protect patients better in the future, in my humble opinion the relationships among commercial sponsors, academic medical institutions, and individual researchers need further consideration.  Is the easy money supporting research coming from commercial firms with vested interests in the outcome of that research really worth the risks of biased results, hidden results, and to research subjects?   

Will Anything Change and Will Anyone be Held Accountable?

Once these two reports were delivered, it now seems to be up to university managers to make needed changes.  In general, these are the same managers who are described above as so "defensive," who not only ignored complaints, but appeared to try to silence those who complained.  If they are left in charge, why should we expect them to make any meaningful changes?  Instead, should they  not be held accountable for their actions?  

Will the University Cease Hostilities Against Dr Elliott?

Again, as noted above, university managers did not merely disagree with Professor Elliott.  They disparaged him, appeared to try to intimidate him, and reprimanded him.  It seems at the very least he is owed an apology.  So far, nothing in the news coverage suggests he has or will receive one.

Will Anyone Notice? 

So far, this case has gotten good coverage in Minnesota media.  However, it has largely been ignored in the national media.  Beyond Minnesota, I could only find mention in some blogs, e.g., in PharmaLot by Ed Silverman, and in Forbes by Judy Stone.  I have seen nothing in any US medical or health care journal, although the British Medical Journal did cover it in a news feature.  This case clearly has global implications, and ought to be considered one of the most important cases illustrating the perils of commercially sponsored human research, but it remains proportionately anechoic.

Summary

The latest reports seem only to confirm that clinical research at major academic institutions has gone way off track.  It now seems that in their haste to bring in external funding, university administrators and the academic researchers who are beholden to them have sadly neglected the protection of their own patients.  As we have said ad infinitum, true health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (25 March, 2015) - See also numerous posts by Professor Elliott on the Fear and Loathing in Bioethics blog,  by Bill Gleason in the Periodic Table blog,  and by Mickey Nardo on the 1BoringOldMan blog. 

ADDENDUM (30 March, 2015) - Note that after receiving offline comments, I changed the first paragraph to emphasize the clarity is about the trial, rather than the patient's death, and second paragraph to clarify that the order to commit was stayed.

Princess Health and How the Anechoic Effect Persists: The Case of the Continued Punishment of Dr Elliott . Princessiccia

Princess Health and How the Anechoic Effect Persists: The Case of the Continued Punishment of Dr Elliott . Princessiccia

academic freedom adverse effects anechoic effect free speech intimidation manipulating clinical research mission-hostile management University of Minnesota

Gusty 13:02 Add Comment

We have frequently discussed the anechoic effect, how evidence and opinions that challenge the dysfunctional status quo in health care, and that might discomfit those in power in benefit from it, have few echoes.  One major reason for the anechoic effect is that people are afraid to speak up because thus disturbing the powers that be may have bad consequences for the speakers.   

A December 21, 2014 article in the Minneapolis Star-Tribune updated an ongoing example of how the leaders of health care may seek to silence their critics.  The article updated the career trajectory of Dr Carl Elliott, a psychiatrist physician and bioethicist at the University of Minnesota who dared challenge the university's handling of the untimely death of a patient in a university run clinical trial.

Background - the Dan Markingson Case

We first blogged about this case in 2011.  The case itself dates from 2003, and first got media attention in 2008.  A good quick summary appeared in the Center for Law and Bioscience blog out of the Stanford Law School. 

Dan Markingson � a vulnerable, psychotic young man � was forced to choose between enrolling in a Pharma-funded drug study or being involuntarily committed (in other words, locked up).  A UMN [University of Minnesota]  doctor enrolled him in the study despite having just determined that Dan 'lack[ed] the capacity to make decisions regarding [his] treatment,' rendering it highly unlikely that Dan could have given valid informed consent to participate.  As Dan's mother, Mary Weiss, observed his mental condition deteriorating, she repeatedly tried to have Dan removed from the trial � at one point asking  'Do we have to wait until he kills himself or someone else before anyone does anything?'  But the UMN co-investigators in the drug study refused to terminate his participation.  Shortly after Ms. Weiss made her desperate plea, Dan Markingson killed himself by cutting his own throat.

Dr Elliott, an expert in bioethics who had concentrated on issues such as the effect of conflicts of interest and commercial influences on clinical research, started probing the death of Mr Markingson after the 2008 media reports.

Some of what Dr Elliott found appeared in a May 23, 2014 article in Science. He concluded that previous efforts to investigate the death of Mr Markingson were flawed.

 Elliott came to believe that every investigation�not only by FDA but also by the Minnesota Board of Medical Practice, the university's IRB, and its general counsel's office�had been flawed or incomplete. FDA did not seek Weiss's perspective, the views of Markingson's caseworker, or interview staff at the halfway house who had interacted with Markingson, for instance. (FDA would not comment on the Markingson case for this story.) Nor did the agency examine conflicts of interest. Weiss's lawsuit was dismissed not on its merits, but because the university's IRB and Board of Regents were deemed immune from liability thanks their role as state employees. (The judge did argue that informed consent was obtained appropriately, because Markingson had signed the consent form and had not been declared mentally incompetent by a court.)

Furthermore, he found reasons to think that the problems with the trial in which Mr Markingson died were not unique.  He and a colleague

heard from other individuals who insisted that they had been harmed in UMN psychiatric drug trials or had witnessed others' mistreatment. One man said he had worked in the psychiatric units of the hospital where Markingson was treated. Another identified herself as a counselor for teenagers. Elliott heard from parents, who said their son or daughter had enrolled in a study under pressure.

Thus, Dr Elliott and others concluded that the university should do a thorough investigation of the case,

In November 2010, eight faculty members, including Elliott and [McGill University bioethicist Leigh] Turner, wrote a letter to the university's Board of Regents, requesting an independent, university-commissioned investigation into the Markingson case.

The Punishment of a Dissident

As the Science article noted, former Minnesota Governor Arne Carlson said that the

university hired Elliott because it 'found him to be one of America's most outstanding bioethicists. The moment he comes up with something that is sensitive to them, he becomes the village idiot.'

In fact, as we noted in 2013, in a 2012 post in the Center for Law and Bioscience blog, not only did university officials rebuff the call for a new, thorough investigation of the untimely death of Mr Markingson, but the university general counsel, who had been operating at the heart of this case, appeared to threaten the leading bioethicist dissident, Dr Carl Elliott:

 After Carl Elliott, the University of Minnesota bioethicist, refused to drop the matter, [university chief counsel] Rotenberg asked the university�s Academic Freedom and Tenure Committee to take up the question of '[w]hat is the faculty[�s] collective role in addressing factually incorrect attacks on particular university faculty research activities?' � a question that appeared both to accuse Elliott of 'factually incorrect attacks' and to call for some unspecified action to 'address' them.  Other faculty, including the president of the Minnesota chapter of the American Association of University Professors, viewed this as an attempt to intimidate Elliott into silence.  If so, it backfired.  The story ended up in the press, putting the Markingson case back in the public eye and once again making the University of Minnesota look really bad.

The December 21, 2014 Star-Tribune article reported that university administrators seem to be out to get Dr Elliott once again. First, it interviewed the university's chair of psychiatry,

[Dr S Charles] Schulz, the department chair, says he can�t even bear to read Elliott�s published accounts anymore. 'It�s too painful,' he said.

Both he and Olson say that Elliott gives only one side of the story and that he ignores the facts that don�t support his case.

'I think [people] believe that because Carl Elliott is a professor of bioethics and a member of the Center for Bioethics, that he must be telling the truth,' said Olson. But 'he�s not pursuing this in an academic way. I don�t think it�s conduct that becomes a faculty member and a peer.'

What is not academic or unbecoming about investigating the death of a vulnerable psychiatric patient during a clinical trial is not clear. Then,

University officials have not been amused. They accuse Elliott of whipping up hysteria with 'false and unfounded' allegations, and undermining research efforts in the process. And while the university hasn�t tried to fire him, it has reprimanded him for 'unprofessional conduct,' a move that he�s now challenging under the tenure code.

Again, rather than investigating the death of Mr Markingson, or at least responding to specific allegations, university administrators have set about to punish their own distinguished faculty member who wondered why a vulnerable patient died during a university run clinical trial. 

Finally,

So far, academic freedom has protected Elliott�s job. But last winter, the university claims, he crossed a line. It accused him of using a 'fabricated letter' in a speech about the Markingson case at Hamline University and demanded that he issue a retraction.

The 2004 letter, addressed to Weiss, Markingson�s mother, appears to be from a university lawyer disputing her right to her son�s medical records. The U says it�s a forgery; Elliott says he doesn�t believe it, and he refused to issue a retraction. He called it an attempt to discredit Weiss, adding: 'I won�t be part of it.'

Elliott received a letter of reprimand in August from Dr. Brooks Jackson, the current dean of the Medical School, citing him for 'significant acts of unprofessional conduct.' The reprimand is on appeal.

The evidence that the letter was a forgery was not apparent.  Yet while they pursue their own faculty member for his investigation of Mr Markingson's death, university managers still apparently have not addressed the many problems in the university's version of the story of Mr Markingson's death, from the fragmentary nature of previous investigations to the problems just revealed in a Scientific American blog with the knowledge of an expert witness for the university in the lawsuit brought by Mr Markingson's mother against it.  

Summary

Dr Carl Elliott is a respected physician bioethicist who has uncovered problems with commercial contract research organizations doing human research (see our blog posts here and here), and has written a critically acclaimed book, White Coat, Black Hat (reviewed here by Dr Howard Brody on his blog.)  Yet his previous work counted for naught when he dared look into possibly unethical clinical research done at his own university.  As noted in the Star-Tribune article,

Within the U�s Center for Bioethics, where he has worked since 1997, he says the tension is so palpable that he dreads setting foot in his office. He does most of his work from coffee shops.

In my humble opinion, it appears that top university managers have put their personal interests ahead of the mission of their university, the role of their faculty members in upholding that mission, and even the welfare of patients who put their trust in the university's academic medical center.  The hard life that Dr Elliott has lead since he started to challenge his own university's administrators show how the anechoic effect is generated.  As long as leaders of academic medical institutions, and other health care organizations can put their own interests ahead of the mission, health care professionals and other academics who object are likely to have their lives made miserable, possibly lose their jobs, or worse.  How many will have both the courage, and the resources to stand up for what is right under such a threat.

True health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (30 December, 2014) - Post corrected.  Dr Elliott trained as a physician but is not a psychiatrist.

ADDENDUM (30 December, 2014) - also see comments on the 1BoringOldMan blog. 

Princess Health and The Reappearance of a Ghost of Seasons Past. Princessiccia

Princess Health and The Reappearance of a Ghost of Seasons Past. Princessiccia

Actonel conflicts of interest ghost writing manipulating clinical research Procter and Gamble suppression of medical research University of Sheffield whistle-blowers

Gusty 08:01 Add Comment

About a year after we started Health Care Renewal, in late 2005, we wrote multiple posts about the complex and unfortunate case of Dr Aubrey Blumsohn's attempts to keep a research project honest. The early posts were here, here, here, and here. In this post, we summarized the case thus:

• Dr Aubrey Blumsohn, a senior lecturer at Sheffield University, and Professor Richard Eastell performed a research project on the effects of the drug risedronate (Actonel, made by Procter & Gamble Pharmaceuticals [P&G]) under a contract between P&G and the University.
• Although the research contract designated Blumsohn and Eastell as "Investigators" under whose direction the project would be carried out, Blumsohn was not given access to the original data collected by the project.
• Despite numerous requests, (like this one), P&G refused access to this data repeatedly.
  Blumsohn was concerned that he and Eastell could be accused of scientific fraud if they continued to make presentations and write articles and abstracts without access to the data which they were supposedly writing about.
• Blumsohn became suspicious that some of the analyses done by P&G could be misleading, especially related to a graph shown to him that omitted 40% of patient data.
• Blumsohn objected to P&G arranging for papers and abstracts to be written by a professional writer, but with Blumsohn listed as first author. Blumsohn was concerned that such ghost-written documents were mainly meant to convey "key messages" in support of P&G's commercial interests.
• Eastell warned Blumsohn not to aggravate P&G, because the company was providing a grant to the University which "is a good source of income."
• After repeated failed attempt to get the data, Blumsohn complained to numerous officials at Sheffield University, including Eastell, medical school Dean Tony Weetman, University Vice-Chancellor Robert Boucher, and the Head of the University's Department of Human Resources, Ms R Valerio.
• Still unable to get the data, he spoke with news reporters about his case. At this point, Sheffield suspended him, but then offered him a severance agreement if he signed a contract binding him not to make any detrimental or derogatory statements about the University and its leaders.

So the case involved suppression and manipulation of research, ghost-writing, institutional conflicts of interest, and attempts to silence a whistle blower. It provides lessons about the downsides of letting commercial firms sponsor and hence control human research designed to evaluate the products or services they sell; and of academic medicine becoming dependent on research money from such firms for such research. Although Health Care Renewal, being US based, most often writes about such issues in the US, this case is a reminder that they are global. (Note that we posted more about this case in 2006, here, here and here, but since then it has not gotten much public attention.)

Last weekend the (UK) Guardian returned to it:

The Guardian has learned that one of Britain's leading bone specialists is facing disciplinary action over accusations that he was involved in 'ghost writing'.

The General Medical Council will call Professor Richard Eastell in front of a fitness to practice committee. Eastell, a bone expert at Sheffield University, has admitted he allowed his name to go forward as first author of a study on an osteoporosis drug even though he did not have access to all the data on which the study's conclusions were based. An employee of Proctor and Gamble, the US company making Actonel, was the only author who had all the figures.

Experts believe the practice is widespread in Britain.

In a letter published in the Journal of Bone and Mineral Research, which carried the original study, he stated: 'In the original paper one of the authors, a statistician working for P&G, Ian Barton, had full access to all the data.' The authors had full access to all the analyses of the data that they requested, he said � but those analyses were carried out by the company.

The letter, published in 2007, also acknowledged flaws in the study. A later independent analysis of the data 'identified some errors and poor practice', he wrote. The study was designed to show the strengths of Actonel which was in fierce competition with a rival bone-strengthening drug called Fosamax, made by Merck.

Eastell's paper concerned a study carried out on behalf of Proctor and Gamble, comparing the bone density of women prescribed Actonel with others who were not. Only the company knew which women were on the drug and which were taking something else.

Eastell's colleague, Dr Aubrey Blumsohn, wanted the codes which would say which of the patients who suffered fractures had been on the drug. The company refused. Blumsohn took his concerns to Eastell, but in a conversation which Blumsohn says he taped , Eastell said he was concerned that persistent requests might damage the relationship they had with the company. Eastell is said to have told him: 'The only thing that we have to watch all the time is our relationship with P&G. Because � we have the big Sheffield Centre Grant [from P&G] which is a good source of income, we have got to really watch it.' .

So, after four years, this case has generated an official hearing of sorts. The hearing is obviously late, and seemingly will only be devoted to only one aspect of this case (ghost writing). However, at least our friends in the UK are doing something. I cannot recall a single case that resulted in any serious consideration of imposing negative consequences on anyone who was accused of suppressing research, manipulating research, endorsing ghost-writing, or intimidating a whistle-blower. In fact, many of the more troubling cases have never resulted in any sort of public discussion either at the institutions at which they occurred, or at any organization with relevant regulatory, or even just moral authority. So the GMC hearing is at least a step forward. Two cheers for the British GMC, and none for US universities, academic medical centers, professional societies, and government regulators.

(If anyone can remind me of a case in which there was a public discussion at the relevant institution, or some public consideration of the case by a regulatory agency, professional society, or some group with moral authority, please remind me of it, and I would be happy to post about it.)

Princess Health and "Seeking Justice for My Son". Princessiccia

Princess Health and "Seeking Justice for My Son". Princessiccia

conflicts of interest manipulating clinical research

Gusty 10:27 Add Comment

At Healthcare Renewal we often write of the dangers of financial conflict of interest towards medical research and practice.

Here is a plea from a father of an 18 year old patient whose death became a cause c�l�bre against conflict of interest, only to then be swallowed up in the sea of silence known as the "anechoic effect." The plea is in our local newspaper, but deserves much wider attention:

Philadelphia Inquirer

Posted on Thu, Sep. 17, 2009

Seeking justice for my son

He died in a gene-therapy trial. Penn and the FDA should release the records.

By Paul Gelsinger

Ten years ago today, my 18-year-old son, Jesse Gelsinger, died at the University of Pennsylvania in a gene-therapy trial. Who is responsible? Could his life have been saved? Are other patients at risk? These questions have yet to be fully answered.

Jesse lived with a rare metabolic disease. The point of the research trial was to see if an adenovirus (a cousin of the cold virus) could safely deliver corrective genes to Jesse's liver. Instead, the adenovirus killed Jesse.

Jesse became the poster child for what not to do in human-subjects research. Neither he nor I was warned that, as the Washington Post later reported, monkeys had died in a prior trial. And the Wall Street Journal reported that the researcher who developed the adenovirus, James Wilson, had a seven-figure financial interest in the trial's outcome, as did Penn.

I stood by Penn, Wilson, and the two principal investigators, Mark Batshaw and Steven Raper, until I understood the extent of Wilson's financial ties and the extent to which Jesse was misled about the risks and efficacy of the therapy. I eventually sued and ultimately settled. The amount of the settlement was sealed; the documents were not.

The federal government also sued, claiming that the researchers blew through clinical stop signs in conducting the trial, ignoring evidence that Jesse was not well enough to receive the adenovirus and failing to sufficiently alert the Food and Drug Administration about severe incidents involving prior patients. The researchers disagreed, saying they had the discretion to proceed despite Jesse's test results, and that they had alerted the FDA. The government also reached a settlement, which restricted the researchers' activities for a period of years.

Before the government settled, I urged federal officials to make the documents they collected public. They refused, saying this is simply not done.

I believe a better understanding of what happened to Jesse could improve practices. So I gave the documents collected for my lawsuit to a law professor, Robin Wilson, who teaches at Washington and Lee University in Lexington, Va. They appear in her new book, Health Law and Bioethics: Cases in Context.

While they are incomplete, the documents show a chilling pattern. They show that a lot of good people inside Penn raised alarms about Wilson's financial ties from the get-go, but that Penn approved the deal anyway. The documents also show misleading disclosures to Jesse about the risks posed to him. For example, although animals died in prior trials, we were told that "animals have not shown toxic effects ... at the dosage of virus that is needed to transport the gene in this study."

I thought the lawsuits brought by me and the government would change research practices and the rules governing research. When I settled, real reform seemed likely. The Senate had held hearings, the FDA was investigating whether mistakes were made in the trial, and influential medical bodies such as the Association of American Medical Colleges had begun to examine disclosure practices and financial ties.

But, sadly, we have not yet learned enough from Jesse's death. The shroud of secrecy that envelops legal settlements has helped hinder reform. No one has publicly accounted for the mistakes that led to Jesse's death.

We don't know whether the FDA was misled or dropped the ball. We don't know whether the researchers' claims of efficacy had any basis in fact or were just wishful thinking. We don't know why Penn approved the deal despite warnings. And we don't know whether the researchers' decision to administer the virus to Jesse was reasonable or reckless.

Ten years ago today, my son died in a science experiment. A complete record of what the researchers and FDA regulators knew is the best precaution against future tragedies like Jesse's death.

I am asking that the University of Pennsylvania and the FDA finally do the right thing and release their records. If they did nothing wrong, let us see the proof. If they made a mistake, let us all learn from it and do better in the future. We owe it to Jesse to make his life and death mean something.

[Emphases mine - ed]

Other than stating that I strongly agree that these records should be released for others to learn from, I do not think additional commentary is necessary.

-- SS

Princess Health and An Australian Survey of Threats to Research Integrity. Princessiccia

Princess Health and An Australian Survey of Threats to Research Integrity. Princessiccia

manipulating clinical research suppression of medical research surveys

Gusty 07:48 Add Comment

Another important article on threats to the integrity of clinical research has appeared in the Medical Journal of Australia. (Henry DA et al. Medical specialists and pharmaceutical industry-sponsored research: a survey of the Australian experience. Med J Aust 2005; 182: 557-560.)
The authors sent a survey to 5000 Australian specialists, excluding general practitioners, but also surgeons and anesthesologists, and obtained a 39% response rate. 388 specialists (41% of respondents) had done pharmaceutical industry sponsored research. Of these,

• 100 (25.7% of those engaging in research) reported that the first draft of a research report was written by pharmaceutical company or contract research organization personnel
• 55 (14.2%) reported a delay in presentation or publication of key study findings
• 41 (10.6%) reported failure to publish key findings
• 22 (5.7%) reported editing of the report to make the drug appear better than was justified by the study results
• 18 (4.6%) reported concealment of relevant findings.

This study suggests that manipulation and suppression of research results in favor of commercial research sponsors' products is an international pheonomenon, and one that involves not only academic researchers but those in private practice.
An accompanying editorial (Gotzsche PC. Research integrity and pharmaceutical industry sponsorship. Med J Aust 2005; 182: 549-550) suggested that "testing drugs in patients" should be "a public enterprise." It asked, "who would buy a washing machine that is five or 10 times more expensive than other washing machines just because its manufacturer has compared it with other machines and claims that it is the best?"
Thanks to Sue Pelletier's Capsules blog for the tip.

Princess Health and An Australian Survey of Threats to Research Integrity.Princessiccia

Princess Health and An Australian Survey of Threats to Research Integrity.Princessiccia

manipulating clinical research suppression of medical research surveys

Gusty 07:48 Add Comment

Another important article on threats to the integrity of clinical research has appeared in the Medical Journal of Australia. (Henry DA et al. Medical specialists and pharmaceutical industry-sponsored research: a survey of the Australian experience. Med J Aust 2005; 182: 557-560.)
The authors sent a survey to 5000 Australian specialists, excluding general practitioners, but also surgeons and anesthesologists, and obtained a 39% response rate. 388 specialists (41% of respondents) had done pharmaceutical industry sponsored research. Of these,

• 100 (25.7% of those engaging in research) reported that the first draft of a research report was written by pharmaceutical company or contract research organization personnel
• 55 (14.2%) reported a delay in presentation or publication of key study findings
• 41 (10.6%) reported failure to publish key findings
• 22 (5.7%) reported editing of the report to make the drug appear better than was justified by the study results
• 18 (4.6%) reported concealment of relevant findings.

This study suggests that manipulation and suppression of research results in favor of commercial research sponsors' products is an international pheonomenon, and one that involves not only academic researchers but those in private practice.
An accompanying editorial (Gotzsche PC. Research integrity and pharmaceutical industry sponsorship. Med J Aust 2005; 182: 549-550) suggested that "testing drugs in patients" should be "a public enterprise." It asked, "who would buy a washing machine that is five or 10 times more expensive than other washing machines just because its manufacturer has compared it with other machines and claims that it is the best?"
Thanks to Sue Pelletier's Capsules blog for the tip.

Princess Health and "Crying All the Way to the Bank" Revisited: Pfizer's Trials of Torcetapib-Atorvastatin. Princessiccia

Princess Health and "Crying All the Way to the Bank" Revisited: Pfizer's Trials of Torcetapib-Atorvastatin. Princessiccia

manipulating clinical research Pfizer

Gusty 13:05 Add Comment

The current issue of the New England Journal of Medicine continues the journal's recent skeptical approach to the business practices of pharmaceutical companies. A perspectives article (Avorn J. Torcetrapib and atorvastatin - should marketing drive the research agenda? N Engl J Med 2005; 352: 2573-2576) reviews Pfizer's trials of a new drug that may boost HDL ("good") cholesterol, torcetrapib, but only in fixed combination with Pfizer's block-buster "statin," Lipitor (atorvastatin).
Since the US Food and Drug Administration (FDA) has approved this approach, should the trials be succesful, Pfizer would be allowed to market the new torcetrapib-atorvastatin combination as a brand-name drug beyond 2010, when its patent on Lipitor runs out. The FDA approval also would allow Pfizer to avoid the risk of anti-trust litigation, which otherwise might have been engendered by it offering a drug only when "bundled" with another of its products.
The trials would not result in any information about how torcetrapib performs alone, or in combination with a statin other than atorvastatin. Physicians would not have the options of prescribing torcetrapib alone, in combination with generic atorvastatin, or in combination with another statin. Thus this approach would limit scientific data available to physicians and researchers, and would limit therapeutic options for patients.
We previously posted about this issue here, based on a March New York Times article.
Avorn commented,

• "the current trial design may not optimally meet the scientific needs of prescribers, the clinical needs of patients, the economic needs of payers, or the regulatory needs of policymakers. But they superbly meet the business needs of the sponsore - to create new knowledge in a way that will protect the market share of the largest drug company's most important product."

Therefore, he concluded, "the torcetrapib story suggests that we have become too dependent on manufacturers as the predominant source of our scientific knowledge about the effects of medication." He thus advocates having the National Institutes of Health (NIH) start supporting "public-interest" drug trials "fairly comparing competing therapies (especially costly new ones) with clinically realistic alternatives."
Maybe now that the NIH has strict conflict-of-interest rules, and top NIH officials are no longer allowed to get lucrative consulting contracts with pharmaceutical companies, (see post here), this idea will get more welcome reception there.

Princess Health and "Crying All the Way to the Bank" Revisited: Pfizer's Trials of Torcetapib-Atorvastatin.Princessiccia

Princess Health and "Crying All the Way to the Bank" Revisited: Pfizer's Trials of Torcetapib-Atorvastatin.Princessiccia

manipulating clinical research Pfizer

Gusty 13:05 Add Comment

The current issue of the New England Journal of Medicine continues the journal's recent skeptical approach to the business practices of pharmaceutical companies. A perspectives article (Avorn J. Torcetrapib and atorvastatin - should marketing drive the research agenda? N Engl J Med 2005; 352: 2573-2576) reviews Pfizer's trials of a new drug that may boost HDL ("good") cholesterol, torcetrapib, but only in fixed combination with Pfizer's block-buster "statin," Lipitor (atorvastatin).
Since the US Food and Drug Administration (FDA) has approved this approach, should the trials be succesful, Pfizer would be allowed to market the new torcetrapib-atorvastatin combination as a brand-name drug beyond 2010, when its patent on Lipitor runs out. The FDA approval also would allow Pfizer to avoid the risk of anti-trust litigation, which otherwise might have been engendered by it offering a drug only when "bundled" with another of its products.
The trials would not result in any information about how torcetrapib performs alone, or in combination with a statin other than atorvastatin. Physicians would not have the options of prescribing torcetrapib alone, in combination with generic atorvastatin, or in combination with another statin. Thus this approach would limit scientific data available to physicians and researchers, and would limit therapeutic options for patients.
We previously posted about this issue here, based on a March New York Times article.
Avorn commented,

• "the current trial design may not optimally meet the scientific needs of prescribers, the clinical needs of patients, the economic needs of payers, or the regulatory needs of policymakers. But they superbly meet the business needs of the sponsore - to create new knowledge in a way that will protect the market share of the largest drug company's most important product."

Therefore, he concluded, "the torcetrapib story suggests that we have become too dependent on manufacturers as the predominant source of our scientific knowledge about the effects of medication." He thus advocates having the National Institutes of Health (NIH) start supporting "public-interest" drug trials "fairly comparing competing therapies (especially costly new ones) with clinically realistic alternatives."
Maybe now that the NIH has strict conflict-of-interest rules, and top NIH officials are no longer allowed to get lucrative consulting contracts with pharmaceutical companies, (see post here), this idea will get more welcome reception there.

Princess Health and "Scientists Behaving Badly" and "Unreasonable Managerial Demands". Princessiccia

Princess Health and "Scientists Behaving Badly" and "Unreasonable Managerial Demands". Princessiccia

manipulating clinical research

Gusty 12:37 Add Comment

An article in Nature reports on "Scientists Behaving Badly."(1) This was a broadly based anonymous survey, with a 52% response rate, and a sample size of 3247. Of note, the numbers of respondents who reported engaging in the following behaviors in the last three years were:

• Falsifying or "cooking" research data - 0.3%
• Ignoring major aspects of human-subject requirements - 0.3%
• Failing to present data that contradicts one's own previous research - 6.0%
• Improperly assigning authorship credit - 10.0%
• Changing the design, methodology, or results of a study in response to pressure from a funding source - 15.5%

The authors noted "a proper understanding of misbehaviour requires that attention be given to the negative aspects of the research environment. The modern scientist faces intense competition, and is further burdened by difficult, sometimes unreasonable, regulation, social, and managerial demands."
This assertion was probably written before the publication in the New England Journal of Medicine of an article that showed what a large proportion of medical schools and academic medical centers are willing to sign away faculty members' control of their research to research sponsors (see our previous post here.) That article showed that about 2/3 of schools and medical centers were willing to sign away their faculty members' ability to alter research methods specified by the sponsor, and about 1/2 were willing to let the sponsor write up the research reports, which faculty could comment on, but not change, even though they were likely to be listed as principle authors. The data in the NEJM article is certainly compatible with the proportion of respondents to the Nature study who noted "pressure from a funding source." Thus, the "managerial" demands that researchers face may often go beyond merely being difficult, or even unreasonable.
This is just another reminder of the spectre of powerful health care organizations acting in conflict with physicians' and medical researchers' core values.
How much more evidence will be needed before something is done about how such organizations are lead?
Reference
1. Martinson BC, Anderson MS, deVries R. Scientists behaving badly. Nature 2005; 435: 737-8.

Princess Health and "Scientists Behaving Badly" and "Unreasonable Managerial Demands".Princessiccia

Princess Health and "Scientists Behaving Badly" and "Unreasonable Managerial Demands".Princessiccia

manipulating clinical research

Gusty 12:37 Add Comment

An article in Nature reports on "Scientists Behaving Badly."(1) This was a broadly based anonymous survey, with a 52% response rate, and a sample size of 3247. Of note, the numbers of respondents who reported engaging in the following behaviors in the last three years were:

• Falsifying or "cooking" research data - 0.3%
• Ignoring major aspects of human-subject requirements - 0.3%
• Failing to present data that contradicts one's own previous research - 6.0%
• Improperly assigning authorship credit - 10.0%
• Changing the design, methodology, or results of a study in response to pressure from a funding source - 15.5%

The authors noted "a proper understanding of misbehaviour requires that attention be given to the negative aspects of the research environment. The modern scientist faces intense competition, and is further burdened by difficult, sometimes unreasonable, regulation, social, and managerial demands."
This assertion was probably written before the publication in the New England Journal of Medicine of an article that showed what a large proportion of medical schools and academic medical centers are willing to sign away faculty members' control of their research to research sponsors (see our previous post here.) That article showed that about 2/3 of schools and medical centers were willing to sign away their faculty members' ability to alter research methods specified by the sponsor, and about 1/2 were willing to let the sponsor write up the research reports, which faculty could comment on, but not change, even though they were likely to be listed as principle authors. The data in the NEJM article is certainly compatible with the proportion of respondents to the Nature study who noted "pressure from a funding source." Thus, the "managerial" demands that researchers face may often go beyond merely being difficult, or even unreasonable.
This is just another reminder of the spectre of powerful health care organizations acting in conflict with physicians' and medical researchers' core values.
How much more evidence will be needed before something is done about how such organizations are lead?
Reference
1. Martinson BC, Anderson MS, deVries R. Scientists behaving badly. Nature 2005; 435: 737-8.