Not So Wondrous Drugs? - New Warnings about Severe Adverse Effects of New, Heavily Marketed Drugs for Hepatits C,

Background - Wonder Drugs for Hepatitis C

In our April, 2014, post we noted how Sovaldi (sofosbuvir), the new antiviral drug made by Gilead for hepatitis C was touted as a "triumph of of medical technology."  In that, and subsequent posts we discussed how such claims were not buttressed by much good data from clinical research.

We could find only one published randomized clinical trial of sofosbuvir (and ribavirin), which compared it to the older drug used to treat hepatitis C, peg-interferon (and ribavirin).  At best, the new drug showed about the same ability to eliminate detectable virus from the patients' blood in the short-term as did the older drug.  The new drug also produced fewer unpleasant side effects, but possibly more severe adverse effects.  Just like all previous known published trials of hepatitis C treatments, this trial of sofosbuvir did not follow patients long enough to determine if the drug had any effect on the serious, but not inevitable long-term complications of hepatitis C infection, severe hepatitis, cirrhosis, liver failure, liver cancer, and premature death.

I could find no other published trials of sofosbuvir versus either older drugs or placebo.  Most of the subsequently published, and loudly hyped studies of the drug were of highly selected patients, and did not include control groups which did not receive sofosbuvir.  So the very high short term "cure" rates - which were really rates of elimination of detectable virus from the blood, could have been mainly a function of these studies' highly selected patient populations.

Yet the lack of strong evidence that sofosbuvir, and subsequent competing drugs actually made patients better, i.e., feel better, function better, avoid serious subsequent medical problems, or live longer, did not stop tremendous enthusiasm in the media for the new drug.  Much of it doubtless stemmed from huge marketing and public relations expenditures.  Nor did did the lack of evidence stop Gilead and other drug makers from pricing the new drugs in the stratosphere.  Initially a 12 week course of of Sovaldi cost $84,000.

Since then, there has been tremendous buzz about the price of these new antiviral drugs for hepatitis C, and tremendous anxiety about the consequent difficult access to these presumptively "life saving" therapies.  However, my and others' questions about whether these drugs actually benefit patients, and whether any benefits might be worth their harms, remained anechoic (See appendix below.)

The Harms of the "Wonder Drugs" Begin to Appear

Nowadays new drugs, devices, and other health care technologies are often touted based on little evidence.  What evidence is produced mainly comes from commercially sponsored clinical trials.  Commercial sponsors may manipulate the design, implementation, analysis and dissemination of these studies to increase the likelihood that they will make their products look good.

In particular, such trials may fail to detect adverse effects of the new products to be hyped.  The trials  often enroll only small numbers of patients, decreasing the likelihood of finding rare but serious problems.  Often patients who have any health problems other than the disease of interest are excluded from trials, decreasing the likelihood of detecting adverse events that might affect patients with multiple morbidities or on other treatments.  Trials may fail to follow patients long-term, so they may fail to detect adverse effects that appear only after prolonged therapy.  These sorts of problems certainly afflicted the very few real clinical trials of sofosbuvir, and other new antiviral drugs for hepatitis C.   

So it should not have been surprising that sofosbuvir has now been found to produce two kinds of severe adverse events that were undetected, or at least undisclosed when it was launched.  The second kind of adverse event was just announced, and also seems to occur after administration of other new anti-hepatitis C drugs.

Severe Heart Rhythm Abnormalities

In March, 2015, as discussed by Dr John Mandrola in Medscape,

As reported by heartwire , the US FDA recently announced a change in labeling for the hepatitis-C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after their manufacturers reported bradycardia, pacemaker intervention, and even death in patients who took the medications along with amiodarone. Notably, six of these nine cases occurred within 24 hours of sofosbuvir dosing.

While Dr Mandrola was concerned about this adverse effect, the news media put more emphasis on the Wall Street analysts who thought the problem would have "zero impact" on sales of the fabulously expensive antiviral drugs. (See this post by Ed Silverman on PharmaLot.)

So all remained serene, until this week.

Reactivation of Hepatitis B Infection

On October 4, 2016, Medscape reported

Patients with a past or current hepatitis B virus (HBV) infection can experience sometimes fatal HBV reactivation if they take any of nine direct-acting antivirals for hepatitis virus C (HCV) infection, the US Food and Drug Administration (FDA) announced today.

The agency will require a boxed warning for the drugs advising clinicians to screen patients for evidence of a past or current HBV infection before ordering antiviral treatment for HCV.

Also,

The FDA said in a news release that it had identified 24 cases of HBV reactivation in coinfected patients treated with these antivirals from November 22, 2013, to July 18, 2016, in reports to the agency and published literature. Two patients died, and one needed a liver transplant.

Why were we not made aware of this before?  Failure to detect this adverse effect was apparently due to the exclusion of patients with a history of hepatitis B from previous studies of the new drugs.  As we mentioned above, commercially sponsored trials often exclude patients with nearly any medical conditions other than the one of interest.  Yet hepatitis C patients often have comorbidities.  I

clinical trials for the HCV drugs in question did not report HBV reactivation because they excluded patients infected with HBV.

Will this prompt a reexamination of our enthusiasm for new antiviral hepatitis C treatments? I suspect not. Even FDA officials suggested we should not be too alarmed. In particular, Dr. John Farley, deputy director of FDA's Office of Antimicrobial Products, said according to NBC News,

I think it is important to recognize that these hepatitis C drugs are lifesaving medications. What we don't want to do is discourage patients with hepatitis C from getting treatment,...

But remember, there has never been a controlled trial that showed that treatment of hepatitis C with anything actually reduced the risk of later severe hepatitis, cirrhosis, liver failure, liver cancer, or premature death. And there may be other adverse effects of this new treatment that remain unknown.

Even government regulators, who are supposed to put the public health ahead of the profits of the pharmaceutical industry, seem to have fallen for the life saving miracle drug meme in this case.

Summary

The ongoing story of hepatitis C treatment demonstrates how hype and buzz, largely generated by marketing and public relations, and likely fueled by financial relationships among commercial health care firms and health care professionals and academics, has triumphed over rigorous skeptical evaluation of the best available evidence from clinical research.

There has never been good evidence that hepatits C treatments prolong life, or prevent severe liver disease in the long run.  There has never been good evidence that these drugs' clinical benefits outweigh their harms.  Yet they have been relentlessly promoted as game changers, miraculous, triumphant lifesaving medicines.

One obvious lesson is that health care professionals, policy makers, and the public at large have to be much more skeptical about commercial claims for drugs, devices, tests, etc.  We need to figure out when claims are coming from marketing departments and public relations hacks.  We need to figure out when researchers and professionals who are supporting these claims could be influenced by financial relationships with the firms benefiting from the claims.

Furthermore, it is high time to revisit all the regulatory and policy changes over the last 30 years that have put manufacturers in charge of the research meant to test their own health care products.

In conclusion, 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. If only such skepticism were easier to find.


.......
APPENDIX - Clinical Research about Hepatitis C Treatments

Starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA Internal Medicine from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts here,  here, and here.)

References

 1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014;174(7):1170-1171. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.

ADDENDUM (11 October, 2016) - This post was republished on the Naked Capitalism blog. 

How the System is Rigged - Johnson and Johnson Board Member Pretends to be Independent Brookings Institution Scholar

Fears that "the system is rigged" may cause the lack of trust marring this year's political season. These fears are not baseless.

Dr McClellan of the Brookings Institution on Drug Prices

A recent series in the New York Times focused on the biases of the think tank "independent scholars" whose work is used to justify much policy making.  An article entitled "Think Tank Scholar or Corporate Consultant? - It Depends on the Day" actually provided a health care example that was much worse than what the title implied.

It noted that

Dr. McClellan, a former commissioner at the Food and Drug Administration who until January was a senior fellow at Brookings, has been a go-to expert for the federal government as it debates how to cope with surging costs of prescription drugs.

In particular, Dr McClellan has opined on the increasingly recognized problem of ever-rising drug prices, and on one class of drugs that we have discussed on Health Care Renewal.

At public events, Dr. McClellan emphasized the extraordinary progress by the pharmaceutical industry in coming up with treatments for diseases like diabetes, H.I.V. and hepatitis C.

'Lots of diseases have been transformed,' Dr. McClellan said at a hearing in November sponsored by the Department of Health and Human Services. He ran through a series of slides prominently stamped with Brookings’s name. He also argued that even though these drugs were very expensive, they were worth it given the improvement in a patient’s quality of life.

'They are, over all, a pretty good deal,' Dr. McClellan said, referring to treatments for hepatitis C. One such drug, manufactured by Johnson & Johnson, generated $2.3 billion in sales in its first full year, representing about 7 percent of the company’s overall drug sales in 2014. The pills cost $66,000 for a standard 12-week regimen.

Little Evidence that New Drugs for Hepatitis C Represent "Extraordinary Progress?"


Note that despite Dr McClellan's enthusiasm, there is no good data from clinical trials that show that the new drugs for hepatitis C have long-term clinical benefits.  As we wrote here last month....

In fact, starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA Internal Medicine from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts here,  here, and here.)

In July, 2016 we had written about the enthusiasm for these drugs expressed by Mr Bill Gates, chairman of the Gates Foundation.  Maybe one can somewhat excuse Mr Gates, who is hardly a clinical research expert, for this unjustified enthusiasm.  (Although maybe someone at his foundation, given its emphasis on global health, should have briefed him to the contrary.)

Why Was Dr McClellan So Unjustifiably Enthused?

Give Dr McClellan's background, why was he not more skeptical about the the supposed miraculous properties of hepatitis C drugs?.  His biography, provided for the US Department of Health and Human Services Pharmaceutical Forum, suggested he ought to know something about clinical research.  It stated,  

Mark McClellan, MD, PhD, is a senior fellow and director of the Health Care Innovation and Value Initiative at the Brookings Institution. Within Brookings, his work focuses on promoting quality and value in patient centered health care, and he leads the Richard Merkin Initiative for Payment Reform and Clinical Leadership.

A doctor and economist by training, he also has a highly distinguished record in public service and in academic research. Dr. McClellan is a former administrator of the Centers for Medicare & Medicaid Services (CMS) and former commissioner of the U.S. Food and Drug Administration (FDA), where he developed and implemented major reforms in health policy. These include the Medicare prescription drug benefit, the FDA’s Critical Path Initiative, and public-private initiatives to develop better information on the quality and cost of care. Dr. McClellan chairs the FDA’s Reagan-Udall Foundation, is co-chair of the Quality Alliance Steering Committee, sits on the National Quality Forum’s Board of Directors, is a member of the Institute of Medicine, and is a research associate at the National Bureau of Economic Research. He previously served as a member of the President’s Council of Economic Advisers and senior director for health care policy at the White House, and was an associate professor of economics and medicine at Stanford University.

From time to time, McClellan advises U.S. government officials on health care policy issues. In his capacity as a health policy expert, he is the co-director of the Bipartisan Policy Center’s Leaders’ Project on the State of American Health Care; co-chair of the Robert Wood Johnson Foundation Commission to Build a Healthier America; and chair of the FDA’s Reagan-Udall Foundation. McClellan is also co-chair of the Quality Alliance Steering Committee, sits on the National Quality Forum’s Board of Directors, is a member of the Institute of Medicine of the National Academy of Sciences, and is a research associate at the National Bureau of Economic Research.

McClellan holds an MD from the Harvard University–Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, a PhD in economics from MIT, an MPA from Harvard University, and a BA from the University of Texas at Austin. He completed his residency training in internal medicine at Boston’s Brigham and Women's Hospital, is board-certified in Internal Medicine, and has been a practicing internist during his career.

However, that biography left out one important item.  Per the NY Times article,

There was no mention in a video of the event that Dr. McClellan joined Johnson & Johnson’s board of directors in October 2013, or that he earned nearly $530,000 over the past two years in overall compensation from the company. That is in addition to his salary at Brookings, where he is one of the top-paid scholars, with $353,145 in wages and other compensation from the think tank in 2014, tax records show.

I suspect that most attendees at the conference had not read our 2013 post on Health Care Renewal that noted Dr McClellan's transit through the revolving door that ended up with his position on the Johnson & Johnson board.

Dr McClellan's Chronic Failure to Disclose His Johnson and Johnson Board Membership

Despite the fact that Dr McClellan's position on the Johnson & Johnson board of directors is public, as are the identities of all the members of US publicly held corporations, Dr McClellan has seemingly made a point of avoiding its mention when he assumes the persona of health care policy expert.

For example, he did not disclose it in some recent publications on aspects of health policy that likely would relate to Johnson & Johnson's interests.  These included:
- a 2014 Brookings report entitled "Improving Health Care While Reducing Cost Growth: What is Possible?"(3) in which he is only described as "Director, Health Care Innovation and Value Initiative, Senior Fellow, Economic Studies; The Brookings Institution."
- a 2014 article on "Health Reform and Physician-Led Accountable Care" in JAMA(4) which simply noted Dr McClellan came from the Brooking Institution, and which contained the assurance that all authors completed "the ICMJE Forum for Disclosure of Potential Conflicts of Interest and none were reported."
- a 2015 article on increasing "pharmaceutical innovation" in Health Affairs(5) which similarly only described Dr McClellan as "senior fellow and director of the Health Care Innovation and Value Initiative at the Engelberg Center for Health Care Reform at Brookings."

Furthermore, Dr McClellan's new employer, Duke University, currently provides a biography which also omits any mention of his position on the Johnson & Johnson board.

Dr McClellan Denies any Conflict of Interest

The NY Times article suggested that Dr McClellan may think his position at Johnson & Johnson is irrelevant to his day job as health policy expert.

Dr. McClellan, in a statement, disputed any suggestion that he might have had a conflict.

'My entire career in academics, government and public policy has focused on evidence-based ways to improve health and restrain costs for consumers, and my extensive track record speaks for itself,' he said.

I suppose that Dr McClellan might have justified his failure to disclose his membership on the Johnson & Johnson board of directors by his perception that this membership caused no conflict of interest.

How Board Membership May Cause Severe Conflicts of Interest

I will omit detailed discussion of all the evidence that even receiving small gifts may affect thinking and actions through the social obligation to reciprocate.  Yet Dr McClellan did not just receive small gifts.  He is a member of a corporate board of directors.

 In 2006, we first noticed that leaders of academic medicine also were serving as board members of large for-profit health care corporations.  The first example we discussed was that of Marye Anne Fox, Chancellor (equivalent to president) of the University of California - San Diego, and hence the person to whom the University of California, San Diego School of Medicine and its academic medical center report. The conflict was between this position, and her service as a member of the board of directors of Boston Scientific, a medical device manufacture, and the board of directors of Pharmaceutical Product Development Inc., a contract research organization.

Later that year, we discussed a "new species of conflict of interest."  At that time we wrote:

Medical schools and their academic medical centers and teaching hospitals must deal with all sorts of health care companies, drug and device manufacturers, information technology venders, managed care organizations and health insurers, etc, in the course of fulfilling their patient care, teaching, and research missions. Thus, it seems that service on the board of directors of a such public for-profit health care company would generate a severe conflict for an academic health care leader, because such service entails a fiduciary duty to uphold the interests of the company and its stockholders. Such a duty ought on its face to have a much more important effect on thinking and decision making than receiving a gift, or even being paid for research or consulting services. Furthermore, the financial rewards for service on a company board, which usually include directors' fees and stock options, are comparable to the most highly paid consulting positions. What supports the interests of the company, however, may not always be good for the medical school, academic medical center or teaching hospital.

As Robert AG Monks put it, board members must "demonstrate unyielding loyalty to the company's shareholders" [Monks RAG, Minow N. Corporate Governance, 3rd edition. Malden, MA: Blackwell Publishing, 2004. P.200.]  (Of course, after the global financial collapse of 2008 made us sadder and a little wiser, we realized that many board members actually seem to have unyielding loyalty to their cronies among top management.)  However, in any case, the stated or actual interests of a member of the board of a health care corporation, like a pharmaceutical company or medical device company, could be very different and at odds with the mission of not only academic medical institutions, but of think-tanks professing to provide unbiased policy relevant research.

Presumably, were Dr McClellan in a situation in which he had an opportunity to promote Johnson & Johnson's interests, such as speaking at an influential conference about drug prices, and failed to uphold the company's interests, stockholders could consider legal action against him for failing in his fiduciary responsibilities.  Thus the mind boggles at how Dr McClellan could believe that his role as a corporate director does not pose a conflict of interest for him in his better publicized role as think tank and now academic health care policy expert.

Discussion

It is hardly news that US health care is broadly dysfunctional, that it suffers from ever rising costs, and questionable quality, while access has only somewhat improved after the 2009 Affordable Care Act.  The big question is why these problems seem so intractable.

Our latest case illustrates that the problem may be that health policy making is dominated by people with conflicts of interest.  In the current case, one of the more influential voices on health care policy turns out not to have just a garden variety conflict of interest.  He actually has a duty to uphold the corporate interests of one of the biggest US drug, biotechnology and device companies.  Could one really expect such a man would have a serious interest in controlling health care costs, especially those driven by the prices charged by drug, biotechnology, and device makers?

A system in which the top "independent" health policy experts may have conflicts of interest, may even be members of boards of directors of health care corporations, certainly suggests a system that has been rigged. 

As we have said again and again, the web of conflicts of interest that is pervasive in medicine and health care is now threatening to strangle medicine and health care.  Furthermore, this web is now strong enough to have effectively transformed US health care into an oligarchy or plutocracy.  Health care is effectively run by a relatively small group of people, mainly professional managers plus a few (lapsed?) health care professionals, who simultaneously run or influence multiple corporations and organizations.

For patients and the public to trust health care professionals and health care organizations, they need to know that these individuals and organizations are putting patients' and the public's health ahead of private gain. Health care professionals who care for patients, those who teach about medicine and health care, clinical researchers, and those who make medical and health care policy should do so free from conflicts of interest that might inhibit their abilities to put patients and the public's health first.

Health care professionals ought to make it their highest priority to ensure that the organizations for which they work, or with which they interact also put patients' and the public's health ahead of private gain, especially the private gain of the organizations' leaders and their cronies.


 References

1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014;174(7):1170-1171. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.
3.  McClellan M, Rivlin AM. Improving Health Care While Reducing Cost Growth: What is Possible?
Engelberg Center for Health Care Reform at Brooking; 2015.  Link here.
4.  Mostashari F, Sanghavi D, McClellan M. Health reform and physician-led accountable care: the paradox of primary care physician leadership. JAMA 2015; 311: 1855-56.  Link here.
 4.  Daniel GW, Caze A, Romine MH, Audibert C, Leff JS, McClellan M. Improving pharmaceutical innovation by building a more comprehensive database on drug development and use.  Health Aff 2015; 34: 319-327.  Link here.

Abort, Retry, Fail - Billionaire Bill Gates Opines, Sans Evidence, on ... the Efficacy of Hepatitis C Treatment?

If you needed advice about the technical characteristics of computer operating systems you probably would not go to your doctor for it.  So why would you seek the opinion of a software company mogul about the efficacy of pharmaceuticals?

Software Mogul Bill Gates on the Pricing and Efficacy of Antiviral Drugs for Hepatitis C 

Nonetheless, per Bloomberg, last week Bill Gates pontificated about drugs for the treatment of hepatitis C.  When apparently asked about the priorities of the Bill and Melinda Gates Foundation, Mr Gates said

market forces were working properly in hepatitis C, invoking Gilead Sciences Inc.’s treatments Sovaldi and Harvoni, which have been criticized by insurers and politicians as too expensive at $1,000 a pill or more for 12 weeks of treatment, before discounts and rebates.

While Gilead is the market leader, it’s now facing competition from Merck & Co. and AbbVie Inc., forcing prices lower.

'Curing hepatitis C, this is a phenomenal thing, and now you have multiple drug companies competing in terms of the quality and the price of that offering,' he said.

More broadly, Mr Gates defended the high prices of drugs in the US, partly because:

The drug companies are turning out miracles....

Not a Wonder Drug, According to the Clinical Research Evidence

Mr Gates, it seems, has not done a critical review of the data on the new antiviral treatments for hepatitis C.  In fact, starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA Internal Medicine from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts here,  here, and here.)

Why Do Rich People Who Run Foundations Tout Expensive Drugs?


Yet there is something about hepatitis C and the newer treatments of it that seems to inspire rich people who run foundations to sound like marketers for Gilead, sans evidence to support their viewpoints.  About one year ago, former US President Bill Clinton, now a leader of the well-publicized Clinton Foundation and of the now apparently independent Clinton Health Access Initiative, said something similar, as we posted here:

Clinton pointed to new hepatitis C drugs, Sovaldi and Harvoni, which are sold by Gilead Sciences for more than $80,000 for a 12-week program of treatment. Those medications often cure a disease that can cause liver disease and eventually lead to transplants or death, which are expensive, too. But the sticker price on the drug has caused a backlash by payers and patients.

'Who wants to let somebody's liver rot? Nobody,' Clinton said. 'Who's got $80,000 to spend? Not many. And if you're a small businessperson and you're in a small pool [of employer-based insurers], are you going to fire somebody who needs that treatment? These are all practical problems, and we can solve them.'

So what is going on here?  In a general sense, it may be that people who have become very rich, and have held very high level executive positions, start to believe they are expert on everything, especially in a country increasingly dominated by market fundamentalism/ neoliberalism in which money is touted as the ultimate measure of everything important.  But more specifically, Mr Gates may also be spending too much time with the top brass of his foundation, who may be all too used to hawking expensive drugs.

Former Pharmaceutical and Biotechnology Executives Running Supposedly Charitable Foundations

In particular, the current CEO of the Gates Foundation is Dr Susan Desmond-Hellmann.  When Dr Desmond-Hellmann's appointment as Chancellor of UCSF was announced in 2009, I suggested that she was a very unusual choice because of aspects of her track record in the pharmaceutical/ biotechnology business.  During her previous service as President of Drug Development at Genentech, Dr Desmond-Hellmann had defended the then sky high pricing of bevacizumab.  Of course, Dr Desmond-Hellmann, as a top executive, personally profited from such pricing.  In her last year at Genentech while the company was still independent, her total compensation was over $8,000,000.  As we discussed in 2014, while she was at UCSF, questions arose about her committment to public health when it was revealed she and her husband had large stock holdings in the tobacco company Altria.  Yet she continued to dismiss the importance of her many apparent conflicts of interest.

Also, in 2011, prior to the hiring of Dr Desmond-Hellmann, as we discussed here, a PLoS Medicine article by Stuckler et al(3) suggested a revolving door between the leadership of the Gates Foundation and of pharmaceutical and biotechnology companies,

Members of personnel also move between the Foundation and pharmaceutical companies. For example, in April 2010, a former Merck senior vice president, Richard Henriques, became the chief financial officer of the Gates Foundation. At least two other members of the Gates Foundation leadership have transferred from the leadership of GlaxoSmithKline to sit on the Foundation’s board of directors, including Kate James, the chief communications officer, and Tachi Yamada, until February 2011, the head of the Foundation’s global health program. Similar patterns were observed with the other foundations studied.

Foundations Promoting the Biotechnology and Pharmaceutical Agenda

Dr Desmond-Helmann has continued to use her bully pulpit at the Gates Foundation to promote high-tech medicine that uses the newest, most expensive drugs.  For example, in an interview in December, 2015 in the Washington Post, she promoted "precision public health" which would emphasize the supposed "innovation, that speed, that ability to use big data" characteristic of precision medicine brought to public health.  However, "precision medicine" has so far not been proven to fulfill its promise to benefit patients.

In addition, in May, 2016, a Wall Street Journal article noted that she has led the Gates Foundation to invest in commercial biotechnology firms,

Dr. Desmond-Hellmann cited a $52 million investment by the foundation in CureVac, a German biopharmaceutical company, as the type of partnership that could produce new tools against epidemics. CureVac is developing vaccine technologies based on messenger RNA that would instruct the body to produce its own defenses against infections. The funding, which the foundation announced in 2015, is for construction of a manufacturing facility; the foundation said it would provide additional funding to develop vaccines for several infectious diseases.

Are these investments the best way to provide better global health care?  An aside in the Bloomberg article suggests they may be more about making money.

The foundation reported in May that it had received an unexpected boost to its endowment when a stake in a small biotechnology firm, Anacor Pharmaceuticals Inc., sold for $86.7 million -- about 17 times the fund’s original investment. While the foundation had invested in Anacor to encourage the company’s work in neglected diseases, Anacor shares took off after its toenail fungus drug was approved.

I am sure that toenail fungus is not a major public health problem anywhere, much less in the developing world.

The tragedy here is that the Gates Foundation, which appears to be the largest private foundation in the US (and the world), has a huge impact on global health, and yet its leadership is squandering its moral authority in the pursuit of the pharmaceutical/ biotechnology agenda.  A review of a new book out about the foundation in November, 2015 in the Intercept noted that the book's author

spends much more time discussing whether the Gates Foundation is protecting the patents of pharmaceutical companies and whether it is making common cause with Monsanto to spread genetically modified crops in Africa

In January, 2016, the  Global Policy Forum put out a report that, per a Guardian article,  accused

organisations like the Bill and Melinda Gates Foundation, the Rockefeller Foundation and others are promoting solutions to global problems that may undermine the UN and other international organisations, says the report by the independent Global Policy Forum, which monitors the work of UN bodies and global policymaking.

Futhermore, the report asserted,

 Through their multiple channels of influence, the Rockefeller and Gates foundations have been very successful in promoting their market-based and bio-medical approaches towards global health challenges in the research and health policy community – and beyond.

More specifically, an article in the Independent accused the foundation of having a

ideological commitment to promote neoliberal economic policies and corporate globalisation

The report, per the Guardian, also accused the foundation of conflicts of interest,

The report also questions why the Gates foundation invests heavily in companies like Monsanto and Bayer. 'In addition to its grant-making activities, the Gates foundation has recently stepped up its support for the biotechnological industry directly.'

Also, similar to the PLoS Medicine article cited above(3)

'There is a revolving door between the Gates foundation and pharmaceutical corporations. Many of the foundation’s staff had held positions at pharmaceutical companies,' the report adds.

More dramatically, per the Independent,

the Gates Foundation 'often appears to be a massive, vertically integrated multinational corporation, controlling every step in a supply chain that reaches from its Seattle-based boardroom … to millions of end-users in the villages of African and south Asia.'

Furthermore, per the Intercept book review article, the larger problem is that the Gate Foundation and its CEO are largely unaccountable,

Bill and Melinda Gates answer to no electorate, board, or shareholders; they are accountable mainly to themselves. What’s more, the many millions of dollars the foundation has bestowed on nonprofits and news organizations has led to a natural reluctance on their part to criticize it. There’s even a name for it: the 'Bill Chill'  effect.

I would note parenthetically the foundation's board of trustees only includes Bill and Melinda Gates, Mr Gates' father, and Mr Warren Buffet.  Most large foundations have considerably larger boards of trustees, with at least some diversity in family membership and backgrounds.

In an interview with the Financial Times in March, 2016, Dr Desmond-Hellmann made a hash of addressing the accountability issue:

Accountability is another concern. To whom do these multibillion-dollar foundations answer?

For once, Dr Desmond-Hellmann’s confident responses falter. In reply to a suggestion that trans­parency is not the same thing as accountability — putting everything online means you can see what the foundation is doing, but does not mean that it is being held to account — she seems uncharacteristically stuck for words.

'The way that people can hold us accountable is to look at what we achieved as a foundation through our collaborations,' she says, quickly regaining her poise.

So even the foundation's CEO cannot say to whom, and how she is accountable.


Conclusions

So maybe Bill Gates' seemingly ill-informed apologia for the extremely high drug prices charged in the US, and his lack of understanding of the evidence about the efficacy, or lack thereof, of some of these high priced drugs is a small humorous story that indicates just the tip of the iceberg.  It appears that in our current market fundamentalist, neoliberal world, foundations may be more about promoting the commercial interests of their board members and officers than about improving the lot of humanity.  Yet for the most part they may succeed in obfuscating what they are doing through the haze of marketing and public relations.

True health care reform would first make transparent the web of institutional and individual conflicts of interest that seems to tie together nearly all big health care organizations, and open discussion of how to make health care organizations better serve health care rather than the narrow financial interest of their top leaders.

Graphic Interlude

A "blue screen of death"

 References

1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.
3.  Stuckler D, Basu S, McKee M. Global health philanthropy and institutional relationships: how should conflicts of interest be addressed? PLoS Med 8(4): e1001020.  doi:10.1371/journal.pmed.1001020.  Link here.

Bill Clinton, Paid to Speak to Biotech Conference, Extolled $1000 Pill to Prevent "Liver Rot," Despite Lack of Evidence that It Does

What were they thinking?

Former President Clinton Talkes to Pharma and Biotech Executives

In mid June, 2015, the Philadelphia Inquirer reported that former US President

Clinton was the keynote speaker at Klick Ideas Exchange, sponsored by Klick Health, a Toronto-based digital marketing agency, along with Veeva Systems and the Biotechnology Industry Organization. BIO, the Washington-based trade association, is holding its annual convention at the Pennsylvania Convention Center this week, attracting 15,000 people.

For his troubles he was apparently paid, however

his foundation did not respond to a request for information about Monday's speaking fee. Hillary Clinton's campaign also did not respond to a similar request. A spokeswoman for Klick Health declined to provide Clinton's fee.

It is likely he was well paid, since his going rate is very high:

disclosure forms indicated Bill Clinton received between $225,000 and $275,000 for each of eight speaches delivered between March 31 and May 14 of this year.

Clinton Endorses the Miraculous $1000 Pill

So what would a former president say to a bunch of pharmaceutical and biotechnology executives and their friends?  He chose to talk about the prices of new drugs:

Former president Bill Clinton said Monday in Philadelphia that high prices for some medicines are hard to justify, and the biotech and pharmaceutical industries should try full explanation and disclosure to make their case.

'Explain, explain, explain and disclose, disclose, disclose,' Clinton said in a speech and question-and-answer session before about 200 biotech and health-care executives at the National Museum of American Jewish History. 'Don't expect everybody to love you, but at least they will hear your side of the story.'

Who could quarrel with more explanations and disclosures?  President Clinton did not stop there, and went on to opine about prices versus drugs' purported value to patients, with a focus on new drugs for hepatitis C.

Clinton pointed to new hepatitis C drugs, Sovaldi and Harvoni, which are sold by Gilead Sciences for more than $80,000 for a 12-week program of treatment. Those medications often cure a disease that can cause liver disease and eventually lead to transplants or death, which are expensive, too. But the sticker price on the drug has caused a backlash by payers and patients.

'Who wants to let somebody's liver rot? Nobody,' Clinton said. 'Who's got $80,000 to spend? Not many. And if you're a small businessperson and you're in a small pool [of employer-based insurers], are you going to fire somebody who needs that treatment? These are all practical problems, and we can solve them.'

So the implications are clearly
-  President Clinton thinks it is reasonable to charge $80,000 for a course of treatment with Sovaldi, but society needs to figure out who will pay
-  Apparently he thinks it is reasonable because without treatment, patients with hepatitis C will get "liver rot," but the drugs will prevent that.

The Evidence Fails to Support the President

President Clinton's preparation for this talk apparently did not include speaking with someone who had critically reviewed the best evidence from clinical studies about hepatitis C, and the effects of new drugs on it, particularly, the effects of sofosbuvir (Sovaldi.)  Neither did President Clinton read Health Care Renewal.

If he did, he would have found out starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts here,  here, and here.)

But because, as we noted here, concerns about the lack of evidence in support of Sovaldi and its new competitors have been anechoic, it might not have been so easy for President Clinton to quickly determine if hepatits C usually causes "liver rot," and whether Sovaldi almost always prevents "liver rot," and hence might just be worth $1000 a pill.

Hype Wins, Logic and Reason Lose

Unfortunately, the problem is not merely that the BIO folks hired a celebrity to tell them what they wanted to hear.  President Clinton has a lot more gravitas than a Hollywood star, even given his famous equivocation about the meaning of the word "is."

More unfortunately in this context, President Clinton is also the husband of the current front running Democratic candidate for President.  Should former Senator and Secretary of State Hilary Clinton win the election, would her health policy choices be influenced by the (probably erroneous) belief that the current extremely high prices of medical treatments, particularly new drugs, are reasonable because of their magical curative properties?  Furthermore, President Clinton is also the Founder and presumed current leader of the the Bill, Hilary and Chelsea Clinton Foundation whose goals include working "to improve global health and wellness,..."  Is this work based also based on the assumption that the astronomical prices of new drugs are justified by their miraculous powers?

Thus President Clinton's apparent endorsement of the wonderful powers of Sovaldi, despite the lack of good evidence underlying them, may carry a lot of weight.  

Conclusion

How distorted is health care these days.  Misinformation, even disinformation seems to dominate evidence and logic.  Concerns about health care dysfunction are suppressed by the anechoic effect.  Perhaps inspired by the generic managers who now run health care organizations, everyone seems to have become a health care expert, and so the reach of viewpoints on health care seems to be more about the celebrity of their proponents rather than their knowledge, or the logic and evidence underlying their views.

As a start, true health care reform has to somehow liberate good clinical evidence from where it has been hidden, and encourage logical discourse over marketing, public relations, hype, propaganda, and disinformation.

If only someone who knows something about health care, logic and evidence could get their views heard by ex Presidents and others who dominate our 24/7 conversation. 

ADDENDUM (2 July, 2015) - This post was republished on the Naked Capitalism blog

See also comments by Micky on the 1BoringOldMan blog.

References
1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.