Health Science

It seems to be the season of the revolving door in health care.  The latest version got some media attention, because it involves one of the most important health care leadership positions in the US government, the Director of the Food and Drug Administration (FDA).  However, the case actually seems much more serious than what the media has recently reported.

The Basics

For an introduction, we turn to the Wall Street Journal from September 15, 2015:

President Barack Obama plans to nominate the prominent cardiologist and medical researcher Robert Califf as the next commissioner of the Food and Drug Administration, the White House said Tuesday.

Dr. Califf had been named the FDA’s deputy commissioner for medical products and tobacco—effectively the No. 2 post—in February. He joined the FDA from Duke University, where he had served as a professor of medicine, a leading pharmaceutical researcher and the vice chancellor for clinical and translational research.

The new nomination got some rave reviews. For example, from the WSJ article,

Francis Collins, director of the National Institutes of Health and a scientist who has worked with Dr. Califf for years, called this 'a fantastic nomination.'

Then this in the NY Times (Sept 15, 2015):

'He’s never forgotten that at his core he’s a doctor, and he cares deeply about providing evidence to help people take better care of patients,' said Dr. Robert Harrington, professor and chairman of the department of medicine at the Stanford University School of Medicine, who worked with Dr. Califf at Duke.

Also, a MedPage Today article was entitled, "Califf Nomination for FDA Chief Gets Most High Marks," and included such testimonials as,

'He has a very good understanding of industry and academia, and think that will serve him well,' Caleb Alexander, MD, co-director of the Johns Hopkins Center for Drug Safety and Effectiveness in Baltimore, told MedPage Today....

Also, this from Dr Harlan Krumholz,

He's a broad thinker and a very creative and visionary individual. He will be an outstanding choice.

And this from Dr Sanjay Kaul,

I can't think of a more qualified person than Dr. Califf to lead the FDA at the present time. He is an accomplished leader in cardiovascular disease research whose work has resulted in therapies that save lives and improve the quality of life for millions of patients.

Is it time to break out the confetti yet?

Conflicts of Interest a Fly in the Ointment?

The only fly in the ointment was the matter of Dr Califf's ties to industry. The WSJ article included,

Diana Zuckerman, president of the National Center for Health Research, a Washington-based group focusing on medical-product safety, questioned his ties to the drug industry.

'Dr. Califf’s expertise and his close ties to the pharmaceutical industry are both well-known,' she said. 'His ties to industry have been a source of great concern to public-health experts when he was previously considered for FDA commissioner, and those ties raise important questions about this nomination.'

The MedPage Today article noted that Public Citizen's Health Research Group stated,

'During his tenure at Duke University, Califf racked up a long history of extensive financial ties to multiple drug and device companies, including Amgen, Astra-Zeneca, Eli Lilly, Johnson & Johnson, Merck Sharpe & Dohme and Sanofi-Aventis, to name a few,' Michael Carome, MD, the group's director, said in a statement. 'Strikingly, no FDA commissioner has had such close financial relationships with industries regulated by the agency prior to being appointed.'

The MedPage Today article, however, then went on to undermine those concerns, implying that only fringe people like those at Public Citizen were really worried. 

Most experts contacted by MedPage Today seemed to think Califf would not have a problem getting Senate confirmation. 'I expect him to be confirmed," said [Dr. Steven] Nissen. 'He is very well liked by people ... in both parties, and I would expect the nomination to go well.'

'All signals suggest that Dr. Califf is well-respected on both sides of the political aisle,' Jay Wolfson, DrPH, JD, senior associate dean at the University of South Florida's Morsani College of Medicine, in Tampa, said in an email.

'There are some who believe his relationship with [the drug industry] may be a problem, but most see it as a value-added factor in building a functional, more streamlined relationship with the industry in order to improve the speed with which truly effective and quality drugs and devices are made available, mitigate the excessive costs associated with pharmaceuticals, and influence policies and practices intended to improve health status.'

Note that the experts were not all named, or their expertise described, the first two paragraphs were really about Dr Califf's political support, and the third paragraph clearly reflected the views of someone who thought that the FDA needs to have a lighter regulatory touch. 

There was additional reporting about Dr Califf's conflicts of interest, but again with the effect of minimizing their importance.  The Wall Street Journal published a second article on September 18, 2015 which first reported,

From 2009 through early 2015, Dr. Califf received consulting fees of roughly $205,000 from companies including Johnson & Johnson, Merck & Co., GlaxoSmithKline PLC and one medical-device maker, records show. The payments are documented by the federal Open Payments database, and PharmaShine, a database of pharmaceutical disclosures operated by Obsidian Healthcare Disclosure Services LLC. Drug makers spent an additional $21,000 on travel, meals and other expenses for Dr. Califf, data show.

But the article provided this counterpoint,

Kevin Griffis, a spokesman for the Department of Health and Human Services, said Dr. Califf had ceased all work with drug makers once he was hired by the FDA and that he has gone through a rigorous screening process for potential conflicts of interest. Mr. Griffis said Dr. Califf had donated all the consulting fees he has received since the mid-2000s to nonprofit groups.

'Dr. Robert Califf’s professional career has been dedicated to advancing biomedical research, including the rigorous evaluation of the safety, efficacy and appropriate use of both new medical products and those already on the market,' said Mr. Griffis, assistant secretary for public affairs at HHS.

Note that Dr Califf already is at the FDA, in a position that I do not believe required Senate confirmation.  It is striking, however, how the agency's own public relations people have jumped to his defense now as a nominee who has to be confirmed by the Senate.  However, I suppose that had Dr Califf donated all this fees to a local soup kitchen, they could not be called much of a conflict of interest.  But Mr Griffis said "nonprofit groups," without specification, not "soup kitchens." And continue reading to find out more. 

A simultaneous NY Times article enlarged a bit on Dr Califf's industry relationships,

He has written scientific papers with pharmaceutical company researchers, and his financial disclosure form last year listed seven drug companies and a device maker that paid him for consulting and six others that partly supported his university salary, including Merck, Novartis and Eli Lilly. A conflict-of-interest section at the end of an article he wrote in the European Heart Journal last year declared financial support from more than 20 companies.

However the NYT article also quoted Mr Griffis about the donations to "nonprofits," and added,

A résumé studded with industry funding is not unusual in academic medicine, Dr. Califf’s supporters note. Doctors are paid consulting fees all the time, and universities routinely conduct clinical trials on behalf of companies. Those contracts help support university researchers’ salaries, a standard practice. Many emphasize that it does not imply an inherent conflict.

His supporters contend that Dr. Califf’s vast experience in the clinical science world could be a major asset in his new post.

Furthermore,

Supporters and former colleagues say Dr. Califf’s background makes him perfectly suited to the job of commissioner. He has spent years improving the way clinical trials are conducted, coming up with groundbreaking trial designs for medicines against blood clots.

'His integrity in scientific matters is impeccable, and his innovation in clinical trial design is legendary,' said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, who has been an outspoken critic of both the F.D.A. and drug companies.

Even better,

Dr. Califf is often in the gym on the StairMaster before 6 a.m., said a former colleague at Duke, Dr. Adrian Hernandez. He often invites younger doctors to join him in golf and has a passion for Duke basketball that he expresses by wearing the team colors on game days.

How could anyone criticize a man who is at the gym at 6 AM?

More seriously, note that while the recent reporting may bring up questions about Dr Califf's conflicts of interest in terms of financial relationships with drug, device and biotechnology companies when he was on the Duke faculty, all the reporting also included passages minimizing the importance of these conflicts.  To minimize the issue of conflicts of interest, articles cited unnamed experts, suggesting the logical fallacy of an appeal to authority; noted that the financial ties that were criticized are standard practice in academic health care, suggesting the logical fallacy of an appeal to common practice.  The articles also cited Dr Califf's positive attributes which may have been relevant to his work at the FDA, like knowledge of research, but were not related to the question of conflicts of interest. This suggests another appeal to authority, or something of a reverse ad hominem (pro hominem?) fallacy.  It seems odd that what appear to be straightforward journalistic reports of a presidential nomination included such attempts to defend the candidate.  Note further that many of these logical fallacies appeared not in quotes from Dr Califf's supporters, but in text apparently written by journalists (e.g., "industry funding is not unusual," "in the gym on the Stairmaster," etc.)

Nonetheless, this is the state of play as of this moment.  The thrust of the media coverage suggested that Dr Califf is a brilliant physician and researcher, and while he as some ties to industry, they do not amount to much of a problem, except in the eyes of the likes of Public Citizen.


If one digs deeper, however, there is more. When Dr Califf was appointed to his current FDA position in February, 2015, and years earlier when his name was first mentioned as a possible candidate to run the FDA, evidence appeared that his ties to pharmaceutical, biotechnology and device companies were much more serious than what the recent accounts suggested.  

Where Does the Money from Industry Sponsored Research Grants Go? 

The recent coverage of Dr Califf's nomination in the NY Times dismissed his multiple corporate research grants as common practice.  Yet in the TIME coverage of  his original appointment to the FDA in February, 2015, this reminder of the significance of corporate sponsored research grants appeared.

Califf says his salary is contractually underwritten in part by several large pharmaceutical companies, including Merck, Bristol-Myers Squibb, Eli Lilly and Novartis.

Note that apologists for physician and academician interaction with industry often claim that industry funding of research grants that does not go directly to individuals does not cause important conflicts of interest. In one sentence, however, this article underlined how these grants support academic salaries, and hence lead to the dependency that is at the heart of conflicted relationships.

As we posted in 2007, academic medical institutions now depend on "external," including corporate research funding to support their research faculty's salaries, and via "overhead," their overall budgets.  Dr Lee Goldman, then Dean and Executive Vice President at Columbia University, called faculty who bring in a lot of grant money "tax payers," who earn gratitude, and likely bonuses and perks.  Thus Dr Califf's multiple large corporate research grants cannot be completely dismissed as conflicts of interest. 


A More Extensive List of Industry Relationships

Furthermore, a relatively obscure February, 2015, report from MDDIOnline noted that Dr Califf had more industry relationships than were reported this month,

Conflict of interest disclosures dating back to 2007 made public by the DCRI show that Califf has been paid for consulting or other services provided to a number of medical device pharmaceutical, and biotech companies, including Medtronic, Acumed, Bayer Healthcare, Merck, Novartis, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly & Co. Califf also disclosed that he held equity in two pharmaceutical companies—Boulder-based N30 Pharmaceuticals and South San Francisco, CA-based Portola Pharmaceuticals—as recently as 2014. Califf retired from Portola’s board of directors January 26, according to a press release from the company.

A somewhat more obscure commentary by Martha Rosenberg in OpEdNews provided even more extensive listings of Dr Califf's industry relationships. And it suggested having a look at the disclosures he has made in the past in medical journal articles. A statement in a 2013 JAMA commentary was particularly telling,

Dr Califf receives research grants that partially support his salary from Amylin, Johnson & Johnson, Scios, Merck/Schering-Plough, Schering-Plough Research Institute, Novartis Pharma, Bristol-Myers Squibb Foundation, Aterovax, Bayer, Roche, and Lilly; all grants are paid to Duke University. Dr Califf also consults for TheHeart.org, Johnson & Johnson, Scios, Kowa Research Institute, Nile, Parkview, Orexigen Therapeutics, Pozen, WebMD, Bristol-Myers Squibb Foundation, AstraZeneca, Bayer/Ortho-McNeil, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GlaxoSmithKline, Li Ka Shing Knowledge Institute, Medtronic, Merck, Novartis, sanofi-aventis, XOMA, University of Florida, Pfizer, Roche, Servier International, DSI-Lilly, Janssen R&D, CV Sight, Regeneron, and Gambro; all income from these consultancies is donated to nonprofit organizations, with most going to the clinical research fellowship fund of the Duke Clinical Research Institute. Dr Califf holds equity in Nitrox LLC, N30 Pharma, and Portola.

These lists of corporations from which Dr Califf got salary support and consulting fees are much longer than previous lists.  He acknowledged 13 commercial research sponsors, and consulted for 32 organizations, most of which were pharmaceutical companies.  Again, given that the salary support and overhead likely supplied by corporate research grants do suggest conflicts of interest, Dr Califf may have had many more of these sorts of conflicts than current reports implied  

A Seat on a Pharmaceutical Company Board of Directors

Note that the MDDIOnline article mentioned that Dr Califf was a member of the board of directors of Portola Pharmaceuticals. That was a significant source of income.  According to the Portola Pharmaceuticals 2015 proxy statement, Dr Califf received $259,623 in cash and stock options from the company in 2014.  I cannot find anything to suggest that this payment did not go directly to him.  This position, and the money it paid were not mentioned in the recent coverage. That payment alone seems to represent a major conflict of interest.

However, being on the board of directors of a health care corporation presents a deeper conflict than that produced by a simple payment of money or stock options, no matter how large. In 2006, we discussed corporate directorships as a new and important species of conflict of interest for medical academics.  As we have previously posted, corporate directors have fiduciary responsibilities to the company and its shareholders to support its financial success.  They are supposed to "demonstrate unyielding loyalty to the company's shareholders" [Per Monks RAG, Minow N. Corporate Governance, 3rd edition. Malden, MA: Blackwell Publishing, 2004. P.200.]   Thus corporate directors have a much more significant commitment to the corporation than do corporate consultants, or researchers supported by corporate grants. 

Where Did Those Donated Consulting Payments Go?

Also note that the disclosure statement in the JAMA article mentioned that most of the consulting payments Dr Califf received went to the clinical research fellowship of the Duke Clinical Research Institute (DCRI).  Dr Califf was the first director of DCRI, 

So, while Dr Califf apparently did donate the consulting fees to a non-profit organization, that organization actually was part of Duke, and an organization that Dr Califf once led. It appears likely that Dr Califf benefited at least indirectly in terms of institutional gratitude and reputation from these consulting fees that he donated to his own institution.  So it appears that Dr Califf's donations of his consulting fees did not reduce the conflicts of interest generated by these fees to the extent suggested by the current FDA spokesperson and current media reports. 

Payments for "Educational Activities" 

Finally, perusal of disclosures of Dr Califf's commercial relationships made by the Duke Clinical Research Institute for the years 2010-2015 showed that he received payments for "educational activities" in 2011 from Amylin.  Information about earlier years is not available on this site, but in 2009, Dr Daniel Carlat wrote this about Dr Califf's then rumored candidacy for leadership of the FDA in the Carlat Psychiatry Blog,

look at these industry disclosures. He took money—lots of money--from 18 different pharmaceutical or device firms. Most of this was not for research, but for consulting and speaking, including CME. If Dr. Califf believes that it is ethical for physicians to help drug companies market their products, that’s his own business. But to elevate him to a position in which he is the country’s chief watchdog over unsafe medications and foods seems a dangerous move. With money from 18 drug companies padding his bank account, he will presumably spend most of his FDA career recusing himself from crucial decisions. Not a good idea.

There has been no mention of Dr Califf being a paid speaker for pharmaceutical companies in any of the recent reporting.  Dr Carlat implied that Dr Califf was paid to speak to further marketing objectives of pharmaceutical companies, that is, was giving "drug talks."  Since the publication of "Dr Drug Rep" in the New York Times in 2007, authored by Dr Carlat, the public has learned that such talks mainly include content provided by the pharmaceutical companies, and are meant by the companies as marketing exercises.  From that case we also learned that physicians who deviate from the marketing message do not last long on speakers' bureaus.  (See posts here and here.)

Paid speakers may be regarded by pharmaceutical companies as paid "key opinion leaders," KOLs, who serve a marketing function in the guise of academics. As noted here and here, the companies buying their services may believe they have bought the services of sales people.    Evidence about key opinion leaders actually performing like marketers has come from documents revealed during litigation (e.g., see this recent example of a huge monetary settlement made of charges that GlaxoSmithKline, a major multinational drug company committed fraud among other things, and in the course of its unethical activities used key opinion leaders as marketers).   Also, see the Neurontin marketing plan (see post here), and the Lexapro marketing plan (see post here) for examples of how company keaders view key opinion leaders as marketers.

So the revelation that Dr Califf received corporate payments for "education" suggests a bigger commitment to corporate marketing objectives than has previously been revealed.  

Summary

So, looking at not only current media reports, but media reports from earlier this year, and also proxy statements, the fine print of journal articles, and old blog posts, it appears that Dr Robert Califf really did have very substantial financial interactions with the drug, device and biotechnology industry.  These interactions likely underwrote his salary and his standing with the leaders of his former employer, Duke University.  Dr Califf seemed to be a paid speaker for drug companies on at least two occasions, suggesting that the companies may have put him in a covert marketing role, or viewed him as a paid key opinion leader.  Finally,  Dr Califf served on the board of directors of one drug company, a much deeper commitment than being a sponsored researcher or consultant.

Thus Dr Califf really appears to be one of the most, if not the most drug, device and biotechnology industry connected individual ever nominated to lead the agency that is the most important regulator of the US drug, device and biotechnology industry.  Some of his connections, particularly his previous membership on a pharmaceutical company board, and his previous roles as a paid pharmaceutical speaker, suggested not only financial relationships, but commitments to companies' financial and marketing goals.  These appear to be major conflicts of interest vis a vis Dr Califf's current leadership position at the FDA, and his nomination to be the ultimate leader of this regulatory agency.  This is the revolving door writ large.

As we have said very recently,  the revolving door can be veiwed as a species of conflict of interest.  Government officials who can look forward to extremely lucrative employment in health care industry may be much more inclined to seem friendly to the industry while in office.  Government officials who just came from industry are likely to maintain their industry mindset and be mindful of their industry friends.

Worse, some experts have suggested that the revolving door is in fact corruption.  As we noted here, the experts from the distinguished European anti-corruption group U4 wrote,

The literature makes clear that the revolving door process is a source of valuable political connections for private firms. But it generates corruption risks and has strong distortionary effects on the economy, especially when this power is concentrated within a few firms.

Furthermore, the ongoing and increasing revolving door phenomenon clearly suggests excess coziness between industry and government, now to the extent that industry and government leaders of health care are becoming interchangeable.  This suggests that health care is increasingly run by this cozy ingroup, who very likely put their own interests ahead of those of patients and the public.

The continuing egregiousness of the revolving door in health care shows how health care leadership can play mutually beneficial games, regardless of the their effects on patients' and the public's health.  Once again, true health care reform would cut the ties between government and corporate leaders and their cronies that have lead to government of, for and by corporate executives rather than the people at large.

ADDENDUM (28 September, 2015) - This post has been republished on the Naked Capitalism blog,  and OpEdNews.

ADDENDUM (28 September, 2015) - See also more detail on Dr Califf's activities on the Portola board on the PEU Report blog. 

And the hepatitis C follies continue...

As we have frequently written, most recently last week, the hepatitis C screening and treatment bandwagon keeps rolling along.  There is constant public argument about the prices of treatment regimens, which approach $100,000 per patient in the US.  However, nearly all the public chatter, which seems mostly to come from corporate public relations people and marketers, investors and investment advisers, physicians with financial conflicts of interest, and pundits with little background in clinical epidemiology, seems never to question the assumption that the new drugs for hepatitis C are miraculous cures, which, of course, makes it hard to argue that they should not cost royal amounts.

The Lack of Good Evidence for the New Hepatitis C Treatments

However, 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.)

Yet the lack of evidence, and the discussion up to last week of this lack of evidence, was mostly anechoic.  The public argument continued to be based on the assumption that new treatments of hepatitis C are miraculous.  

The BMJ Elicits An Interesting Response

Last week the British Medical Journal provided the first opportunity for a large audience to be exposed to skepticism about the hepatitis C bandwagon.  As we discussed here, the article by Koretz et al(3) based an affirmation of the four points above on a critical examination of the evidence. 

The article, and even our blog post about it, seem less anechoic than the previous articles and blog posts mentioned above.  At least a few commentators were inspired to a defense of the currently received wisdom.  However, in my humble opinion, the commentators mainly succeeded in demonstrating how received wisdom is often supported by illogic.

Defending the Received Wisdom with Logical Fallacies - Analysis of an Anonymous Comment 

Let me start with examples derived from dissecting the arguments of the first anonymous comments we received on our  blog post.

Examples of the Straw Man Fallacy

The commentators arguments included,

 The article suggests that the INF+RBV therapy is just as good as Harvoni,

Note that whether by "the article" the commentator meant the article by Koretz et al,(3) or the blog post on Health Care Renewal was not clear. In any case, neither made a statement to that effect.  Incidentally, I am not aware of any trial that directly compared Harvoni to some combination of interferon and ribavirin.

Both Koretz et al and I did refer to the ONLY trial in which one of the new antiviral drugs (sofosbuvir) was directly compared to peg-interferon and ribavirin.(4)    I discussed that trial in detail here ( http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html)  It showed no significant difference between the sustained viral responses at 12 weeks produced the two regimens.  As far as I can tell, there is NO evidence from any controlled trial that the new drugs are more effective than the old drugs.

So the commentator's argument was based on a misstatement of either Koretz and colleagues' or my argument.  In any case, it is therefore an example of a logical fallacy, the straw man fallacy.  The commentator was not arguing with something we wrote, but rather a straw man assertion which the commentator constructed.  

The commentator also said,

the claim that INF+RBV causes adverse effects in less than 1% of treated is just false,

Again, neither Koretz et al nor I wrote that.  So this began another argument based on the straw man logical fallacy. 

Koretz et al and I again referred to data from the Lawitz et al controlled trial.  That trial did suggest that the new drug produced more, not less severe adverse effects than the old drug.

The Red Herring Fallacy

The commentator wrote,

The statement that most patients will not go on to severe liver damage/liver cancer is unproven.

Presumably, this meant most patients with untreated hepatitis C will not go on to severe liver disease/ cancer.  This, however, is a statement about the natural history of a disease.  How a statement about disease prognosis could be "proven," however, is not clear.  It is not ethically easy, or perhaps possible, to do an experiment to prove the natural history of disease.  Our knowledge of prognosis therefore relies on observational studies.  While such studies can show association, they cannot prove causation.  So it is true that the prognosis of hepatitis C is unproven, but in practical terms it cannot be proven, or unproven.  While the commentator implied that longer term studies would show that patients have very bad outcomes, but no one knows that with certainty.  Thus, the assertion seems to be an example of a red herring, bringing up an irrelevant point to distract from the issue. 

Appeal to Authority

The commentator wrote,

SVR12 is a commonly accepted evidence for complete eradication of the virus

So the argument was that some people, perhaps, as was said at the conclusion of “Raiders of the Lost Ark,” top men believe that SVR means complete cure.



Why anyone believes that SVR12 means cure, and particularly whether this belief is based on evidence and logic was not explained. Just because some people, even top men, believe it does not mean it is true.  Thus this assertion is an example of another logical fallacy, an appeal to authority. By the way, there are plenty of people, including Koretz et al, who do not believe this. 

ADDENDUM (27 January, 2015) - I have now independently verified that the comments made on our blog by "anonymous" were made by a patient, and were made honestly, not cynically.  Furthermore, English is not the patient's first language, so he or she may have used English words such as "unproven" and "commonly accepted" somewhat differently than I understood. 

More Logical Fallacies in the BMJ Rapid Responses

Similarly, the article by Koretz et al has generated a few rapid responses which contain their own share of logical fallacies.  Some examples follow from comments through January 19, 2015.

Begging the Question and the Burden of Proof Fallacy

In the January 15, 2015 comments by Donna R Cryer

[The article by Koretz et al] severely undervalues the harms, to the individual and society, of active HCV infection. Reduction or avoidance of end stage liver disease or death are not the only appropriate measures of value of screening or the effectiveness of new medications.

Ms Cryer did not state what the values of the harms are, nor what the other appropriate measures might be, and provided no evidence for either assertion.  So this boils down to, "you are wrong and I am right."  More formally, this could be an example of begging the question, that is, an argument - in this case that screening is warranted - simply based on assumptions without explanation or supporting evidence.  On the other hand, this could also be an argument of the burden of proof fallacy.  Ms Cryer implies that Koretz et al must prove their conclusions, while she simply needs to assert hers. 

Appeal to Fear

Again from Cryer,

To propose that widespread birth cohort screening efforts be undermined is a disservice to every individual living, unknowingly, with the silently devastating disease that is hepatitis C.

Note that this sentence again appears to include begging the question, with the assertion that hepatitis C is "silently devastating," without explanation or supporting evidence, and the burden of proof fallacy, since it implicitly rejected Koretz and colleagues' argument that hepatitis C is not devastating to all patients, which was based on at least some evidence, without supplying any evidence that it is devastating.  Furthermore, this has an element of an appeal to fear in its use of the emotionally loaded word, "devastating."  Note that Koretz et al instead talked about specific complications of hepatitis C. 

Wishful Thinking

In the January 18, 2015, comments by Nowlan Selvapatt

newer regimes will ultimately improve pricing competition and sustained virologic response rates compared to interferon based therapies.

The author did not explain why these improvements will occur.  This could be another example of begging the question.  On the other hand, it also could be wishful thinking, which at least some people consider a logical fallacy as well as a cognitive bias.  Obviously, it would be nice for the newer treatments to achieve better results at lower prices in the future, but the future is not so predictable.

An even more explicit example of wishful thinking, alsoby Selvapatt, was,

The hope would be that ... [screening] would serve to reduce the economic and healthcare pressures associated with end stage liver disease caused by hepatitis C.

That would be the hope, certainly, but should the decision to screen be based on hope, or on evidence and logic.

Appeal to Authority

In the January 19, 2015, comments by Padmanabhan Badrinath

Regarding side effects Koretz et al state 'However, in a trial of sofosbuvir versus peginterferon plus ribavirin, 3% of participants taking sofosbuvir experienced serious adverse events compared with 1% in the peginterferon plus ribavirin arm (difference not significant)'. According to NICE 'Evidence Review Group (ERG) was satisfied that the evidence showed that treatment with sofosbuvir-based regimens was generally well tolerated and led to fewer adverse events than treatment with peginterferon alfa and ribavirin'.

Note that Koretz et al provided data, and again, that from the only clinical trial that compared a new drug (sofosbuvir) to an old drug, peg-interferon.  However, Badrinath contrasted that evidence with conclusions from the NICE report that were about apparently any, rather than just severe adverse events, and Badrinath did not provide any justification of or evidence supporting these conclusions.  While NICE is admittedly often considered to be pretty authoritative, simply stating its conclusions in the absence of evidence to refute Koretz's presentation of evidence amounts to an appeal to authority.

Summary

So it appears that the BMJ article on hepatitis C rendered the skepticism about the miraculous qualities of the innovative new antiviral drugs for hepatitis C less anechoic.  However, the response to these echoes seems to have been enriched with illogic.

So it goes in the brave new world of health care.  In the current money driven system, new "innovations" touted as miraculous constantly appear.  When a few skeptics question the evidence or logic supporting these claims, these doubts usually start as anechoic.  If the doubts are more widely expressed, the first line of defense seems to be often based on logical fallacies.  We most recently saw such fallacies deployed defending another drug, sacubitril, touted as miraculous from annoying skeptics.

Health care professionals, health care policy makers, and the public at large should not be swayed by illogic.   Our continuing series about how logical fallacies are used to support the status quo and the powers that be in health care suggests, if nothing else, that health care professional education ought to include courses in logic.

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 Inte 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. Koretz RL, Lin KW, Ioannidis JPA, Lenzer J.  Is widespread screening for hepatitis C justified? Br Med J 2015; 350: g7809. Link here.
4.  Lawitz E, Mangia A, Wyles D et al.  Sofosbuvir for previously untreated chronic hepatitis C infection.  N Engl J Med 2013; 368: 1878-1887.  Link here.

We frequently discuss how commercial sponsors manipulate clinical research to serve their interests.  There have been many cases of commercially sponsored controlled trials ostensibly designed to assess their sponsors' products manipulated to make these products look better.

Unfortunately, often such manipulation seems to escape public notice.  What skepticism they may generate often gets little notice, an example of the anechoic effect.  Very rarely do the people responsible for the trial deign to address skeptical criticism. 

However, we recently noted that cogent criticism of a very recently published trial got some circulation, leading to a dialogue with the trial's principal investigator.  The results seemed to show why those involved with manipulated sponsored trials often try to just ignore criticism.

Introduction - the PARADIGM - HF Trial of Valsartan - Sacubitril


As we recently posted, based on a new article now online in the New England Journal of Medicine, a combination of a new drug, sacubitril, in a new class, naprilysin inhibitors, with an older drug, valsartan, an angiotensin receptor blocker (ARB), has been hailed as a "game changer" for patients with heart failure.  However, although the study (entitled PARADIGM - HF) had many good features, it also had some major problems which made its interpretation difficult, and made the hype about "new hope" seem excessive.  Unbeknownst to me when I wrote the post, some pithy overlapping criticisms of PARADIGM - HF by Dr Vinay Prasad were posted on CardioExchange.

Surprisingly, Dr Prasad's post elicited a lengthy comment by Dr Milton Packer, the principal investigator of PARADIGM - HF, defending the study's methods.  This resulted in a back-and-forth between him and Dr Prasad.  (Available by subscription only.)  This seems to be on of those rare instances in which a pillar of the medical establishment was willing to defend the way things are done these days in health care, and in this case, the way commercially sponsored randomized controlled trials are designed.

In my humble opinion, this exchange illustrated one reason that most criticisms about flaws in commercially funded clinical research get the silent treatment: there really are not good explanations for them, other than they resulted from the intention to increase the likelihood that the sponsors' products would look better than they really are.

Let us consider in detail some of the written comments by Dr Packer addressing two major criticisms by Dr Prasad.

The Question about the Choice of Comparator

Dr Prasad and I both questioned the choice of the drug to which valsartan - sacubitril was compared.  Dr Prasad wrote,

In PARADIGM-HF, oral enalapril was dosed up to 10 mg twice daily, whereas LCZ696 was dosed up to 200 mg twice daily (which includes a cumulative 320 mg of valsartan). The problem is that 320 mg is the maximum HF dose of valsartan per drug labeling, but enalapril can be dosed up to 40 mg daily (20 mg twice daily) — double the maximum dose proscribed per protocol.

So,

In effect, drug dosing in PARADIGM-HF was a 'straw man' comparison. The reported outcomes may be entirely a consequence of more ARB versus less ACE inhibitor. That is reason enough to doubt the findings. Sacubutil, the novel drug, could have been a sugar pill, and the results may well have turned out the same. But there are two more good reasons to be skeptical.

Note that in effect Dr Prasad charged that the entire trial was based on a logical fallacy, the "straw man" fallacy.

Dr Packer's Response: Red Herrings, Ad Hominem Fallacies, and Appeals to Authority

Red Herring - Comparison to Trial with a Different Patient Population

Dr Packer made several responses to this criticism.  First,  he asserted that using the maximum dose of enalapril as a target dose would have been inappropriate,

Dr. Prasad proposes that the dose of enalapril was too low, and we should have used 40 mg daily of enalapril as a comparator. However, when 40 mg of enalapril daily has been used in a clinical trial (CONSENSUS), these extremely high doses were poorly tolerated due to hypotension and renal insufficiency.

However, that appears to be to be an example of the red herring fallacy.  The PARADIGM - HF trial was meant to include patients with mild to severe symptoms of CHF (CHF classes II - IV), although it actually included a few (about 5%) patients with no symptoms (class I).  However, as Dr Prasad pointed out in his later comeback,

Dr. Packer suggests that CONSENSUS trial proves that enalapril 40 cannot be given safely. It is worth noting this trial enrolled only NY Heart Classification IV patients, while these were less than 1% of pts in PARADIGM HF. Many patients in PARADIGM HF might well have been able to tolerate and benefit from enalapril 40mg.

So Dr Packer's argument based on a trial of only the sickest patients with CHF seems likely not be relevant to discussion of a trial of patients with much milder disease.

Red Herring - Physiologic Changes vs Patient-Centered Outcomes

Then, Dr countered Dr Prasad's concern that the design of PARADIGM - HF could not distinguish whether the apparent benefits of valsartan (at maximum dose) and sacubitril versus enalapril (at a moderate dose) were due to the valsartan alone versus the combination thus,

Furthermore, Dr. Prasad can provide no evidence whatsoever than valsaratan 160 mg BID produces more blockade of the renin-angiotensin system than enalapril 10 mg BID. It is simply not true.

This seems to be an even better example of the red herring fallacy.  The argument is not about the physiological changes the drugs may or may not produce.  It is about the design of a clinical trial and how that design could affect interpretation of patient-centered outcomes.  Degree of renin-angiotensin system blockade may not directly predict survival, hospitalization, functional status, etc.

Red Herring - References to a Trial of Valsartan in Addition to ACE Inhibitors

Appended to the above, Dr Packer wrote,

In fact, valsartan 160 mg BID does not even have a mortality effect when compared with placebo, whereas enalapril 10 mg BID does have a survival benefit.

It later became apparent that the evidence he felt supported this assertion came from yet another trial with an alphabet soup name, Val - HEFT.  But, as Dr Prasad argued, this was yet another red herring,

The VAL-HEFT trial– where Valsartan 160 BID was no better than placebo– occurred in the setting where 92% of patients were already on an ace-inhibitor. As such, it cannot be used to say what the effect of valsartan is among patients not taking an ace-inhibitor, as was the case in PARADIGM-HF.

To explain a bit, the Val - HEFT trial enrolled patients who were nearly all already taking an ACEI, including enalapril.  So its data could only speak to the question of whether adding valsartan to an ACEI has an effect, not whether valsartan alone is efficacious in CHF.  It does not appear that there has ever been a large, long-term randomized controlled trial that tested valsartan versus placebo for CHF.   So Dr Packer seemed to have supplied another quite large red herring.

Of course that raises the question of why  PARADIGM - HF only assessed the combination of  sacubitril plus valsartan, rather than sacubitril combined with other ARBs.  This question was not directly addressed in the exchange between Dr Packer and Dr Prasad.  Parenthetically, note that valsartan is sold by Novartis, the sponsor of PADADIGM - HF, as Diovan.

Dr Packer only complicated things later by writing,


if Dr. Prasad dismisses the evidence from Val-HeFT, he eliminates ALL of the evidence that supports the use of valsartan in heart failure. If he sets the Val-HeFT trial aside, what evidence is there that valsartan 160 mg BID does ANYTHING in heart failure?

Again, Dr Packer was the one supposedly responsible for the choice of valsartan as the ARB to combine with sacubitril.

In summary thus far, I could not find any instance in the exchange in which Dr Packer logically used evidence to explain why his trial compared valsartan (targeted to maximum dose) plus sacubitril to enalapril (targeted to a moderate dose).  Instead, his arguments seemed to consist of multiple examples of the red herring fallacy.

Ad Hominem - Dr Prasad's Degree of Understanding of the Heart Failure Literature

Instead, he also threw in some additional general points which appeared to be rather gratuitously fallacious, To start,

 

I wish that Dr. Prasad understood the field of heart failure trials better than he does,

Then,

I wish Dr Prasad understood the heart failure literature better.

These seem to be examples of the ad hominem fallacy.  Rather than addressing the logic and evidence used by Dr Prasad, Dr Packer implied that Dr Prasad simply lacks understanding. Dr Prasad's polite response was,

Dr. Packer could tighten his posts by reducing the number of times he wishes I understood the heart failure literature better.

Appeal to Authority - Dr Packer's and Colleagues' Implied Superior Expertise on the Medical Literature

That did not prevent Dr Packer from coming back with,

 

I suggested that Dr. Prasad become more familiar with the medical literature because it would save him considerable time in formulating useful arguments.

With this repetition, Dr Packer seems to be not only using the ad hominem fallacy, but implying the fallacy of the appeal to authority. The implication is that Dr Packer clearly is an expert, and Dr Prasad is not, and the expert should be heeded. Just to underline this, Dr Packer later wrote,

Dr. Prasad suggests that others share his concerns. If he were here in Barcelona at the ESC meeting, he would know that that was not the case. However, I realize that It is common for those who seek only to win debates to claim that others agree with them. But Dr. Prasad, wishing that people agree with you does not make it true.

That just makes it worse. The implication is that all the experts in Barcelona agree with Dr Packer, and hence as a group they must be right. By the way, it is obvious from our previous blog post, comments on it, and other comments on the CardioExchange exchange that there are at least other people who agree with Dr Prasad.

Appeals to Authority - The New England Journal of Medicine and the US Food and Drug Administration Must Always be Totally Right

Not to leave it there, Dr Packer added as general comments several other appeals to authority.  At the end of his first set of comments there was this,

The real lesson of PARADIGM-HF is that combined angiotensin receptor neprilsyin inhibition is superior to inhibition of the renin-angiotensin system alone in patients with chronic heart failure. That is the conclusion of our paper, which passes stringent peer review in the New England Journal of Medicine.

The implication is that no paper published in the New England Journal of Medicine should ever be questioned about anything.  Also,


 

it does not appear that you are aware of the criteria that the FDA uses to evaluate or approve new drugs for cardiovascular disease.

This added the appeal to authority that since the FDA approved this trial, there must be nothing major wrong with it, to another implied ad hominem about Dr Prasad's lack of awareness.

Thus it seemed that Dr Packer's defense of his PARADIGM - HF study's choice of drugs to compare was based almost entirely on a string of logical fallacies, rather than logic and evidence.

The Question of Run-In Period Bias

Dr Prasad's other major criticism of his trial had to do with its use of active run-in periods.  He wrote,

The reason why drug run-in periods are problematic is discussed at length in the literature. In short, run-in periods exclude intolerant and nonadherent patients, foster spuriously large treatment effects, and (most troubling) create inclusion criteria that are irreproducible — i.e., that apply to no population we can clearly describe, as reasons for dropout are multifaceted and unique.

Even more concerning is that drug run-in periods test a different question than the one we think we are testing. In PARADIGM-HF, the run-in tested whether sticking with LCZ696 or switching to enalapril is better for HF patients who have taken and tolerated enalapril followed by LCZ696. It effectively turns the trial into a withdrawal study. If stopping LCZ696 is harmful, that counts against enalapril.

Dr Packer's Response: Appeals to Common Practice 

Dr Packer's main argument in defense of the run-in period involved yet another logical fallacy, the appeal to common practice, for example,
  

Dr. Prasad seem ill-informed here. Drug run-in periods are not a controversial study-design choice. In fact, this type of design is strongly preferred because it closely mimics clinical practice.

Again,

I wish I understood Dr. Prasad’s arguments against run-in periods. We have used them in many heart failure trials, and it was used in the SOLVD Treatment Trial,...

Dr Prasad ultimately responded so as to underline the essence of the fallacy,

The fact that many (and often industry sponsored) studies use drug run in periods is not a justification for their use. 

Summary

The recently published paper reporting the results of PARADIGM - HF has already generated considerable media hype (and an uncritical editorial) proclaiming valsartan - sacubitril as a new wonder drug for congestive heart failure.  While the trial was not without good features, several critics, including Dr Vinay Prasad and yours truly, suggested the study had multiple problems which make its results difficult to interpret.  The Principal Investigator of the study, Dr Milton Packer, chose to publicly defend his trial, yet so far his defense seems built more on logical fallacies than on logic and evidence.  After he published his remarks in defense of the trial, the hype seems no more justified than it did before.

Not only was PARADIGM - HF sponsored by Novartis, but many of its investigators had ties to Novartis and other pharmaceutical companies.  Dr Packer should be applauded for disclosing clearly the number of companies with whom he works in his dialogue with Dr Prasad.

Competing interests: Personal fees from AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi, Janssen, Novartis, and Sanofi.