Desperate, Vulnerable Research Subjects, Cost-Cutting Contract Research Organizations and Threats to the Integrity of Clinical Research

Introduction - Clinical Research Done by Contract Research Organizations

Dr Carl Elliott seems to be one of the few people willing to investigate how modern medical research may threaten vulnerable research subjects.  His book, White Coat, Black Hat, opened with a chapter on vulnerable "guinea pigs," people willing to be clinical research subjects for money.  Such people may be desperate for money, and further may be homeless, and have psychiatric problems, including psychosis or drug or alcohol problems.  Dr Elliott just wrote another important article on the plight of vulnerable research subjects. As Dr Elliott wrote,

Most people think of pharmaceutical research as a highly technical activity that takes place in world-class medical centers. The reality is somewhat different.

This is apparent in a grainy video that I watched a few years ago. It had apparently been recorded on a cell phone, and the camerawork started off wobbly. A tanned man wearing sunglasses and a necklace appeared and was introduced as Dr. Johnny Edrozo, a psychiatric researcher. His shirt was unbuttoned partway down his chest. 'The latest stimulant coming out of the market is Vyvanse, which is a Dexedrine preparation,' Edrozo told the interviewer, pausing occasionally to chew gum. For reasons that were not explained, the interview took place in a parked car.

This was my introduction to South Coast Clinical Trials, a chain of private research sites in Southern California that specializes in testing psychiatric drugs. Pharmaceutical companies now typically outsource clinical studies to contract research organizations like South Coast, which run trials faster and at lower cost than universities do. Their job is simply to follow the instructions of their sponsors.

This formula is working: The contract research industry has grown steadily since the early 1990s and may now generate over $100 billion in annual income, according to the Tufts Center for the Study of Drug Development. At the top of the heap are corporations like Quintiles, which has 28,000 employees and operates in about 100 countries. At the other end are private physicians and small companies like South Coast, which are often based in strip malls or suburban office parks.

We first wrote about contract research organizations in 2005 based on a Bloomberg report that noted research conducted in a crumbling physical plant, on poor, often drug-addicted patients who "barely read" informed consent documents, bad record keeping, supervision by poorly trained or unlicensed clinicians.  It appears the problems have only gotten worse.

Vulnerable, Desperate Research Subjects


Dr Elliott made it clear that many of the research subjects enrolled by companies like South Coast are vulnerable. He noted that the companies purposefully recruit subjects from rooming houses and homeless shelters. Here is a description of the sorts of pitches they use.

'I was tired, I was hungry, and half an hour earlier the police had treated us like crap,' Burns said. 'And this woman is saying, ‘Imagine, in 40 days you’ll have $4,000!’ The recruiter made testing drugs sound like a vacation in a five-star hotel, Burns said. 'It’s like a resort selling time shares. They talk about all the benefits first, and it sounds great, but then you start to ask: What do I have to do?' 

Dr Elliott emphasized that such research studies can endanger subjects, but that poor, homeless, drug or alcohol addicted, or psychotic people offered thousands of dollars for participation are not likely to worry about the danger. He also suggested that monitoring and protection of such subjects may not be the most intense.

Obviously, this may be very bad for such research subjects. This is why it has long been considered unethical to recruit such vulnerable subjects in such dubious circumstances. But in this day and age of "greed is good," it may be all to easy to dismiss the risks as contingent on life styles that were already full of "bad choices."

Threats to the Validity of Clinical Research

Recruiting vulnerable patients, especially the poor, homeless, drug or alcohol addicted, or psychotic, into clinical research has dangers for patients not in those trials, and for health care professionals.

Remember that the principles of evidence-based medicine suggest that health care professionals should base decisions for patients on the best clinical research evidence. The quality of these decisions determine the quality of patient care and strongly affect patient outcomes. .

Yet if an increasing proportion of clinical research is being done on vulnerable, that is poor, homeless, drug or alcohol addicted or psychotic people, the validity of that research may be badly compromised.

Consider this narrative from Dr Elliott's article,

I walked round the corner to a shelter, where I talked to an elderly white man. 'I’d say the majority of guys here take advantage of that,' he told me, 'because they get a lot of money and they’re broke as hell.'

So, for example, to qualify for a study of drug addiction treatment,

I mentioned a recruitment flyer I’d seen outside the shelter asking for subjects with 'cocaine dependency.' George nodded. He told me that a lot of people start taking drugs just so they can qualify for those studies.

'You take that s*** two days before to get it into your blood.' He mentioned that he had recently screened for a trial at a research site running addiction studies. 'There were people in the waiting room high as a kite,' he said. 'They were incoherent.'

Also,

The main ethical issues here, of course, are the competence and judgment of the prospective subjects. 'When you say ‘money,’ everything else goes out the window,' said Hanif Jackson, a former program supervisor at the Ridge Avenue shelter in Philadelphia, which recently closed down. I heard the same thing from Harvey Bass, a chaplain who has worked at the Sunday Breakfast Rescue Mission shelter for 15 years. He said drug study recruiters often park outside the shelter and approach residents on the sidewalk. Although Bass didn’t think it was his place to warn residents away from the studies, it was clear that he was not exactly a fan. 'These guys have no job, no home, and a habit, he said. 'You have people at their lowest state, and they’ll say yes to anything.' 

As someone who has reviewed innumerable reports of clinical trials and other clinical research studies for journal clubs, journals, and grant review committees, I know that on paper clinical research studies have elaborate and specific criteria to include and exclude patients, and require patients to undergo detailed study protocols. However, can one really expect patients who are so desperate for money that "they'll say yes to anything" to admit to conditions which would exclude them from a trial? Can one really expect that they will faithfully adhere to research protocols that might require, for example, complete abstinence from alcohol? Can one really expect accurate answers on surveys meant to define their clinical outcomes?  There are numerous threats to the validity of trails conducted on poor, vulnerable, often psychotic or drug or alcohol addicted patients.

Cost-Cutting CROs and Shoddy Research

However, it is unlikely that contract research organizations who recruit such patients and run such studies are really up to implementing these complex, detailed, exacting protocols. Consider this narrative by Dr Elliott,

I visited a research unit at Lourdes Medical Center of Burlington County in Willingboro, New Jersey. The unit was operated by CRI Worldwide, the same company that Burns told me he had spoken with. (The company is now known as CRI Lifetree.) Its focus was on inpatient Phase I trials, which often involve gradually increasing the dose of a drug until subjects begin to feel toxic side effects. Some Phase I studies also require painful or unpleasant invasive procedures. For these reasons, the payment to subjects in Phase I trials is usually much higher than it would be for an outpatient study.

My first thought about the CRI unit: Its appearance did not exactly suggest clinical excellence. Most of the furniture looked as if it had been rescued from a Salvation Army store. Homemade notices with titles such as 'Smoke breaks' and 'Money requests' hung on the walls. No studies seemed to be going on, but a few people were wandering around or watching television, presumably waiting to be screened or assessed.. 

It was in this unit that a patient named Walter Jorden died. Dr Elliott narrated the events that took place before his death. Note that,

according to Jeffrey Fierstein, a cardiologist retained as an expert witness by Jorden’s family, the physicians involved deviated from expected standards of care by not more seriously considering the possibility that Jorden was having a heart attack. In Fierstein’s opinion, they not only ignored classic signs of a heart attack, but also neglected to perform an EKG and missed the opportunity to give Jorden the clot-busting drugs that might have saved his life. As Fierstein points out, 'My understanding is that it [the emergency department] was around the corner; it was right there.'

In addition, a companion article by Peter Aldhous  suggested that CROs and the drug, device and biotechnology companies that employ them are willing to allow physicians with questionable backgrounds to run clinical research. He found that a not insignificant minority of physicians listed as in charge of trials in a US Food and Drug Administration (FDA) database had records of dubious conduct, including various sanctions by state medical boards. He focused on one physician who had run trials since the 1980s, starting with Lovelace Scientific Resources. His record included one-year probation for drug issues, a diagnostic omission described by the medical board as "grossly negligent," then a three-year probation for that and other clinical care problems, then a license suspension, then finally license cancellation. Throughout all the years involved he continued to run clinical trials. In general, Mr Aldhous wrote,

My trawl netted dozens of doctors selected to work on clinical trials over the past five years who had previously been censured by state medical boards. Thousands of doctors are hired each year to test experimental drugs, making this a small minority. But most doctors have clean records, so companies should have few problems finding recruits without red flags against their name. 

His conclusion was,

After spending months in the world of clinical trials, I’m left with an impression of a system that has evolved beyond the FDA’s ability to manage it. I’ve also been struck by the profound disconnect between the disciplinary system that governs everyday medicine, and the separate regulations meant to protect clinical trial volunteers.

Speed and efficiency seem to be what matters to industry, and at times these factors appear to trump concerns about the doctors who run trials. 'The whole thing is profit driven,' says Michael Carome at Public Citizen, a consumer advocacy organization in Washington, D.C. 'You can see where corners might be cut, looking the other way when there might be concerns about an investigator.'

Some experts argue that the FDA’s entire rulebook for clinical trials, with its talk of things like 'institutional' review boards, reflects the academic past of clinical research—not today’s industrial juggernaut of for-profit clinical trials firms and for-hire review boards, which oversee a workforce of doctors drawn from regular medical practice. 'They are regulations for a world that doesn’t exist anymore,' says Elizabeth Woeckner, president of Citizens for Responsible Care and Research, which campaigns for the safety of medical research volunteers.

Again, this is similar to results of previous journalistic investigations of contract research organizations (some examples are here), going back to the Bloomberg article we discussed in 2005, and what Dr Elliott wrote in White Coat, Black Hat.  Thus we need to be extremely skeptical of the validity of clinical research implemented by contract research organizations, especially when the research subjects are vulnerable. 

Summary - Another Set of Threats to the Integrity of the Clinical Research Base

So given the push to do research rapidly at the lowest cost, the lack of supervision and regulation by the FDA, the hiring of physicians with problematic backgrounds, the willingness to take vulnerable patients desperately motivated by money, can we trust that the nice, clean, detailed descriptions of clinical trials implemented by contract research organizations presented in research articles and trial registries have anything to do with the reality of what went on? If not, what then should we make of the validity of the results of such trials?

This is compounded by our inability to tell who actually implemented any given trial.  While articles in most major clinical journals will list what companies sponsored trials, and whether the official paper authors had financial relationships with these companies, the articles do not describe who actually implemented the trials, or disclose whether contract research organizations were involved.

So the first obvious reform would be to require trial reports to disclose involvement of contract research organizations, and perhaps to list the personnel who actually were most responsible for implementing studies in addition to listed authors.

We already have discussed repeatedly how clinical research sponsored by organizations with interests in the outcomes favoring their products and service may be manipulated, and may be suppressed if even such manipulation fails to produce desired results.  We usually have assumed, however, that the published trial reports are generally accurate in their descriptions of trial implementation.  If they are not accurate, particularly because vulnerable subjects may say or do anything to stay in trials that pay them, and sometimes because of poorly qualified or impaired physicians running trials, this adds another layer of questions about the validity of commercially sponsored research.  This is yet another reason to ask whether we need to take research on human subjects meant to evaluate commercial products or services out of the hands of the companies that make those products and provide those services. 

Retrospective on the Blumsohn - Procter and Gamble -Sheffield University Affair: the Unhappy Lives of Whistleblowers and the Anechoic Effect

Introduction - the Unhappy Lives of Whistleblowers

The UK Times Higher Education Supplement just published a feature on the unhappy fate of academic, including academic medical whistleblowers.

Whistleblowers in universities can hit the national headlines for shining light on issues of public interest, only for their careers to end up in very dark places.

Some of higher education’s most prominent whistleblowers paint a bleak picture about the impact on their subsequent careers. They talk about being persecuted by colleagues after coming forward. But even after leaving their jobs, some believe they still suffer a legacy. One talks about being 'effectively blackballed' from ever working again in higher education.

For other whistleblowers, exile is self-enforced.

It is noteworthy that the graphic for the article showed a whistleblower with a ball and chain, but the ball is in the shape of a whistle.

Summary - The Blumsohn - Actonel - Procter and Gamble - Sheffield University Case

The article focused on the case of Dr Aubrey Blumsohn, which we discussed recently, and have posted about since 2005 (here).  For all relevant posts, look here.

The Times provided a good summary.  It is worth quoting it here, as a reminder of a very important case which has had far too few echoes.

[The] case began in 2002, when he was working in the research unit led by Richard Eastell, professor of bone metabolism at Sheffield. The unit was researching the effects on patients of Procter & Gamble’s anti-osteoporosis drug Actonel.

Blumsohn raised concerns about abstracts for conference papers submitted by P&G, under his primary authorship, but without the firm having granted him full access to the drug trial data.

His concerns were first raised with senior colleagues and then reported in Times Higher Education in 2005.

The data analysis for the research was carried out by P&G, which paid for the research and which did not release key data to Eastell and Blumsohn. According to Blumsohn, this prevented honest publication of research.

After coming forward, Blumsohn has previously said, his other research work was used as the basis for a series of research grant applications that Eastell sponsored and signed off for a PhD student, without acknowledging Blumsohn’s input and despite his objections.

In 2005, he told the university that he was speaking to the media after losing faith in its internal systems for dealing with such allegations. He was subsequently suspended and told by Sheffield that he could lose his job over alleged 'conduct incompatible with the duties of office', including 'briefing journalists' and 'distributing information, including a Times Higher article, to third parties with apparent intent to cause embarrassment'.

He later reached a settlement with the university and it dropped all disciplinary charges. However, he left the university in 2006.

Blumsohn says of what happened afterwards: 'I withdrew from medicine completely, I withdrew from academia and ultimately withdrew my medical registration as well.'

Given the impact on his career, does Blumsohn regret coming forward with his concerns? 'I had to do that,' he says. 'As a scientist, I couldn’t just go along with having my name attached to manipulated publications, based on secret data ghost-analysed by pharmaceutical companies.'

Could Sheffield have dealt with his concerns more effectively? 'I don’t know how Sheffield could have done better, or indeed how any medical school could have done,' Blumsohn replies.

He clarifies: 'The problem these days is that some parts of universities – most notably medical schools but some other parts as well – have so many conflicts of interest and financial imperatives guiding what they do, I’m not sure other universities would necessarily have behaved differently from Sheffield. When millions of pounds are at stake both in private fees for academics and university funding, and a pharmaceutical company is wanting you to dance, the pressure to go along and to get staff to remain quiet is overwhelming.'

A few comments are in order.  While universities appear to be places of free speech and open discussion, note that Sheffield apparently could punish Dr Blumsohn simply for talking to journalists, but particularly for simply saying things that might embarrass university leaders.  So university leaders wish not to be embarrassed seems to trump free speech and academic freedom.

Second, Dr Blumsohn rightly pointed out that the issue was really scientific integrity, not embarrassment.  He tried to stop what he perceived as manipulation of clinical research by a pharmaceutical company to support its vested interests in selling a particular drug.  Such manipulation threatened scientific integrity, and ultimately threatened patients' health.

Third, Dr Blumsohn also rightly pointed out in retrospect that what university managers really seemed to fear was not just personal embarrassment, but curtailment of money flows from industry to their institution that made them look good, and presumably become more wealthy.

Few Echoes in the Discussion of Whether the Former Procter and Gamble Executive on Whose Watch the Affair Occurred Should be US Veterans Affairs Secretary

As we discussed here, a top executive at Procter and Gamble whose remit at the time the affair occurred seemed to include Actonel and research related to it was nominated to run the US Department of Veterans Affairs, and hence the whole VA health system.  Only two blogs, including this one, raised the issue of the Blumsohn - Actonel - Procter and Gamble - Sheffield University affair as relevant.  There was no other public discussion of this connection.  The former Procter and Gamble executive was confirmed, and now runs the Department of Veterans Affairs.

Summary

This is another example of how leaders of big health care organizations remain unaccountable for their organizations' misdeeds.  The lack of any mainstream discussion of the Blumsohn - Actonel - Procter and Gamble - Sheffield University affair in connection to the VA nomination demonstrate the anechoic effect.  Even the most determined whistleblowers often do not get the public notice they deserve, and their revelations do not have the effects they ought to have, even after the whistleblowers have paid a very high price to try to spark public discussion.

So anyone thinking about trying to get public notice for some fact or issue that threatens the powers that be will think twice, both about the potential downsides to the whistleblower, and the potential ineffectiveness of these attempts.    

In the past two weeks, I have heard in confidence about three stories in which discussion of issues that might offend the powers that be, specifically, the leaders of big health care organizations, has been suppressed.  I am convinced that for every Dr Aubrey Blumsohn, there are dozens who are aware of deception, other unethical conduct, even crime and corruption that could harm patients and patient care, but are afraid to speak out.

Of course, as long as these issues remain hidden, the damage to patients and the public's health continues to be done.

We clearly need changes in public policy to protect whistleblowers and foster free speech about important issues in academics and health care.  We need health care professionals, health care researchers, health care policy makers, and those among the public who care about health care and health care need to organize to support free speech and academic freedom.  Otherwise, the anechoic effect will continue to befog all of health care.

Hat tip to Dr Carl Elliott writing for the Fear and Loathing in Bioethics blog.

Medicare Pays $220 Million a Year for Acthar Without Any Controlled Trials that Prove it Works - While We Have No Money to Develop Ebola Vaccines or Treatment?

Introduction - No Money for Ebola Vaccine Development

While a new Ebola epidemic continues in Africa, people in developed countries are getting worried. Even the 0.1%, who may have rarely worried about our dysfunctional health care system before, are getting nervous. For example, this week, the Donald seemed panic stricken that Ebola infected American health workers might be allowed to return to the US, no matter what the precautions.  As reported by Politico,

Donald Trump has a message for the Ebola patient coming to the United States for treatment: Stay out.

'Ebola patient will be brought to the U.S. in a few days — now I know for sure that our leaders are incompetent,' Trump tweeted Thursday night. “KEEP THEM OUT OF HERE!”

Yet, as we posted here, money was the major barrier to developing treatments of vaccines that could have helped contain the epidemic in Africa, but whose availability in the US could also have reassured the Donald.  Dr John Ashton, a top public health physician in the UK, wrote in the Independent,

 

We must also tackle the scandal of the unwillingness of the pharmaceutical industry to invest in research to produce treatments and vaccines, something they refuse to do because the numbers involved are, in their terms, so small and don't justify the investment. This is the moral bankruptcy of capitalism acting in the absence of an ethical and social framework.

 

It seems that in the US and UK, our market based health care system can only cannot develop treatments for dangerous diseases when the treatments will produce huge returns on investment.   The irony is that even people (like Mr Trump) who preached market triumphalism and limiting government, presumably from doing things like developing drugs, may now fear diseases for which the market alone provides no remedy.  

 

Meanwhile, while there was no money to develop vaccines and drugs for Ebola, a story about how much money we are spending on questionable remedies has reappeared.  

 

But a Huge Increase in Money for Acthar

This week, writing in ProPublica and the New York Times, Charles Ornstein noted the huge amounts being paid by the US government for a previously obscure drug,

An obscure injectable medication made from pigs' pituitary glands has surged up the list of drugs that cost Medicare the most money, taking a growing bite out of the program's resources.

Medicare's tab for the medication, H.P. Acthar Gel, jumped twentyfold from 2008 to 2012, reaching $141.5 million, according to Medicare prescribing data requested by ProPublica. The bill for 2013 is likely to be even higher, exceeding $220 million.

Over approximately the same time course, commercial US health care insurers and the Tricare program for military dependents noted a surge in the amounts they were paying for this drug too,

 At a recent conference hosted by Sanford C. Bernstein, Dr. Ed Pazella, Aetna's national medical director for pharmacy policy and strategy, explained the shift on Acthar.

Questcor's 'combination of aggressive marketing and aggressive price increases finally caused it to become a line item that a finance guy looked at and said: 'What the hell are we paying for this? Why? What is it?' And that's when we started looking at what's our policy around this stuff,' Pazella said.

You Heard it Here First - a Huge Price Increase for an Old Unproven Drug

This problem's development took quite some time.  As we first discussed in 2007, some clever  maneuvering by corporate executives around loopholes in government rules benefited the executives, but maybe no one else.

The clinical background is that Acthar is a form of a hormone (ACTH) that stimulates the adrenal gland to produce more cortisol and other related hormones.  The formulation is made from pig pituitaries, and was developed in the 1940s.  It was approved by the US Food and Drug Administration at a time when this action did nor require proof of efficacy, that is, proof that the drug worked.  For years, the drug was only used for a rare form of infantile seizures, and occasionally for symptoms of multiple sclerosis in adults.  As noted in several reviews by the Cochrane Collaboration, there is little good evidence that the drug works for either condition, and no evidence that it is better than simpler, cheaper alternatives, like synthetic alternatives to cortisol, for the latter. (See this blog post).

The drug languished for years, but Questcor purchased the rights to it in 2001, apparently for a mere $100,000 (look here).  In 2007, the company jacked its price up in 2007 from $1650 a vial to $23,000 a vial.

A Further Price Increase, and a Big Marketing Push


As Mr Ornstein noted, its price is now $32,000 a vial.  One might expect that this huge price would quickly generate competition from generic drug manufacturers,  but, per Mr Ornstein,

Although it long ago lost patent protection, the drug is a complex biologic agent, and the manufacturing process is a trade secret. 

Furthermore, infantile spasms may be rare, but, 

Since Acthar came on the market in 1952, the rules about F.D.A. approval have changed. At the time, drug companies simply had to demonstrate that a drug was safe, rather than that it was effective. Acthar was initially authorized as a treatment for more than 50 diseases and conditions. (The list has since been cut to 19.)

Drug companies are barred by federal rules from marketing drugs for "off-label" indications, however, given the above, it was not obviously illegal when Questcor

 began marketing it for a broad menu of uses.

In addition, Medicare could not easily challenge the huge price Questcor was charging for this unproven remedy given to adults

Medicare cannot bar access to medications like Acthar, even in the face of rising expense and questions about efficacy, Aaron Albright, a spokesman for the Centers for Medicare and Medicaid Services, said in a written statement. The law mandates that Medicare's drug program, known as Part D, cover drugs for the uses authorized by the Food and Drug Administration, he said.

Questions about Questcor's Marketing

In fact, while it appears legal to promote Acthar for uses for which it has no proven efficacy, there are some questions about Questcor's marketing practices,

The company has disclosed in filings with the Securities and Exchange Commission that two United States attorney's offices and the S.E.C. are investigating its promotional practices.

A possible reason why was supplied by a companion ProPublica article, also by Charles Ornstein,

 Many of Medicare's top prescribers of the expensive specialty drug H.P. Acthar Gel have financial ties to the drug's maker.

Only 18 practitioners wrote 15 or more prescriptions for the drug in 2012. At least nine — and all of the top four — were promotional speakers, researchers or consultants for Questcor Pharmaceuticals, a ProPublica analysis shows.

Also, there are questions about whether Questcor has been concealing adverse events related to the increasing use of Acthar.  Until recently, as noted by Gretchen Morgenson in the NY Times in July, 2014,

For years, Questcor Pharmaceuticals has highlighted the potential benefits of Acthar, its immune-system drug, while saying little about its ill effects.

But as had been noted also by Gretchen Morgenson in the NY Times in June, 2014, more information about adverse events began coming out, not mainly for the benefit of patients, but apparently due to questions by investors about a pending takeover of Questcor by Mallinckrodt,

Since 2012, the events, as reported to the Food and Drug Administration’s Adverse Event Reporting System, or Faers (pronounced 'fares'), have included 20 deaths and six disabilities among patients reported to have been using Acthar and in which Acthar was recorded as 'suspect,' or the drug most likely to have been associated with the event. From January 2000 through 2011, by contrast, 13 deaths involving Acthar were reported to the F.D.A.’s system.

Although Questcor has reported some of these events to the F.D.A., as required, the company has not discussed the adverse outcomes in its financial filings. A Supreme Court ruling in 2011 concluded that reports of adverse events among patients using a drug, even if few in number, are of interest to investors weighing whether to buy or sell shares in the manufacturer.

The July, 2014 article by Gretchen Morgenson in the NY Times noted further,

according to a regulatory filing made by Questcor early Thursday, the number of patients reporting a so-called adverse event while using the drug last year represented almost 5 percent of prescriptions dispensed. The total number of events in 2013 reported by patients, who can experience multiple ill effects, was almost 14 percent of prescriptions, up from 9.1 percent in 2011.

 It was the first time Questcor, which has received a $5.6 billion takeover bid from Mallinckrodt Pharmaceuticals, had disclosed any problems experienced by Acthar patients, even though such information is of keen interest to investors.

That information might also be of interest to patients and doctors. 

Questions about Questcor's Executive Compensation

While Questcor brought in huge amounts of money from an old unproven drug using aggressive marketing that did not dwell on the drug's adverse effects, its executives have been making lots of money, sometimes in questionable ways.  For example, in February, 2014, Jesse Eisinger also reported for ProPublica that the timing of Questcor CEO Don M Bailey's stock sales has seemed unusually fortuitous,

Questcor Pharmaceuticals is a biotechnology company with a $4 billion market capitalization. Good things keep happening to Questcor in the middle of the month. Here’s what’s notable: The middle of the month just happens to be the time that the company’s chief executive, Don M. Bailey, sells stock through his regular selling plan.

The question is whether the company timed its favorable press releases to coincide with the times its CEO was known to be selling his shares?

Also, in May, a blog on The Street noted that the CEO's daughter also appears to have been quite fortunate, for no obvious reason,

As reported this morning by my colleague Herb Greenberg in his "Reality Check" newsletter (subscription required), Kirsten Fereday, a Questcor employee who also happens to be Bailey's daughter, received a huge salary bump in  in 2013, according to the compensation portion of its yet-to-be-filed proxy two days ago in an amended 10-K.

According to the filing:

Kirsten Fereday, the daughter of Don M. Bailey, our Chief Executive Officer, was employed by us during 2013 as our Senior Director, Business Analytics and Evaluation, and received total cash and equity compensation for the year ended December 31, 2013 equal to approximately $1,035,246 in cash compensation and $200,000 in restricted stock grants (value based on intrinsic value method). Ms. Fereday's employment was approved in accordance with the Related Party Transaction Policy and our Chief Executive Officer is not involved in the determination of Ms. Fereday's compensation. [Emphasis added.]

Why did her pay go up so much compared to that received in the previous year?

Furthermore, while Questcor derives a tremendous amount of revenue from the US government, a deal is in the works for it to be acquired by Mallinckrodt, now based in Ireland, which, if successful, will make top Questcor executives even richer, as Gretchen Morgenson wrote in the NY Times in June, 2014,

If the acquisition by Mallinckrodt goes through, Questcor’s top six executives could receive severance packages totaling $63.5 million under the terms of their contracts, the merger proxy shows.

Also,

During the time that adverse events involving Acthar have risen, Questcor’s top executives have been actively selling shares. So far this year, securities filings show, sales by the top five executives at the company, four of them under prearranged selling plans set up last year, have generated gains of $39 million.

Summary

As Andrew Pollack wrote in the first NY Times coverage of how Questcor used an old unproven drug to generate huge returns,

How the price of this drug rose so far, so fast is a story for these troubled times in American health care — a tale of aggressive marketing, questionable medicine and, not least, out-of-control costs.

 The sorry case of Questcor and Acthar reveal how crazy the costs of health care in the US have become, driven now by a system that itself now seems crazy.  Through clever use of regulatory loopholes, the company acquired rights to an old drug whose efficacy was unproven, hugely increased its price, began aggressive marketing even though the drug's efficacy was completely unproven, while remaining largely silent about the drug's substantial risks.  Fueled by hundreds of millions of dollars in revenue thus generated, mainly from the US government, the company richly rewarded its top hired executives, who then have decided to sell it to a company outside of the US in a deal that will make these executives millions more.  So patients received a drug whose benefits are unknown, and whose risks may be much higher than they were told, at a cost of hundreds of millions of dollars, much of it borne by US taxpayers, while company executives got rich.


Just coupling for now the story of how we spent hundreds of millions on Acthar to enrich company executives with the story that we have no money to develop vaccines or treatments for Ebola virus (look here) demonstrates the massive failure of our experiment to turn our health care system over to market triumphalists and laissez faire mercantilists.  As long as we let the health care system be run by people who put their own enrichment ahead of patients' and the public's health, things will only get crazier.  And even the rich may not be immune from the results of that craziness

So to repeat, true health care reform would put in place leadership that understands the health care context, upholds health care professionals' values, and puts patients' and the public's health ahead of extraneous, particularly short-term financial concerns. We need health care governance that holds health care leaders accountable, and ensures their transparency, integrity and honesty.

But this sort of reform would challenge the interests of managers who are getting very rich off the current system.  So I am afraid the US may end up going far down this final common pathway before enough people manifest enough strength to make real changes.

No Treatment or Vaccine for Ebola, but a $1000 Pill for Hepatitis C

The Ebola virus epidemic in West Africa continues to grow, and now appears to be the worst known epidemic of that disease to date.  In the US and Western Europe, press reports are now raising concerns that the disease could spread there.  For example, CNN, in an article entitled "Ebola Fears Hits Close to Home," was a section headed "Could Ebola spread to the US?" An ABC article was entitled, "How the US Government Could Evacuate Americans with Ebola."

Reasons for fear of spread are the increased mobility of people made possible by air travel, and the lack of specificity of early symptoms of Ebola, so infectious people may not realize the dangers their travel might pose.  A US citizen with Ebola was on his way back to the US via several connections, and made it as far as Lagos, Nigeria before becoming too ill to travel further (per CNN).  Making the fears worse are the high fatality rate of Ebola, the current epidemic included.  According to Vox, the current outbreak is the Zaire subtype of the virus, with an expected mortality rate of 68%.  Finally, there is no known effective treatment or vaccine for the Ebola virus.

Economics, not Science the Reason for Lack of Medical Options for Ebola

The reason there are no vaccines or treatments available for Ebola does not appear to be the scientific difficulty involved in developing them.  Vox also published a discussion for the economic genesis of the problem:

 Researchers have devoted lots of time to building a vaccine that could stop the disease altogether — and according to Daniel Bausch, a Tulane professor who researches Ebola and other infectious diseases, they're making really significant progress.

Bausch says that the obstacle to developing an Ebola vaccine isn't the science; researchers have actually made really great strides in figuring out how to fight back against Ebola and the Marburg virus, a similar disease.

'We now have a couple of different vaccine platforms that have shown to be protective with non-human primates,' says Bausch, who has received awards for his work containing disease outbreaks in Uganda. He is currently stationed in Lima, Peru, as the director of the emerging infections department of Naval Medical Research Unit 6.

The problem, instead, is the economics of drug development. Pharmaceutical companies have little incentive to pour research and development dollars into curing a disease that surfaces sporadically in low-income, African countries. They aren't likely to see a large pay-off at the end — and could stand to lose money.

Prof Bausch elaborated,

These outbreaks affect the poorest communities on the planet. Although they do create incredible upheaval, they are relatively rare events. So if you look at the interest of pharmaceutical companies, there is not huge enthusiasm to take an Ebola drug through phase one, two, and three of a trial and make an Ebola vaccine that maybe a few tens of thousands or hundreds of thousands of people will use.

Of course, that assumes that this outbreak, like previous ones, will remain relatively confined, at least to Africa.

The 10/90 Gap

So the implication is that had things been otherwise, those in developed countries now worried that Ebola could spread their way could have been reassured by the availability of a vaccine, or other treatment.

The irony, if that is the right word, is that we do not have an effective treatment or vaccine for a viral disease that is relatively easily spread, and could likely rapidly kill nearly 70% of those infected.  Yet in the last months, we have been arguing about how the use of an extremely expensive treatment for another viral disease that is difficult to spread, and may kill a few percent of its victims over up to 20 or 30 years after infection.

I am referring, of course, to Sovaldi, the recently announced $1000 pill for hepatitis C.  Hepatitis C does affect a lot of people, including relatively affluent people in developed countries.  As we noted previously, though, the majority of people infected with hepatitis C will never have serious medical repercussion from it.  Small proportions of patients will eventually develop severe liver disease, including cirrhosis, liver failure, and liver cancer, and may die from the disease.  (See the report by the Center for Evidence Based Policy). Yet the treatment is being promoted for all patients with hepatitis C, most of whom could not benefit from treatment.  Furthermore, the evidence that treatment will actually prevent bad clinical outcomes, cirrhosis, liver failure, liver cancer, and premature death, is weak (look here).   Yet considerable money was devoted to developing multiple hepatitis C treatments, with the expectation that huge amounts of money could be made from selling them.

This is an example of the 10/90 gap

A long time ago, in 1998, I was invited to Forum 2 of an organization called the Global Forum for Health Research  The GFHR was an organization dedicated to overcoming the "10/90 gap":

Less than 10% of the worldwide expenditure on health research and development is devoted to the major health problems of 90% of the population

Yet the 10/90 gap is probably getting worse.  In the US, our health care has now been heavily influenced by advocates of neoliberalism, or economism.  Health care is now largely run by generic managers trained in business schools, with no specific training or expertise in health care, and doubtful loyalty to its values.  Current business school dogma emphasizes the primacy of economic efficiency over all other goals (look here), to maximize "shareholder value," which usually practically means maximizing short term revenue, to the immediate advantage of shareholders sometimes, but nearly always to the great and immediate financial advantage of paid managers and executives.  The emphasis on short term revenue uber alles helps explain how we have multiple expensive hepatitis C drugs, and no Ebola drugs or vaccines.

The real irony is now that some very well paid managers may be worrying about the possibility of contracting Ebola whose transmission was facilitated by our increasingly global economy, globalized in part due to the advocacy of those advocating neoliberalism and economism.

Summary

Unfortunately, the fortunes of the Global Forum for Health Research seem to have faded.  It went into sudden decline in 2010, and was subsumed into COHRED, the Council on Health Research for Development.  The last Global Forum meeting was in 2012, although there seem to be plans for another next year.    Meanwhile, multiple international organizations. including Medicins Sans Frontieres, established a Drugs for Neglected Diseases initiative, although its progress seems to be slow (see Pedrique B, Strub-Wourgaft N, Some C et al.  The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.  Lancet Glob Health 2013; 1: e371.  Link here.).

In my humble opinion, as long as much of the health care system is run so as to put short-term revenue ahead of all else, a manifestation of financialization encouraged by the generic managers who run so much of health, partly in their own self-interest, and by business schools promoting the shareholder value theory, we will not make much progress on the 10/90 gap.  Ironically, the realization that even rich generic managers may no longer be protected from some of the deadliest diseases that used to only afflict the poorest people in the world may have an effect on this problem.   

As I have said before,  true health care reform would put in place leadership that understands the health care context, upholds health care professionals' values, and puts patients' and the public's health ahead of extraneous, particularly short-term financial concerns. We need health care governance that holds health care leaders accountable, and ensures their transparency, integrity and honesty.

But this sort of reform would challenge the interests of managers who are getting very rich off the current system.  So I am afraid the US may end up going far down this final common pathway before enough people manifest enough strength to make real changes.

ADDENDUM - This was re-posted on the Naked Capitalism blog. 

New ONC Director Karen De Salvo seems no better than her predecessors - risk, harms and deaths due to health IT apparently OK for now, and all we need is a "Safety Center"

Karen De Salvo has assumed the role of Director of ONC, the office of the National Coordinator for Health IT at HHS (http://www.healthit.gov/newsroom/dr-karen-desalvo-md).

A pretty face, but here's evidence of the same old tired political hucksterism and spin concerning healthcare information technology. 

In response to perhaps the most candid exposé in the public media to date of the risks and defects of current commercial health IT, industry conflicts of interest, and injuries and deaths, that appeared on July 20, 2014 in the Boston Globe under the title "Hazards tied to medical records rush" (http://tinyurl.com/lm7x34h) by the Globe's Washington bureau chief Christopher Rowland, Ms. De Salvo authored a letter to the editor.

DeSalvo is new to the job, but not to the political message of unbridled health IT hyper-enthusiasm and pointless "Safety Centers", instead of formal regulation as in other mission critical industries using IT (including pharma, for one).

Her letter to the Boston Globe attempts to put lipstick on a pig regarding a technology largely reviled by physicians and nurses due to its poor user experience and defects (rampant due to the free-for-all of this healthcare sector's unprecedented regulatory accommodation, that is, no regulation) that cause patient endangerment.  See http://hcrenewal.blogspot.com/2010/01/honest-physician-survey-on-ehrs.html, http://hcrenewal.blogspot.com/2014/02/ehrs-real-story-sobering-assessment.html and http://hcrenewal.blogspot.com/2013/11/another-survey-on-ehrs-affinity-medical.html as just a few examples.

What politicians do:  they spin like neutron stars

Her letter, with my comments:

http://www.bostonglobe.com/opinion/editorials/2014/07/26/many-health-success-stories-note/MyyGM3uq2LU0GqGLLqYJ7M/story.html

Letters | CHALLENGES IN THE MOVE TO ELECTRONIC MEDICAL RECORDS

July 27, 2014

Many health-IT success stories to note

I was disappointed to read “Risks, some dire, tied to medical records rush” (Page A1, July 20), as it failed to mention any examples of patients and their health care providers benefiting from the use of health information technology, including electronic health records. 

As to "disappointment", nearly the entire healthcare and lay press is filled with "success stories" and other propaganda.  There is, in fact, no need for artificial and industry-favoring "balance" in the rare article about the downsides. The industry has its own very large mouthpiece.  (This is the response we at HC Renewal give to critique that we're not "balanced" in every post.  It would be as if every article on defective avionics and pilot training issues that cause hundreds to die (e.g, Air France Flight 447, http://en.wikipedia.org/wiki/Air_France_Flight_447) should be accompanied by articles on just how many non-fatal flights there are, too; or as if every article about criminals has to mention there are good people, too.)

Such success stories are playing out across the country daily, including in Boston, and their omission from the article incompletely portrays the important role of electronic health records in improving patient safety and outcomes.

Is this and example of a far-left "you have to break an egg to make an omelette" (even if the 'egg' is a human being) thinking?   This statement, attempting redirection from the downsides, in effect says: "It's OK to sacrifice 100 in experimentation to (potentially) 'save' 10,000 - or 1,000 to 'save' 100,000."

Problem is, this is not how Western medicine is supposed to work - by HHS's own policies on research ethics, and international agreements and treaties based on work that arose after WW2's medical abuses, no less, e.g., the Nuremberg laws.

In medicine, legal and ethical standards such as the NIH Guidelines for Conduct of Research Involving Human Subjects (http://grants.nih.gov/grants/policy/hs/regulations.htm), the World Medical Association Declaration Of Helsinki (http://www.wma.net/en/30publications/10policies/b3/) and others restrict introduction of new drugs and medical devices without informed consent, and without extensive preclinical and clinical testing and post-marketing surveillance, especially when risks of the technology are unknown.  

And health IT is decidedly experimental, considering we don't even know the true extent of harms, by multiple admissions (by FDA, IOM, ECRI etc., see http://hcrenewal.blogspot.com/2014/04/fda-on-health-it-risk-reckless-or.html).

Also see my post Mar. 12, 2012 post "Human Subjects Experimentation Directives Ignored in the Grand Health IT Experiment?" at http://hcrenewal.blogspot.com/2012/03/human-subjects-experimentation.html.  The highlights, emphases mine:

Directives for Human Experimentation
NUREMBERG CODE

1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice [that is, to opt-out - ed.], without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his health or person [information on HIT risk exists, such as on this blog - ed.] which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
3. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
4. During the course of the experiment the human subject should be at liberty to bring the experiment to an end [go back to paper - ed.] if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
5. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage [go back to paper - ed.], if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Perhaps they don't teach these things at Harvard?

Back to De Salvo's letter:

A fully electronic health system can help identify and prevent potential medical errors. The Office of the National Coordinator for Health IT has taken steps to address the safe use and implementation of electronic health records, including sponsoring the Institute of Medicine report referenced in the story.

And since that 2012 report, which acknowledges that bad health IT causes risks, errors and harms to a definite but unknown magnitude (see bottom section of my post at http://hcrenewal.blogspot.com/2012/03/doctors-and-ehrs-reframing-modernists-v.html), ONC has done next to nothing. People are exposed to risk, harms and deaths and that seems just fine to ONC, for if it were not, they would have acted aggressively - say, as if a type of jet plane, or nuclear power plant had been revealed to pose risks and dangers to the community.

As Mr. Rowland himself pointed out in the Boston Globe article:

... In 2011, the Institute of Medicine said the lack of a central repository for reporting error-prone software, patient injuries, and deaths, combined with nondiclosure and confidentiality clauses in vendor contracts, “pose unacceptable risks to safety.”

It strongly recommended that the Obama administration mandate that vendors report “deaths, serious injuries, and unsafe conditions” to a centralized, government-designated entity. Such reports should be made available to the public, it said, without information that would identify individual patients and providers.

Three years later, no such reporting system exists.

Instead, ONC takes the GM ignition switch approach (http://en.wikipedia.org/wiki/2014_General_Motors_recall):

... On February 7, 2014, GM recalled about 800,000 of its small cars due to faulty ignition switches, which could shut off the engine during driving and thereby prevent the airbags from inflating ... GM says it expects to charge $1.2 billion against its second quarter earnings as a result of its ongoing recalls, and the charge could get worse as lawsuits and investigations continue. 

The fault had been known to GM for at least a decade prior to the recall being declared.  Some have suggested that the company actually approved the switches in 2002 even though they knew they might not meet safety standards.

The company is facing multiple investigations into why it did not attempt to fix these faulty ignitions sooner, including a federal criminal probe, as well as a probe led by Anton Valukas, the latter of which produced a report which GM made public on June 5, 2014.

Instead of a serious approach to safety, ONC and De Salvo champion window dressing:

Most recently, the Office of the National Coordinator, the Food and Drug Administration, and the Federal Communications Commission issued a proposed plan that would include the creation of a health IT safety center, which would assist in the voluntary reporting of health IT-related medical errors. Many patient advocates, medical professionals, and other stakeholders have expressed support for this approach.

"Many?" - The consensus views, often dominated by industry insiders and others with conflicts of interest, is how ONC and De Salvo apparently think safeguarding the public is to be done.  Those who veer from this "consensus" with facts of risk and harms are to be ignored.

As to the hypocrisy and absurdity of a toothless "health IT safety center", see my April 9, 2014 post "FDA on health IT risk: reckless, or another GM-like political coverup?" at http://hcrenewal.blogspot.com/2014/04/fda-on-health-it-risk-reckless-or.html.

The hundreds of thousands of providers successfully and safely using electronic health records today show that health IT can, and does, improve health and health care.

Dr. Karen DeSalvo
National coordinator for health information technology
Department of Health and Human Services
Washington

Ms. De Salvo apparently never got this Mar. 14, 2014 CMS memo that was sent in response to a query by the American Association  of Physicians and Surgeons:

CMS: "we do not have any information that supports or refutes claims that a broader adoption of EHRs can save lives."  [But let's spend hundreds of billions of dollars anyway.]  Click to enlarge.

However, in politics, such issues do not seem to matter as compared to passing along the party line. 

In medicine, they do matter.  Very much so (see http://hcrenewal.blogspot.com/2011/06/my-mother-passed-away.html).

-- SS

New Allegations About Universal Health Services Inc - Why We Should Not be Surprised

Current Allegations of Poor Treatment and Threats to a Whistle Blower

This month, a Boston Globe article reported trouble at a local hospital,

Arbour HRI, a Brookline psychiatric hospital in recent trouble with regulators, disciplined a mental health worker for talking to the Boston Globe about problems there — an action the employees’ union is fighting.

The hospital also required all staff to sign a policy forbidding them from speaking with the media about Arbour — or risk losing their jobs, according to the union.

An article that appeared in the Globe on May 30 described findings of federal investigators that the hospital failed to provide treatment for at least four patients during a February inspection. Instead of attending group therapy, the patients, whose diagnoses included bipolar disorder and paranoid schizophrenia, spent many hours sleeping or wandering the hallways.

One Tuesday afternoon, three patients on a unit for those diagnosed with both mental illness and a substance abuse disorder were in therapy. Inspectors found eight patients in bed.

Frank Barnes, a longtime mental health worker and a union representative for 1199SEIU, was quoted in the story saying that problems at Arbour HRI reflected the culture of an administration more focused on revenue than quality of care.

But then,

 Nine days later, according to documents the SEIU provided to the Globe, a nurse executive verbally warned Barnes. A 'counseling/corrective action form' stated that the consequences for failing to follow the media policy could include termination.

The policy warns employees they 'are not to speak to any member from the media on behalf of the facility or company,' and that they must immediately refer press inquiries to the chief executive.

Arbour spokeswoman Judith Merel said that the policy is intended to protect the privacy of patients and staff. 'These processes are put in place to ensure that the hospital complies with all patient confidentiality and privacy laws as well as to safeguard the trust placed in us by our patients, employees and staff,' she said in a written statement.

But the SEIU, in a complaint against the hospital filed with the National Labor Relations Board, charged unfair retaliation against Barnes and said the 'overly-broad' media policy violates employees’ rights.

'If Universal Health Services is treating the patients under its care with dignity and respect, then why would it prevent caregivers from talking to the media?' union executive vice president Veronica Turner said in a written statement. 'It raises serious questions about what the company is trying to hide.'

So far we have allegations that insufficient or poor care was provided, and that a hospital employee who discussed the allegations with the press was threatened, apparently based on a media policy that was more like a code of silence.

It turns out these are not the first problems reflecting badly on the management of the hospital.

Arbour HRI has a recent history of problems. Massachusetts regulators prohibited the hospital from accepting any patients in November, citing unsafe conditions. They allowed admissions to gradually resume two weeks later, in early December. But then in February, inspectors for the federal Centers for Medicare & Medicaid Services found serious shortcomings in the quality of treatment at the 66-bed hospital in Brookline.

The problems at Arbour HRI should not come, however, as a big surprise.  Arbour HRI is part of

Arbour Health System [which] operates five psychiatric hospitals and 12 mental health clinics in Massachusetts. Its for-profit parent, Universal Health Services [Inc], is a publicly traded company that earned more than $500 million last year....

Although not mentioned in the current Boston Globe report, Universal Health Services Inc seems to have a sorry record.

In 2012, Settlement of Allegations of Substandard Treatment, Falsified Records

About two years ago, Universal Health Services settled somewhat similar allegations about another of its hospitals.  As announced by the Department of Justice,

Universal Health Services Inc. (UHS) and two subsidiaries have reached a settlement in a False Claims Act lawsuit with the United States and the Commonwealth of Virginia, the Justice Department announced today.   Under the settlement, UHS and its subsidiaries, Keystone Education and Youth Services LLC and Keystone Marion LLC, which did business as the Keystone Marion Youth Center, a residential facility in Marion, Va., agreed to pay $6.85 million to the United States and the commonwealth to settle allegations that they provided substandard psychiatric counseling and treatment to adolescents in violation of Medicaid requirements, falsified records and submitted false claims to the Medicaid program.  UHS closed the Marion facility earlier this year.  

The allegations, made by multiple people, were actually quite lurid.  As reported by the Huffington Post, the lawsuit involved assertions that psychological therapy was provided in hallways;  the facility lacked a required education program and clinical direct; inmates were nearly unclothed; responses to resident complaints were sometimes met with "brutal force;" the staff performed an "exorcism" on an autistic boy; and staff sexually abused residents.


Previous Allegations of Neglect, Suicide Attempts, Rape and Murder

Note furthermore that according to the Huffington Post, 

Universal Health Services Inc., a large hospital chain which racked up dozens of allegations of abuse during that time -- including everything from rape to suicide attempts allowed by neglect to murder. Over the years, states have barred children from attending UHS facilities over safety concerns and the feds have put UHS on their radar. Department of Justice lawyers have filed two lawsuits accusing the chain of fraudulent activities. 

By the way, the reason the Huffington Post gave this case extensive coverage, however, was not apparently the grievous nature of the allegations.  It was that on Universal Health Services board sat a politician who was at the time of the report a credible candidate for the Republican nomination to be President of the US.

Former Sen. Rick Santorum (R-Pa.) has become a top-tier candidate for the Republican presidential nomination in recent weeks by appealing to evangelical voters as a man steeped in family values and his Christian faith. From 2007 to 2011, however, Santorum served on the board of directors of Universal Health Services Inc.,...

In 2009, Settlement of Allegations of Kickbacks to Physicians

Finally, also mentioned in the Huffington Post, was another settlement by Universal Health Care.  As reported in Modern Healthcare,

Universal Health Services agreed to pay the federal government $27.5 million to resolve allegations that its three hospitals doing business as South Texas Health System paid kickbacks to physicians in the form of sham medical directorships and leases, the U.S. Justice Department announced.  

Note further that this settlement

also requires South Texas Health System to enter a five-year corporate integrity agreement with HHS' inspector general's office. 

Summary

So given the record public since at least2009, should it be a big surprise that Universal Health Services is again facing allegations of poor and unethical treatment of patients and employees?

This is a familiar pattern.  Now that we have been following organizational misbehavior in health care for some years, we see that organizations that get into trouble once are very likely to get into trouble again.

This may be enabled by how government regulators and law enforcement give large health care organizations such  gentle treatment.  We have talked about the march of legal settlements by such organizations before.  Allegations are usually resolved with legal settlements that involve no admissions of guilt, small monetary penalties (compared with these organizations' total revenues), and sometimes apparently toothless corporate integrity agreements.  Settlements get desultory public notice, rarely informed by previous settlements or other evidence of previous misbehavior.  No individual who may have authorized, encouraged, directed, or implemented the bad behavior is likely to suffer any negative consequences.   It does not help that while nominally public, these settlements get little press, and what coverage there is usually fails to put the whole pattern together.

So we would urge the reporters who cover the next settlements by big health care organizations at least look to see if the organizations had been involved in similar settlements in the past.

Furthermore, as we have said all to often,...   The failure of the current limp legal efforts against such corruption is evident by how many corporations have become ethical repeat offenders.  Pervasive bad behavior by large health care organizations has got to be a major cause of our ongoing health care dysfunction.  So, to really deter bad behavior, those who authorized, directed or implemented bad behavior must be held accountable. As long as they are not, expect the bad behavior to continue.

Sovaldi, a Quantum Leap... Backwards to the Days Before Randomized Controlled Trials?

The Sovaldi (sofosbuvir - Gilead) media circus is continuing.  The New York Times just reported that sales of the new drug for hepatitis C were about $3.5 billion for the last quarter, which should intensify the kerfuffle over its US price ($1000 per pill, $84,000 for a 12 week course of medication).

Meanwhile, reports of its wondrous properties continue to appear in medical journals.

The latest was announced this way in Bloomberg,

Gilead Science Inc Solvadi, controversial because of its price, helps cure hepatitis C in people with HIV, according to researchers who say the drug has the potential to limit a top cause of death in these patients.

In a study of 223 HIV-infected patients, Solvadi combined with ribavirin cleared the most common US strain of hepatitis C in 76 percent of newly treated patients over 24 weeks. Only seven participants stopped treatment because of side effects and there were no adverse effects on HIV treatment, according to a report in the Journal of the American Medical Association.

Not unexpectedly, the study investigators were thrilled,

This is 'the first clinical trial to demonstrate that we can cure hepatitis C in patients with HIV co-infection without the use of interferon,' said Mark Sulkowski, the study author and medical director of the John Hopkins Infectious Disease Center for Viral Hepatitis in Baltimore. 'It represents a transformative step in our approach to this therapeutic area.'

Furthermore, as noted in a Medscape report,

In an accompanying editorial,(1) Michael Saag, MD, also of the University of Alabama at Birmingham, said the finding is a 'quantum leap' forward for people coping with both viruses.

What Clinical Trial?

I have posted previously about the controversy over the high price of Sovaldi.  I noted that most of the arguments, even from people most incensed about paying $1000 per pill, assumed that the drug was nearly miraculous, e.g., "a triumph," or "a revolution" in medicine.  Yet my reading suggested that the published evidence from clinical studies of the drug was in fact weak.  Critical reviews of the evidence from groups in the US, the UK, and Germany (look here, here, and here) also questioned the evidence backing Sovaldi.  Yet doubts about the drug's benefits versus harms have yet to influence the public discussion, which is focused on whether $1000 a pill is too much to charge for a miracle drug.

So I thought that "quantum leap" demonstrated in the latest trial(2) would bear further scrutiny.

The most important feature of the "trial" is how its design is described,

In this multicenter, open-label, nonrandomized, uncontrolled phase 3 trial, all patients received 400 mg of sofosbuvir (Gilead Sciences) administered orally once daily along with ribavirin (Ribasphere, Kadmon) administered orally twice daily, with doses determined according to body weight....

Let me make very clear, in this "trial," all patients got the same therapy.  There was no comparison group.  The study description is therefore inherently self-contradictory.  In fact, this study was a case-series, not a clinical trial.  It had no control group.

The classic Users Guides to the Medical Literature suggests that the first question a critical reviewer should ask about a study to assess a treatment is "was the assignment of patients to treatment randomized?"(3) The rationale was that studies of patients for whom clinicians made treatment decisions could easily be confounded by the reasons clinicians used to make these decisions.  Clinicians are trained to individual treatment decisions, and thus patients prescribed a treatment are likely to greatly differ from those not assigned that treatment.  The ways they differ could have as much, or more effect on their outcomes than the treatments themselves.  Although complex statistical adjustment methods could be used to try to compensate for these differences, it is rarely possible to be assured that all important differences have been taken into account. 

However, this still assumes a comparison between patients getting different treatments, or treatment versus no treatment.  In the case-series of sofosbuvir, there were no patients getting alternative treatments.  Thus the study itself could not be used to make comparative assessments of sofosbuvir.  

Of course, one could imply comparisons with the results of other studies.  However, such comparisons would not only be susceptible to confounding by reasons for treatment decisions as above, but to bias due to  differences between the current case series and previous studies, e.g., in characteristics of patients recruited, details of treatments given, study settings, and changes in patients, diseases, and treatments over time.   

Thus, a very basic rule in critical review is thou shalt not draw any conclusions about therapy from case-series unless the results are truly extraordinary, i.e., patients clearly doomed to die suddenly become completely well.  There were no such extraordinary results in the case-series of patients with HIV treated with Sovaldi for hepatitis C. 

The latest study of Sovaldi for patients with HIV and hepatitis C is virtually useless to assess whether Sovaldi might be the preferred therapy for such patients.   

Comparable Results?

Yet in an accompanying editorial(1), Dr Michael S Saag asserted that this non-trial 

demonstrates the efficacy of the all-oral regiment of the directly acting agent sofosbuvir plus ribavirin in patients with HCV who are coninfected with HIV

To demonstrate efficacy means to show that the treatment caused good effects.  But without a control group, it is not possible to assess causation.

Also,

The PHOTON-1 trial demonstrates that the all-oral combination of sofosbuvir plus ribavirin yielded results comparable with those of standard pegylated-interferon-ribavirin-vased regimens for each of the genotypic groups, thereby demonstrating that an all-oral combination could achieve similar outcomes as those derived from an injectable therapy.

However, this case-series could not assess comparability, because it included no comparison.


There Goes the Neighborhood - Throwing Out Skeptical Evaluation in the Rush to Promote "Innovation"

For years, the randomized, and usually double-blind, controlled trial has been considered the scientific cornerstone of the evaluation of new treatments.  Yet in the rush to bring new "innovative" treatments to market, presaging often tremendous revenues for their manufacturers, suddenly the randomized controlled trial does not seem so necessary.  In the US, the Food and Drug Administration (FDA) no longer seems to require randomized controlled trials to demonstrate efficacy of new drugs deemed to be "breakthroughs."   As noted by Steinbrook and Redberg in the July, 2014, issue of JAMA Internal Medicine(4)

these drugs [for hepatitis C] were approved quickly based on the surrogate endpoint of sustained viral response rate; they were studied in limited populations without long-term follow-up.  Under the US Food and Drug Administration's breakthrough therapy designation, the marketing for sofosbuvir did not include requirements for randomized clinical trials.

Yet without such trials, how could one ever determine if the drug is really so efficacious as to constitute a "breakthrough?"  


As we noted earlier, the two real randomized controlled trials of sofosbuvir did not assess its effects long term, even though it is a drug meant to treat a chronic disease, and particularly did not assess whether it affect clinical outcomes, that is, reduce rates of cirrhosis, liver failure, or liver cancer.  In fact, there has never been a controlled trial meant to assess whether any treatment of hepatitis C affects these outcomes.  Furthermore, while the first author of the case-series above, and many others have claimed the Sovaldi cures hepatitis C, it has never been shown that SVR equals cure.  As Gluud et al wrote in a letter to Lancet,(5)

The claim of cure rests solely on sustained virological response (SVR).  Since some patients who achieve SVRs still go on to develop end-stage liver disease and might die from the interventions, this concept is not correct and might even be wrong in principle.

However, despite all the words written, the concernthat Sovaldi (and possibly other new drugs for hepatitis C) might not be wondrous quantum leaps, because there is really no good evidence to that effect, has remained anechoic.  Not only does the evidence about the benefits and harms of this new drug need to be part of the discussion whether its price is excessive, there needs to be a larger discussion of whether in our rush for "innovation," we will throw out the baby of scientifically valid assessment of new therapies with the bathwater.

Finally,  the Sovaldi case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will not buy us the promised miracles and triumphs.

As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.  

 References

1. Saag MS. Quantum leaps, microeconomics, and the treatment of patients with hepatitis C and HIV coinfection. JAMA 2014; 312: 347. doi:10.1001/jama.2014.7735.  Link here.

2. Sulkowski MS et al.  Sofosbuvir and ribavirin for hepatitis C for patients with HIV coninfection.  JAMA 2014; 312: 353.  doi:10.1001/jama.2014.7734.  Link here.
3. Guyatt GH, Sackett DL, Cook DJ et al. Users' Guides to the Medical Literature: II. How to Use an Article About Therapy or Prevention A. Are the Results of the Study Valid? JAMA. 1993; 270(21): 2598-2601. doi:10.1001/jama.1993.03510210084032. Link here.
4.  Steinbrook R, Redberg R. The high price of the new hepatitis c virus drugs.  JAMA Int Med 2014; 174: 1172.  Link here. 
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