How Can We Promote Evidence-Based Medicine Under a Regime that Insists on Its Power to Say "2+2=5"?

Introduction: Evidence-Based Medicine

We have consistently advocated for Evidence-Based Medicine (EBM), which is about medical-decision making based on critical review of the best applicable evidence from clinical research informed by knowledge of biology and medicine, of the patient's biopsychosocial circumstances, the patient's values, and of ethics and morality. Since EBM depends on the availability of evidence from the best clinical research, we have advocated for the integrity of clinical research, and decried  manipulation of clinical research done to increase the likelihood that its results would please vested interests, and suppression of research whose results offended such vested interest, sometimes done when manipulation did not succeed in producing such pleasing results.

Addressing such threats to the evidence-based required challenging the role of large for-profit corporations, principally pharmaceutical, biotechnology, and device companies, in clinical research.  In doing so, we depended on support from other concerned health care professionals and scientists.  Sometimes, when manipulation and suppression crossed over the line to become fraud and deceptive marketing, government regulators and lawyers stepped in.  We have discussed numerous legal settlements involving penalties - admittedly, often less severe than we would have preferred  - on particular corporations.

So we have counted on governments having a shared interest in promoting the integrity of clinical research, and more broadly of clinical and public health science, and when necessary, acting to enforce such integrity.  

However, we have increasing reason to doubt these shared interests under the current US regime.



Administration Comfort with Suppression of Speech about Research

Consider episodes in which political appointees of the Trump regime seemed comfortable with the suppression of speech about medical, health care and public health research.

In 2016, we discussed several cases in which officials at the Department of Health and Human Services stifled responses to journalists about scientific issues.  In particular, employees of the Center for Disease Control (CDC) were told not to respond to any journalists' requests for information, even "simple data-related questions," in lieu of responses from agency public relations personnel.

In 2017, we discussed how President Trump's first Secretary of Health and Human Services, Dr Tom Price, had been involved in attempted suppression of the results of research about the drug Bildil at the behest of a previous campaign donor.

In addition, three recent episodes, one from August, 2019,  two more in late October, suggest that under Trump, open discussion of the science pertaining to health care and public health, and the pursuit of scientific truth in these areas have been increasingly subordinated to politics, and particularly to supporting the notion that the President is sole keeper of all truth. 

Silencing National Intstitute of Mental Health (NIMH) Scientists about the Relationship of Mental Health to Violence to Avoid Contradiction of a Trump Tweet


Per a Washington Post article from August 20, 2019, after mass shootings in El Paso, TX and Dayton, OH,

'Mental illness and hatred pull the trigger. Not the gun,' Trump said immediately after the shootings. In the following days, he reiterated that statement, arguing that the United States should reopen mental institutions shuttered decades ago as a way to address mass shootings.

But then,

federal health officials made sure no government experts might contradict him.

A Health and Human Services directive on Aug. 5 warned communication staffers not to post anything on social media related to mental health, violence and mass shootings without prior approval.

The particulars were as follows:

On Aug. 5, Trump was scheduled to speak following the weekend shootings. That morning, some HHS employees, including those at the National Institutes of Health, received an email asking those who contribute to official social media accounts to hold off on posts until 'we get the green light from HHS,'

Then,

some employees received another email from Renate Myles, an NIH spokeswoman. Social media posts could resume, the note said, butemployees were asked to 'please send any [social media] posts related to mental health, violence or other topics associated with mass shootings for review before posting.'

The second directive applied most directly to the National Institutes of Mental Health, where nearly all of the agency’s social media activities relate to mental health. It remains unclear how many people received that instruction, which was lifted by week’s end.

The administration's explanation was:

'It’s the department’s long-standing practice to not get ahead of the president’s remarks,' HHS spokeswoman Caitlin Oakley said. 'This allows the president to share his message first with the nation. Any suggestions that this was a formal policy put in place related to social media, or meant to stymie work on this issue, are factually inaccurate. These were staff-level discussions seeking to be sensitive and respectful to the victims and their families affected by tragedies of that weekend.'

However,

By contrast, two former senior health officials in the Obama administration said they did not recall ever receiving such a directive after a mass shooting.

Also,

In the days and months following the mass shooting at Sandy Hook Elementary School in Newtown, Conn., which killed 20 first-graders and six staff members, the National Institutes of Mental Health spoke extensively about mental illness and violence. 'The conversation has evolved, recognizing that violence most often associated with mental illness is suicide, and that most violence is unrelated to mental illness,' the NIMH director said at a meeting three months later. NIMH also hosted a special panel discussion, How Sandy Hook is Changing the Conversation,' during which mental health experts worked to dispel stereotypes that link mental illness to violence.

After this month’s shootings, however, NIMH and its director were largely silent on the shooting. The only mention on the official NIMH Twitter account was a retweet of the NIH account, directing those struggling with grief and emotional distress to the Substance Abuse and Mental Health Services Administration for counseling and support.

Furthermore,

An HHS employee who spoke on the condition of anonymity to describe internal discussions said he had 'no doubt this was meant to prevent anybody from making any statements that might contradict the president.'

The Post consulted one ethics expert:

'To say that scientists and experts who know the data and facts best are not allowed to speak — that’s very concerning,' said Dominic Sisti, a University of Pennsylvania professor who studies ethics in mental health and psychiatry.

Silencing the Director of the National Institute of Environmental Health Sciences (NIEHS)  and National Toxicology Program to Support Industries Favored by the Administration

The case had to do with the health risks posed by PFAS, industrial chemicals found in the environment.

Per an October 24, 2019 article in The Intercept, the background is:

the company that first developed both PFOA and PFOS and sold PFOA to DuPont for many years, still argues that the compounds do not cause health problems. In her testimony before the House Committee on Oversight and Reform in September, Denise Rutherford, 3M’s senior vice president of corporate affairs, said that 'the weight of scientific evidence has not established that PFOS, PFOA, or other PFAS cause adverse human health effects.' The company also requested that The Intercept remove the word “cause” in a recent article about PFAS. That request was denied.

However, Linda Birnbaum, recently retired director of the National Institute of Environmental Health Sciences and the National Toxicology Program, thought

'In my mind, PFAS cause health effects because you have the same kind of effects reported in multiple studies in multiple populations,' she said in a phone interview. Birnbaum pointed in particular to longitudinal studies, which follow populations’ exposures and health over time. 'You have longitudinal studies showing the same effects in multiple populations done by multiple investigators and you have animal models showing the same impact,' said Birnbaum. In addition, she pointed to studies that show the mechanism through which PFAS chemicals cause harm in people.

'That is pretty good evidence that PFAS or certain PFAS can cause health effects in people. It is not as strong for every effect, but there are quite a number of effects where they’re strong enough to say ‘caused,’' Birnbaum said. She pointed in particular to the relationship between the chemicals and immune response, kidney cancer, and cholesterol in humans, saying, 'That data is very clear.'

Dr Birnbaum had upset industry in the past, but in particular,

Her run-in with Republicans on the House Science Committee last year may have had the most severe consequences. Reps. Andy Biggs and Lamar Smith accused Birnbaum of lobbying based on an editorial in the journal PLOS Biology. In it, Birnbaum wrote that 'U.S. policy has not accounted for evidence that chemicals in widespread use can cause cancer and other chronic diseases, damage reproductive systems, and harm developing brains at low levels of exposure once believed to be harmless.' She called for more research on the risks posed by chemicals and noted that 'closing the gap between evidence and policy will require that engaged citizens — both scientists and non-scientists — work to ensure that our government officials pass health-protective policies based on the best available scientific evidence.'

Under the Trump administration, there were consequences:

'everything was scrutinized that I did. Everything I did required clearance. Even in my lab,' said Birnbaum. 'All of a sudden, everything had to go up at least to building 1,' she said, referring to the Bethesda building that serves as the administrative center for the National Institutes of Health. Birnbaum was also denied a salary increase after the incident and became aware that her job was at stake. 'I was told that they were trying to fire to me.'

Also,

Birnbaum was not allowed to use the word 'cause' when referring to the health effects from PFAS or other chemicals.

'I was banned from doing it'” said Birnbaum. 'I had to use ‘association’ all the time. If I was talking about human data or impacts on people, I had to always say there was an association with a laundry list of effects.' Birnbaum said this restriction 'was coming from the office of the deputy director. His job hinged on controlling me.'

Again, while there is room for debate about whether PFAS causes the problems, or are simply associated with the problems.  However, the accusation is not that there was debate within the government, but that Dr Birnbaum's government supervisor silenced her opinions about causation, whaterver the evidence on which she based them.

Silencing the Director of the Centers for Disease Control and Prevention (CDC) Climate and Health Program About "Climate Change"

On October 29, 2019, CBS News reported that Dr George Luber, Director of the CDC Climate and Health Program, had to stop talking about "climate change," particularly its health consequences,

In late 2016 Luber was organizing a climate change conference. Al Gore was to be the keynote speaker. But right after Donald Trump was elected president, Luber's boss called him in.

Luber recalled, 'I was told the optics are not good and that I needed to cancel it.'

Correspondent Mark Strassmann asked, 'Did he explain what the optics issue was?'

"That the meeting was happening three weeks after the inauguration."

'And that the White House would be unhappy?'

'Yeah,' Dr. Luber said.

America's new president had a dim view of Luber's science, referring to climate change as a hoax, 'created by and for the Chinese.'

Dr. Luber said his boss wanted something else: 'Just don't say 'climate change.' Can you call it 'extreme weather?' Can you call it something else?'

Strassmann said, 'You're saying that the Centers for Disease Control was suddenly afraid to use the term 'climate change'?'

'Yeah. Absolutely. I was told to use a different term,' he said.

CBS confronted Dr Patrick Breyesse, Dr Luber's manager, who essentially gave a non-denial denial:

He's the senior manager who Dr. Luber said ordered him to scuttle the science conference.

'It wasn't cancelled; we postponed it,' Dr. Breysse said.

'You didn't feel any pressure at all?' Strassmann asked.

'No.'

'Politically?'

"No."

That conference happened, but without CDC sponsorship.

Strassmann asked, 'Were any CDC employees ever told, 'Stop using the phrase 'climate change'?'

'Not to my knowledge,' Dr. Breysse replied, 'but we did discuss it.'

'That you change from 'climate change' to 'extreme weather,' because 'climate change' was more radioactive?'

'We talked about making the change, but we never made the change.'

Meanwhile, it appears that CDC leadership retaliated against Dr Luber,

In March 2018 the CDC revoked Dr. Luber's badge, phone and credentials. He was escorted off the property. The CDC moved to fire him. He faced more than 30 'troubling allegations,' from falsifying timecards to seeming hung over. Dr. Luber refuted all but one charge, and was allowed to stay.

However,

Dr. Luber still works at the CDC, but potentially faces up to a four-month suspension. He has to work from home, where he reviews scientific papers unrelated to climate change.

When asked about that, Dr Breyesse responded

'I can't talk about personnel matters, I'm sorry, Mark,' he responded.

'Has he been banned from the campus?'

'So, that's a personnel matter that I can't discuss.'

'Is the CDC retaliating against him?'

'I'm just not going to comment on that,' he said.

A Larger Pattern

To summarize, in the second half of 2019, we have seen three episodes of scientists/ health care professionals at the premier US government health and public health agencies silenced about relevant issues to apparently avoid contradicting Trump administration political goals and/or the pronouncements of the President himself.  There is reason to suspect that agency leaders punished or retaliated against the scientists and health professionals for speaking out.

These appear to be part of a larger pattern.  There have been a lot of similar episodes involving other kinds of science.  For example, there was the infamous case of government climate scientists attacked after they contradicted a Trump tweeted his erroneous take on the course of Hurricane Dorian.  As the New York Times reported on September 8, 2019:  

The Secretary of Commerce threatened to fire top employees at the federal scientific agency responsible for weather forecasts last Friday after the agency’s Birmingham office contradicted President Trump’s claim that Hurricane Dorian might hit Alabama, according to three people familiar with the discussion.

That threat led to an unusual, unsigned statement later that Friday by the agency, the National Oceanic and Atmospheric Administration, disavowing the National Weather Service’s position that Alabama was not at risk. The reversal caused widespread anger within the agency and drew accusations from the scientific community that the National Weather Service, which is part of NOAA, had been bent to political purposes.

After that episode, the National Task Force on Rule of Law and Democracy developed a report on government attaacks on the integrity and rigor of government research, as summarized in an op-ed in the Washington Post on October 3, 2019, entitled "Under Trump, the integrity of government research is in shambles." The authors wrote,

This isn’t the first time this administration has retaliated against scientists for doing their jobs. The Agriculture Department recently decided to relocate an entire staff of career economists from Washington to the Kansas City area after they published reports on the financial harms of Trump’s trade policies. The Interior Department moved a climate scientist to an accounting role after he stressed the dangers of climate change to Alaska’s Native communities. A recent tally by the Union of Concerned Scientists listed more than 120 attacks on science by the Trump administration.

The report called for a variety of legislative solutions, but these may be insufficient.

The pattern may be even larger.  In the Atlantic, Quinta Jurecic, the managing editor of Lawfare, wrote on September 11, 2019,

The saga of Dorian is a snapshot of Trump’s refusal to accept the reality of a world that looks any different from what he wants to be true, and a demonstration of how such an instinct in a leader is incompatible with the requirements of democracy.

Furthermore,

Trump’s behavior regarding Dorian is yet another example of his strained relationship with the truth, something that is at this point so routine as to be barely worth commenting on. In the language of the philosopher Harry Frankfurt, he is a 'bullshitter'—someone who does not so much lie in order to consciously obscure the truth as make statements without any thought or care to what the truth might be. Bullshit, Frankfurt argues, is careless, in that it requires no commitment to a stable universe of facts. And Trump’s falsehoods are careless insofar as he makes them without any regard for consistency or internal logic, but there is also a stubbornness to them. His bullshit is a way of insisting that the world take the shape he wants it to have, regardless of the facts on the ground.

Government by BS is not just a threat to science and scientific discussion.

Democracy, as Arendt writes, depends on the existence of a shared universe of mutually agreed-upon facts—like whether or not it is raining in Alabama. It also depends on the willingness of leaders to acknowledge that some things, including the weather, are beyond their control. That is not Donald Trump’s way. He is the strong man standing alone at the front of the crowd, who is strong only when there is no one there to tell him differently.

Trump seems to want to be like the Inner Party in Orwell's 1984. In Part III, Chapter 2, when Inner Party member O'Brien interrogates and tortures Winston Smith, he says:

reality is not external.  Reality exists in the human mind, and nowhere else.  Not in the individual mind, which can make mistakes, and in any case soon perishes: only in the mind of the Party, which is collective and immortal.  Whatever the Party holds to be truth, is truth.  It is impossible to see reality except by looking through the eyes of Party.  

So when O'Brien holds up his hand with four fingers extended, and Smith says he sees four fingers,

And if the Party says that it is not four but five - then how many?

The Party says the answer must be "five"

So the answer to the question posed by the title of this post is "we can't"

As long as we are led by a President who believes he has the power to make 2 + 2 equal "5," we will be unable to meaningfully promote clinical research integrity, much less evidence-based medicine.  Any progress will only come with a new President.  

Bad Apple or Bad Orchard? - A Narrative of Alleged Individual Research Misconduct that Sidestepped the Pharmaceutical Corporate Context

Tales of medical research misconduct seem increasingly prevalent in the media, and are getting increasing attention.    They often may present a simple narrative, like this recent story in the New York Times, "An NYU Study Gone Wrong, and a Top Researcher Dismissed."

The Narrative Arc

A Renowned Researcher

The researcher in question was one Dr Alexander Neumeister.  Oddly enough, the article provided very little information about his background, but made it clear he was at New York University, and was a "top researcher."

The Potentially Ground-Breaking Studies

The NY Times article noted that the studies were of "an experimental, mind-altering drug."  In particular,

In one of the shuttered studies, people with a diagnosis of post-traumatic stress caused by childhood abuse took a relatively untested drug intended to mimic the effects of marijuana, to see if it relieved symptoms.

The study was ground-breaking, in that

It’s a critical time for two important but still controversial areas of psychiatry: the search for a blood test or other biological sign of post-traumatic stress disorder, which has so far come up empty, and the use of recreational drugs like ecstasy and marijuana to treat it.

The drug was not identified, but the article noted that it was

a drug intended to produce some of marijuana's effects, made by Pfizer

and was thus like the drug in "a French trial," that caused six patients to be "hospitalized with severe neurologic problems."

The study was apparently a small short-term randomized controlled trial

Some participants took the drug over a seven-day period; others took a placebo pill. The N.Y.U. team performed scans on each person to see whether brain activation patterns correlated with symptom relief.

The study called for recruiting 50 people with a PTSD diagnosis, according to study documents.

Research Misconduct Discovered

Initially, apparently,

Dr. Charles Marmar, the chairman of the psychiatry department at N.Y.U., said that people working with Dr. Neumeister had reported concerns about the lab’s compliance with research standards.

This led to

The federal inspection, from July 16 to Aug. 5 last year, found that the research team had failed to assess at least three subjects 24 hours after they had taken the experimental drug, contrary to study protocol, according to the F.D.A. letter. In several instances, the agency found, Dr. Neumeister had falsified documents by signing a fellow investigator’s name on reports. 'However, in fact, you or another study employee actually conducted these study procedures,' not the colleague, the F.D.A. concluded.

In summary

The violations 'jeopardize subject safety and welfare, and raise concerns about the validity and integrity of the data collected at your site,' the F.D.A. said in a letter

Note that the article did not explain why the FDA was called upon to investigate this problem.



Aggrieved Research Subjects

The article focused on one Ms Diane Ruffcorn, who "writes a popular Facebook blog on trauma,"

'I think their intent was good, and they were considerate to me,' said one of those subjects, Diane Ruffcorn, 40, of Seattle, who said she was sexually abused as a child. 'But what concerned me, I was given this drug, and all these tests, and then it was goodbye, I was on my own. There was no follow-up.'

After the trial, she was concerned because

Ms. Ruffcorn said she had several odd symptoms after the trial, including a hyper, wired sensation that occurred without the usual memories of abuse.  For months, she tried to find out whether those reactions were tied to the experimental drug, but because the study was shut down and the data belonged to Pfizer, the N.Y.U. doctors could not tell her whether she had taken the drug or placebo.

However,

Earlier this month, after much persistence, she found out that she’d taken the placebo. 'It was a big relief,' she said.

Note that the article did not explain why Pfizer owned the data, and would not reveal it. 

The Researcher Punished

The researcher did not agree that things were so bad,

Georges Lederman, a lawyer for Dr. Neumeister, said there may have been protocol violations, 'but N.Y.U. has taken the position that those violations were more egregious than we believe they actually were.' The issues could have been easily remedied, he said, and noted that they did not cause the sponsor of the research, the pharmaceutical giant Pfizer, to shut it down.

Note that the article did not explain why Pfizer was empowered to shut such a study down.

In any case,

Dr. Neumeister and N.Y.U. continue to disagree over the seriousness of the research violations, both sides said. But the university has tossed out all of the data as unreliable, and tracked down the study participants to check on their health, Dr. Marmar said.

And apparently Dr Neumeister quit, or was fired, although the article only said NYU "parted ways with a top researcher."

Summary

So, in summary, the story was that a prominent researcher was doing cutting edge research at a big university, but people onsite noted some problems, the government was called in to investigate, the investigation found problems, the research was stopped, and the researcher lost his job.  However, while the article mentioned that Pfizer sponsored the study, Pfizer had control of the study's data, and Pfizer had the power to shut the study down, the article did not comment on whether the involvement of Pfizer could have had any relationship to the narrative of alleged individual researcher misconduct.

Research Misconduct as a Problem with Bad Apples

Thus, in my humble opinion, this story followed the usual narrative arc of research misconduct stories: an individual scientist over-reaches, possibly in pursuit of fame and money, is discovered and punished, and things get back to normal.  The implication is that research misconduct is a bad-apple problem, although fueled by a hyper competitive research environment.  For example, last week the (UK) Times Higher Education Suppplement published an article entitled, "Is There a Problem with Research Integrity," that opened,

For many academics today, research is not about pushing intellectual boundaries. It is not about investigating a fascinating issue so much as it is about churning out publications, demonstrating impact and generating revenue in order to meet the performance targets upon which institutional reputation and individual careers depend.

The temptation to cut corners is immense. Tricks include getting your name on a paper that you contributed little towards, or “salami-slicing” the same research across several publications. More seriously, some researchers falsify – misrepresent – their data, or even fabricate them entirely. Some universities tacitly encourage such behaviour and the boundary between academic integrity and malpractice is becoming blurred.

The current case seems to be on of attempted falsification, misrepresentation of research data.

Notice the use of the pronoun "you," emphasizing that research misconduct is about individual misconduct.  Similarly, tha THE article included commentaries by various individuals.  One was by a "research integrity expert," who began,

Having positive and preferably spectacular research findings is wonderful. It helps you to get a publication in a journal with a high impact factor, which will be cited often and may attract a lot of media attention. This is not only a pleasant ego boost but may also be instrumental in getting your next grant or strengthening your academic position. So, in an ever more competitive and metrics-driven scientific environment, it is tempting to make such results occur by any means necessary.

All this is true as far as it goes.  But in my humble opinion, the usual research misconduct narrative is vastly oversimplified, as is the case reported by the New York Times.

We have been writing for years about massive problems with manipulation of clinical research to increase the likelihood that the results would satisfy vested interests, and suppression of research whose results remain unsatisfactory after such manipulation.  The vested interests are most commonly pharmaceutical, biotechnology or device companies and those working with them.  Such suppression and manipulation may make treatments that do not work look efficacious, and treatments that are dangerous look safe, and may lead to excess costs, and worse, harms to patients.  This kind of research misconduct may be facilitated by individual researchers seeking fame and fortune, but is hardly an individual sport.

Focusing on individual research misconduct thus leaves the larger problem of vested interests dominating clinical research anechoic.

Looking carefully at the NYU/ Neumeister case as reported, and a little research on the web suggests that there may be more involved than just the conduct of one researcher.  But that could only be confirmed, or refuted, by investigation beyond what this humble blogger can do.

A Pharmaceutical Company Sponsored, Likely Pharmaceutical Company Designed, Phase II Drug Study Gone Wrong

The NY Times article acknowledged, almost parenthetically, that the study on which the article was focused was sponsored by Pfizer, although it first did so in the context of Dr Neumeister's lawyer arguing that the problems with the study were not that serious:

[he] noted that they did not cause the sponsor of the research, the pharmaceutical giant Pfizer, to shut it down.

Later, the article stated,

Pfizer said that N.Y.U. was responsible for conducting the trial,

but noted

the company had previously tested the same drug, known as an F.A.A.H. inhibitor, for osteoarthritic pain, without significant side effects. 'The safety profile we observed does not preclude future development of our compound,' a Pfizer spokesman said by email.

So this was not a case of a company funding a study merely to advance medical science.  The implication was that the company was testing its own compound in hopes of seeking approval from the US Food and Drug Administration. That must be why it was the FDA that investigated the research misconduct, particularly to the extent that the conduct of the research violated a "protocol" to which the FDA was apprently privy.

More evidence that the study was under the control of Pfizer, rather than of Dr Neumeister, could be inferred from the problems Ms Ruffcorn had in determining whether she had taken the drug or placebo.

For months, she tried to find out whether those reactions were tied to the experimental drug, but because the study was shut down and the data belonged to Pfizer, the N.Y.U. doctors could not tell her whether she’d taken the drug or a placebo.

Note that the "data belonged to Pfizer," not to NYU or Dr Neumeister.

In fact, in perhaps the only critical look given to this story, in a post on Neuroskeptic, 

I believe the compound in question is PF-04457845.

I believe this because ClinicalTrials.gov lists a trial of PF-04457845 for PTSD, a trial which was recently terminated. NYU was one of the research sites. I also think that this trial is the fateful one, as it matches the NYT’s description of that study. Interestingly, ClinicalTrials.gov says that the trial was stopped 'based on Pfizer portfolio prioritization and not due to safety and/or efficacy concern or change in benefit:risk assessment of PF-04457845'.

So given that the study was a small randomized controlled trials of patients, not of healthy volunteers, it appeared to be a Pfizer sponsored, Pfizer designed, Pfizer controlled Phase II study being done in the hope of eventually marketing PF-04457845.

As noted in an article about agreements between academia and industry on the conduct of randomized controlled trials(1),

Many randomized clinical trials (RCTs) are designed and sponsored by for-profit companies. Companies typically contract academic investigators to identify, recruit, and manage patients. Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, including those regarding the publication of trial results

It also appears that Pfizer was spending a more than tiny sum on this work.   A Politico article from 2014 revealed that Dr Neumeister at that time had a $1.7 million grant from Pfizer, presumably for this particular study.  Thus this drug trial was likely providing NYU with more than negligible monetary support, most likely including salary support for Dr Neumeister.

Dr Neumeister apparently has had some previous involvement with pharmaceutical companies, and with Pfizer specifically.  A search of the ProPublica Dollars for Docs 2009-13 database revealed that Dr Neumeister received consulting, travel funds and a more than $227,000 grant from Eli Lilly.  Dr Neumeister apparently is currently on the advisory board for Fiorello Pharmaceuticals.  In a 2015 article in the Journal of Clinical Psychiatry(2), Dr Neumeister acknowledged that he "has received consulting fees from Pfizer."

Conclusion

So it seems that in this case a study which may not have been conducted according to research standards was likely a pharmaceutical sponsored, designed, and controlled Phase II trial done as part of an effort to seek approval for a new drug.  Hence this case was not only about allegations of individual research misconduct, but about yet more problems with the implementation of commercially controlled human experiments designed to ultimately further marketing as well as science.  Yet none of the public discussion so far of this case was about whether Pfizer had any responsibilities to assure the quality of the research in which it was so involved, much less whether interactions between the company, the university which was being funded by the company, and the researcher employed by the university but whose salary was probably partially underwritten by the company might have affected how the study was implemented.

There may be many problems with individual misconduct affecting clinical research.  But failure to consider how this research is now mainly conducted within a commercial milieu seems to be missing the elephant in the room.  If we cannot plainly discuss research misconduct as part of the larger picture of health care dysfunction, we will not be able to do much about it.  True health care reform would help end the taboo on discussion about how powerful organizations and their wealthy and powerful leaders distort health care.  

ADDENDUM (11 July, 2016) - This post was re-published on the Naked Capitalism blog. 

References

1. Kasenda B, von Elm E, You JJ, Blumie A et al. Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials. PLoS Med 13(6): e1002046. doi:10.1371/journal.pmed.1002046. Link here.

2.  Mota N, Sumner JA, Lowe SR, Neumeister A et al. The rs1049353 Polymorphism in the CNR1 Gene Interacts With Childhood Abuse to Predict Posttraumatic Threat Symptoms. J Clin Psychiatr 2015; 76(12):e1622–e1623. Link here.

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.