Would You Like Statins With That?

As we wrote on this blog the other day about research which raised questions about the efficacy of statins for those who have not yet experienced a heart attack– an off label prescription–the WSJ pointed to a new paper in the American Journal of Cardiology from authors at  Imperial College, London, U.K., which suggests that  statins should be made available free of charge to consumers along with the purchase of fast food. The press release from Imperial College can be found here.

Low level doses of statins may be purchased over the counter in England.

In a prior post, I  wrote about meeting with a cardiologist who suggested I commence taking statins because of my various cardio risk factors. A point, however uncomfortable at the time, made ultimately moot by the favorable results of my stress test, echocardiogram and calcium scoring. I had, prior to my surprisingly clean bill of cardiac health, relented mentally to the prospect of what would become a life long prescription. Of statins, I wrote:

“If one has risk factors, it is prophylactic and is prescribed to reduce the risk of heart attack, stroke and other heart diseases. It is doubtful whether once I start taking this drug I will ever stop. There is no foreseeable time (while alive) that I will wish to stop reducing the risk of heart attack or stroke. And that I suppose is the essence of the onset of age– piling up prescriptions. A daily regimen that will follow one to the grave–only the dosages or the brand names changing as each day welcomes a regimen of pills. In short, this prescription feels like the onset of dependence. The forward guard, if you will. A harbinger of a pharmaceutical future.”

One might say I didn’t take the news well. But crucial to my decision to relent were the words of my cardiologist and another heart doctor. I wrote:

Seeing my, shall we say, chagrin, the cardiologist told me that, like over 50% of the cardiologists he knows, he takes a statin. “We’ve seen the data.” Another recently told me  “Yeah, I take it. They should put it in the water.”

And now, apparently, in burgers.

But, we wrote of some  important (and conflicting) recent findings regarding statins here at HRW last week:

A LA Times article has recently highlighted the problems of off label prescriptions.  In the article, it has come to light that the off label use of statins, one of the world’s most prescribed medication, may not have the efficacy that many doctors had previously thought.  The LA Times reports,

Statins were initially approved by the Food and Drug Administration for the prevention of repeat heart attacks and strokes in patients with high cholesterol who had already had a heart attack. And used for that purpose - called “secondary prevention” - the drugs are powerful and effective medications, driving down patients’ risk of another heart attack or stroke by lowering their levels of LDL (or “bad”) cholesterol.

Then physicians came to believe statins could also reduce the risk of a first heart attack in people who have high LDL cholesterol but are nonetheless healthy. This use of statins - called “primary prevention” - has driven the growth in the market for statins over the last decade.

Statins certainly decrease rates of heart attack in people who have clear signs of cardiovascular disease but it’s not so clear they work that way in people who are healthy. In spite of that uncertainty, statins’ use for primary prevention has sky rocketed.

One wonders how so many physicians came to believe that statins could also reduce the risk first time heart attacks.  Dr. John Abramson, from Harvard Medical School, attributes statins’ off label growth to a “conspiracy of false hope.”  He states, “[t]he public wants an easy way to prevent heart disease, doctors want to reduce their patients’ risk of heart disease and drug companies want to maximize the number of people taking their pills to boost their sales and profits.”

So, with all these interests pushing for statins’ off label use, it should not be a great surprise that extensive research has not been performed regarding statins’ primary preventive effects- and conflicting results have emerged.  The LA Times reports,

In the first of three studies published in the Archives last month, medical researchers found that, contrary to widely held belief, statins do not drive down death rates among those who take them to prevent a first heart attack. A second article cast significant doubt on the influential findings of a 2006 study, called JUPITER, that has driven the expansion of statins’ use by healthy people with elevated blood levels of C-reactive protein, a measure of inflammation. A third article suggested potential ethical, clinical and financial conflicts of interest at work in the execution of the JUPITER study and concluded the widely hailed trial was “flawed” and raises “troubling questions concerning the role of commercial sponsors.”

So??? Statins anyone?

Doctors, Patients and a Failure to Communicate

“What we have here is a failure to communicate.”  Fans of Cool Hand Luke (and who is not?) will recall the phrase in graphic detail–and for those of you without that memory, the video will provide.

A recent study highlighted in the Wall St. Journal’s Health Blog points to both a discrepancy in perception between hospital doctors and their patients and a failure to communicate.

The study was conducted by Douglas P. Olson, MD and Donna M. Windish, MD, MPH. The authors noted as “Background” in the study abstract that:

Hospital surveys indicate lack of patient awareness of diagnoses and treatments, yet physicians report they effectively communicate with patients. Gaps in understanding and communication could result in decreased quality of care. We sought to assess patient knowledge and perspectives of inpatient care and determine differences from physician assessments.

The results of the study were derived from two validated questionnaires given to inpatients treated by “house doctors” over a course of roughly eight months at one hospital.The corresponding doctors were also queried. Eighty-nine patients and 43 doctors participated.

According to WSJ:

The survey — which the authors note is limited by its reach (one institution), patient characteristics (older, indigent and less-educated than average), and general responses, rather than one-to-one-patient-physician comparisons — is published in the Archives of Internal Medicine.

The results? From the abstract:

• Only 18% of patients knew their main doctor by name.
• Sixty-seven per cent of doctors believed their patients knew them by name.
• Fifty-seven per cent of patients knew their diagnosis.
• Seventy-seven per cent of doctors believed their patients knew their diagnosis.
• Fifty-eight per cent of patients thought that physicians always explained things in a comprehensible way.
• Twenty-one per cent of doctors stated they always provided explanations of some kind.
• Sixty-six per cent of patients reported receiving a new medication in the hospital, 90% noted never being told of any adverse effects of these medications.
• Ninety-eight per cent of doctors stated that they at least sometimes discussed their patients’ fears and anxieties.
• Fifty-four per cent of patients said their doctors never did this.

Interestingly enough,the WSJ article notes that the

responses didn’t significantly differ by sex, age, race, language or payment source, for the patients, or level and type of training, for the doctors.

Only 57% of patients knew their diagnosis? Which is to say that 43% did not? 90% not told of potential adverse reactions to new medication?

Res Ipsa Loquitur.

Sunlight is a Weak Disinfectant

One of the most robust “memes” in contemporary law is the power of disclosure. In health law, disclosure comes up again and again: patients need to give “informed” consent, insurers are supposed to explain their policies clearly, and conflicts of interest, when not proscribed, should at the very least be exposed. But there are growing challenges to the disclosure meme, both within health law and without.

George Lowenstein and Peter Ubel note some problems with disclosure approaches in this article on the weaknesses of behavioral economics generally:

It seems that every week a new book or major newspaper article appears showing that irrational decision-making helped cause the housing bubble or the rise in health care costs. Such insights draw on behavioral economics, an increasingly popular field that incorporates elements from psychology to explain why people make seemingly irrational decisions, at least according to traditional economic theory and its emphasis on rational choice. . . . But the field has its limits. As policymakers use it to devise programs, it’s becoming clear that behavioral economics is being asked to solve problems it wasn’t meant to address.

[T]ake conflicts of interest in medicine. Despite volumes of research showing that pharmaceutical industry gifts distort decisions by doctors, the medical establishment has not mustered the will to bar such thinly disguised bribes, and the health care reform act fails to outlaw them. Instead, much like food labeling, the act includes “sunshine” provisions that will simply make information about these gifts available to the public. We have shifted the burden from industry, which has the power to change the way it does business, to the relatively uninformed and powerless consumer.

The same pattern can be seen in health care reform itself. The act promises to achieve the admirable goal of insuring most Americans, yet it fails to address the more fundamental problem of health care costs. . . . [T]he act tries to lower costs by promoting incentive programs that reward healthy behaviors. . . . [But s]tudies show that preventive medicine, even when it works, rarely saves money.

At its worst, disclosure can become merely pro forma; as Kafka (via Trudo Lemmens) puts it, “Leopards break into the temple and drink to the dregs what is in the sacrificial pitchers; this is repeated over and over again; finally it can be calculated in advance, and it becomes part of the ceremony.” Omri Ben-Shahar has argued that disclosure is one of many aspects of consumer protection law with little real impact on individual welfare. As Amelia Flood reports,

Ben-Shahar, who spent last summer studying all the mandated disclosure statutes in Illinois, Michigan and California, argues that consumer protection advocates have gotten it wrong when it comes to mandating information access for consumers. He says consumers get lost in a sea of technical language, unread disclaimers and long-shot lawsuits. . . . According to Ben-Shahar, disclosures are of more use to consumer ratings groups like Zagat and Consumer’s Digest than they are to most consumers.

So perhaps there is some hope here: third-party aggregators and raters might use disclosures as part of an overall effort to rate various hospitals or doctors. The question then becomes–who shall pay (and rate) the raters? One irony here is that doctor rating sites have themselves been accused of being insufficiently transparent about the ways in which they evaluate physicians. New York Attorney General Cuomo even pursued the matter. His office eventually settled with insurers who ran rating sites. They pledged to “fully disclose to consumers and physicians all aspects of their ranking system.”

What’s the lesson here? First, that consumers are, by and large, too busy to process piecemeal disclosures by professionals like physicians and other health care providers. Second, third party raters can fill some of this information gap by aggregating information. Third, this process of aggregation and rating itself will likely need to be closely supervised by a good-faith regulator, lest it fail to take into account the full range of interests (and quality of information) proper for the task.

San Francisco Has Cancer on the Brain

Recently, the San Francisco Chronicle reported that the city’s Board of Supervisors has thrown its hat into the ring of the great cell phone brain cancer debate.  The Board voted 9-1 in favor of an ordinance requiring local retailers to display specific absorption rate (SAR) notices detailing radiation levels in cell phones.  SAR measures the rate at which radiofrequency electromagnetic energy is absorbed in a body when using a cell phone.  The FCC requires that cell phones sold in the U.S. not exceed a SAR level of 1.6 watts per kilogram.  (If you’re curious about your own cell phone, check out CNET’s SAR level list for voice calls).  Mayor Gavin Newsom is expected to sign off on the ordinance and his spokesman says “this is a very reasonable and quite modest measure that will provide greater transparency and information to consumers for whom this is an area of interest or concern.” If this really does come through, it won’t affect retailers until 2011 or so.

Meanwhile, the industry trade group CTIA-The Wireless Association has issued a statement admonishing and punishing the Board for its vote:

“CTIA and the wireless industry are disappointed that the San Francisco Board of Supervisors has approved the so-called ‘Cell Phone Right-to-Know’ ordinance.  Rather than inform, the ordinance will potentially mislead consumers with point of sale requirements suggesting that some phones are ’safer’ than others….  [A]ll phones sold legally in the U.S. must comply with the Federal Communications Commission’s safety standards….  While we have enjoyed bringing our three day fall show to San Francisco five times in the last seven years, which has meant we’ve brought more than 68,000 exhibitors and attendees and had an economic impact of almost $80 million to the Bay Area economy, the Board of Supervisors’ action has led us to decide to relocate our show [starting in 2011].”

So is this just fear-mongering or does San Francisco’s Board know something that the rest of us don’t?  According to the 10 year Interphone study conducted by the World Health Organization’s International Agency for Research on Cancer and published online last month by the International Journal of Epidemiology, there is no conclusive evidence supporting or disaffirming any connection between cell phones and the risk of brain tumors.  The study was not without controversy, though, even among the researchers themselves — and it had nothing to do with industry trade organizations– the Mobile Manufacturers’ Forum and the GSM Association– contributing funds for the study.  Last month, the Wall Street Journal reported that the Interphone researchers were puzzled by their data because

[t]he result is a strange set of numbers.  Many levels of cellphone use appeared to reduce the chance of developing a tumor.  Only the people who talked on cellphones the most had a significantly greater chance of developing glioma [a type of tumor] - 40% greater - than those who didn’t use cellphones.

The use of cell phones might reduce the chance of developing a brain tumor?  Go figure.  For now, our very own FDA supports the Interphone study and refers to others which have shown no increased health risk.

Perhaps San Francisco politicians and consumers, like the rest of us, are really just facing a case of caveat emptor.  However, until there is a study which can definitively support or disaffirm any connection between cell phones and the risk of brain tumors,  I wouldn’t mind knowing whether one phone has a higher or lower SAR level than another.  CTIA needn’t worry though.  Having such information won’t make me break my contract with AT&T or stop me from eagerly awaiting the arrival of my iPhone 4 (whose SAR level, according to FCC documents, appears to be lower than my current iPhone 3G but higher than the iPhone 3GS).  At least I’ve now given some thought about the risks to which I may be exposing myself.  So too have the folks in San Francisco.

RFID Tags for Nurses, then Everybody?

The recent City of Ontario v. Quon decision has had a mixed reception among privacy advocates. Though many are disappointed that employees’ privacy rights have once again been narrowed, some have discerned helpful dicta in the case. However, I worry that, whatever the drift of thought among swing justices, economic imperatives and cultural shifts will mean a lot less privacy in the workplace of the future. Health care in particular offers a few interesting bellwethers.

As an opinion piece by Theresa Brown explains, maintaining proper staffing levels in hospitals is becoming increasingly difficult. Surveillance systems are offering one way to address the problem; work can be performed more intensively and efficiently as it is recorded and studied. But such monitoring has many troubling implications, according to Torin Monahan (in his excellent book, Surveillance in a Time of Insecurity):

The tracking of people [via Radio Frequency Identification Tags] represents a . . . mechanism of surveillance and social control in hospital settings. This includes the tagging of patients and hospital staff. . . . When administrators demand the tagging of nurses themselves, the level of surveillance can become oppressive. . . . [because nurses face] labor intensification, job insecurity, undesired scrutiny, and privacy loss. . . . To date, such efforts at top-down micromanagement of staff by means of RFID have met with resistance. . . . One desired feature for nurses and others is an ‘off’ switch on each RFID badge so that they can take breaks without subjecting themselves to remote tracking. (122)

Like the “nannycam” employed by many a wary parent, the nurse-cam may be seen as a way to protect the vulnerable. It may also increase the accuracy of evidence in malpractice cases. On the other hand, inserting a tireless electronic eye to monitor what is already an extremely stressful job may create many unintended consequences, or deter people from going into nursing altogether. Even advocates of pervasive surveillance recognize these difficulties.

The increasing pressure to monitor what happens inside hospitals reminds me of a recent article by Thomas Goetz in Wired (no link yet) on Google co-founder Sergey Brin’s quest to find a cure for Parkinson’s disease. As Goetz describes it, a new form of “high-speed science” depends on rapid accumulation of as much data as possible:

In Brin’s way of thinking, each of our lives is a potential contribution to scientific insight. We all go about our days, making choices, eating things, taking medications, doing things—generating what is inelegantly called data exhaust. . . . With contemporary computing power, that data can be tracked and analyzed. “Any experience that we have or drug that we may take, all those things are individual pieces of information. Individually, they’re worthless, they’re anecdotal. But taken together they can be very powerful.” In computer science, the process of mining such large data sets for useful associations is known as a market-basket analysis.

Goetz has promoted this as a new way to “do science in the petabyte age.”
Read more

Solving the Mysteries of Pregnancy

In last week’s JAMA, the Pandemic H1N1 Influenza in Pregnancy Working Group reported that their analysis of nationwide data on 2009 influenza A (H1N1) in pregnant women revealed that “early antiviral treatment appeared to be associated with fewer admissions to an ICU and fewer deaths.”  Pregnant women who were not treated with antiviral medication until 3-4 days after they began experiencing flu symptoms were more likely to die than those who were treated within 2 days of symptom onset.  Women who were first treated with medication more than 4 days after symptom onset were 54 times more likely to die than those who were treated within 2 days.

The authors speculate that the “reasons for delayed treatment … could include reluctance of pregnant women or clinicians to use antiviral medication because of concern for risk to the fetus, despite available evidence suggesting that treatment benefit likely outweighs the potential risk.”  Given the shocking 54-fold increased risk of death associated with late initiation of antiviral medication, the authors’ use of the qualifiers “suggesting” and “likely” is noteworthy.  They are forced to hedge because, as a group of experts convened by the CDC acknowledged in late 2009, “[l]ittle is known about the effects of the four currently available influenza medications on the fetus.”

In my article The Mysteries of Pregnancy: The Role of Law in Solving the Problem of Unknown But Knowable Maternal-Fetal Medication Risk (forthcoming in the University of Cincinnati Law Review), I point out that this information gap is not unique to antivirals.  We lack data on the efficacy or safety or both of most drugs when used by pregnant women.  A frequent shorthand explanation for the dearth of information is that you cannot test drugs on pregnant women because of ethical concerns.  Without denying or dismissing the real moral conundrums that arise in maternal-fetal medicine, the information gap is deeper and wider than that.  As Ruth Faden puts it: “Everyone thinks, Oh, my God, research on pregnant women!  All kinds of ethical flags go up.  We don’t have to start with high drama.  [There's enough] low-hanging fruit that we could keep lots of medical researchers busy for a long time.”

Two FDA-led efforts promise to begin connecting the dots: the Medication Exposure in Pregnancy Risk Evaluation Program, which will conduct epidemiological research using data on approximately 1 million births gathered by the 11 participating research sites, and the Sentinel Initiative, which is creating a national electronic system with the goal of, among other things, allowing for prompt investigation of the safety of newly-approved drugs in pregnant women.  Other government agencies also have roles to play.  For example, the house committee report accompanying the Departments of Labor, Health and Human Services and Education Fiscal 2010 Appropriations measure encouraged the NIH “to  expand research on pregnant women with the goals of better understanding the long-term health effects on women of disease states in pregnancy, the proper therapeutics for pharmacologic treatments for pregnant women who face illness, and the safety and efficacy of medications administered to pregnant women and fetuses.”   Finally, industry can and should do more.  Congress should empower FDA to require pharmaceutical companies to sponsor maternal-fetal medication research in appropriate cases, authority the agency already has in the pediatric arena.

Industry Responds to Study Said to Demonstrate Link Between Physician Surgicenter Ownership and Volume of Surgeries

[Ed. note: We received the following response via email from the Ambulatory Surgery Center Advocacy Committee to Kate Greenwood's post, "Study Demonstrates Link Between Physician Surgicenter Ownership and Volume of Surgeries."  In the interest of fairness, it appears below without  comment.]

The Ambulatory Surgery Center Advocacy Committee Responds to Study Published

in Health Affairs

Industry Raises Concerns with Conclusions Drawn in New Study

Washington, D.C., April 7, 2010 - The Ambulatory Surgery Center Advocacy Committee (ASCAC), a group of leading ASC operators, state associations and the ASC Association, is compelled to respond to the incorrect assumptions made about the ASC industry put forth in a new study published in the April issue of Health Affairs. The ASCAC reinforces the important role that ASCs play in providing patients with access to convenient, high-quality care at a low cost to the health care system.

The study authors make inaccurate statements about the relationship between physician ownership of ASCs and higher surgical volume, inferring that physician owners are driven to refer patients to their facility by financial incentives. While the study authors recognize limitations with their methodology, the ASCAC is particularly concerned with their sole reliance on surgical volume as a proxy for ASC ownership. Volume is not a valid method for identifying which physicians have ownership interests in ASCs. In fact, many non-owners practice at ASCs.

Research identifies a number of positive factors that have increased the volume of surgical procedures in an ASC, including the migration of procedures and services from outpatient facilities to the less-costly ASC setting as well as patient preference and cost savings.

In 2009, KNG Health Consulting produced a report, which found that 70 percent of ASC volume growth between 2000 and 2007 was due to migration from hospitals to ASCs. It noted that for established specialties of ophthalmology and gastrointestinal (focused on in the study), the volume growth due to migration was 94 percent and 78 percent, respectively. Additionally, a larger and aging population as well as increased patient demand and medical innovation that allows for less-invasive procedures are also contributing factors for higher surgical volume in ASCs.

Patients often prefer the ASC setting for their convenient locations, ease of scheduling, shorter waiting times and faster recovery times. Patients report a 92 percent satisfaction rate after having a procedure in an ASC. Additionally, ASCs have fulfilled an important role in providing patients with access to vital preventive services, such as cancer screenings. For example, ASCs perform 40 percent of Medicare colonoscopies and the U.S. Healthy People 2010 objective to increase cancer screenings would not have been met without this expanded capacity for colon cancer screenings.

The study authors failed to recognize the significantly lower cost to patients and payors when identical procedures are performed in an ASC as opposed to the hospital outpatient department (HOPD). Research shows that Medicare patients save more than a 50 percent on out-of-pocket costs, and overall, ASCs save Medicare approximately 40 percent annually. By shifting just half of all eligible outpatient surgeries to the ASC setting, Medicare could save an additional $2.3 billion annually.

ASCs are staffed by a team of experienced medical professionals, including physicians, nurses, physician assistants and other health care experts. Data indicate that their focused expertise leads to efficient care and better patient outcomes when procedures are performed in an ASC, including low rates of medical error, infections and/or complications leading to readmission.

“With a staff of highly trained and certified medical professionals, physicians in ASCs can perform more surgeries with superior patient outcomes and low rates of medical error in our facilities,” said Brent W. Lambert, MD, FACS, Board Member of the Ambulatory Surgery Center Advocacy Committee and Founding Partner of the Ambulatory Surgical Centers of America, a physician-owned ASC development and management company. “ASCs are important providers of quality, patient-centered care and play an integral role in our country’s health care system.”

Many ASCs are privately owned by physicians, often in partnership with community hospitals or management companies. This structure enables proficient use of the facility, better control of scheduling and an environment conducive to the patient’s needs, as well as adaptable and innovative strategies for governance, leadership, efficiency and improved clinical care.

Data from the Centers for Disease Control and Prevention’s National Survey of Ambulatory Surgery show that ASCs are much more efficient than hospitals. Hospitals have also recognized that ASCs are effective partners in providing high-quality, patient-centered care, with approximately 20 percent of ASCs owned in part or exclusively by hospitals.

Higher volume in the ASC setting can also result from patient-referrals, another scenario the study did not consider.

“A significant number of new patients who ultimately need a surgical intervention are referred to our facilities from current or former patients satisfied with the care they received,” added Dr. Lambert.

The ASCAC and its partners are dedicated to working with physicians, hospitals, policymakers and other health care stakeholders to ensure that ASCs continue their commitment to excellence in quality and outcomes so that patients have the access they need to vital medical services procedures.

About the Ambulatory Surgery Center Advocacy Committee

Ambulatory Surgery Centers are health care facilitates that specialize in providing important surgical and preventive services in an outpatient setting. With approximately 5,200 Medicare-certified facilities throughout the country, ASCs perform more than 22 million surgeries per year. The Ambulatory Surgery Center Advocacy Committee is working on behalf of the industry to raise awareness of the important role that ASCs play in the health care system and the high-quality, cost-effective care that ASCs provide. The ASCAC includes the national and state ASC associations as well as representatives of all types of ASC operators and physicians. For more information about ASCs, visit www.advancingsurgicalcare.com.

Health Reform, “Death Panels,” & Section 1182–What the Text Really Says

This post is a follow-up to my prior post on the Patient-Centered Outcomes Research Institute, a nonprofit corporation created by the Patient Protection and Affordable Care Act (the Health Reform Law), which will oversee comparative clinical effectiveness research–or, in Palin-ese, “the Death Panel.” The pertinent text of the law under which the Institute will operate appears below along with explanation in the plainest English available.

LIMITATIONS ON CERTAIN USES OF COMPARATIVE CLINICAL EFFECTIVENESS RESEARCH

Sec. 1182. (a) The Secretary may only use evidence and findings from research conducted under section 1181 to make a determination regarding coverage under title XVIII if such use is through an iterative and transparent process which includes public comment and considers the effect on subpopulations.

• TRANSLATION: Must be open and transparent and must consider effect on particular groups, but can use research to make determinations regarding coverage

‘(b) Nothing in section 1181 shall be construed as–

‘(1) superceding or modifying the coverage of items or services under title XVIII that the Secretary determines are reasonable and necessary under section 1862(l)(1); or

‘(2) authorizing the Secretary to deny coverage of items or services under such title solely on the basis of comparative clinical effectiveness research.

• TRANSLATION: Coverage cannot be based solely on CER

‘(c)(1) The Secretary shall not use evidence or findings from comparative clinical effectiveness research conducted under section 1181 in determining coverage, reimbursement, or incentive programs under title XVIII in a manner that treats extending the life of an elderly, disabled, or terminally ill individual as of lower value than extending the life of an individual who is younger, nondisabled, or not terminally ill.

• TRANSLATION: CER cannot be used to assign a  lesser value to extending the life of the elderly, disabled or terminally ill (as compared to the younger and healthier) in regard to treatment. Health care dollars cannot be allocated first (or exclusively) to young and relatively healthy individuals under the rationale that extending the lives of the younger and healthier is, by definition, more valuable. The issue is further explored in 1182(e), discussed below. 1182(e) further limits the use of such valuations with regard to the Quality Adjusted Life Year.

‘(c)(2) Paragraph (1) shall not be construed as preventing the Secretary from using evidence or findings from such comparative clinical effectiveness research in determining coverage, reimbursement, or incentive programs under title XVIII based upon a comparison of  the difference in the effectiveness of alternative treatments in extending an individual’s life due to the individual’s age, disability, or terminal illness.

• TRANSLATION: When evaluating treatments to extend an individual’s life, CER can be used to determine whether Medicare will cover one  treatment rather than an alternative. Specifically, an individual’s age, disability, or terminal illness can be a factor in deciding which treatment will be covered, reimbursed and/or incentivized.  For example an elderly person with severe coronary artery disease may have two treatment options: surgery (e.g. revascularization) or drug therapy. Both of these treatments would theoretically extend the life of the patient by reducing the odds of a heart attack or stroke. However (hypothetically) CER data may demonstrate that an individual of advanced age lives longer on average if they opt for drug therapy. In such a circumstance, this section provides that CER data may take into account the individual’s age, disability and terminal illness when comparing two alternative treatments. It may also be the case that CER data shows that individuals with certain disabilities are less likely to respond to surgery or to different treatment, possibly due to immobility, or even impending death. Again, these facts can be taken into account in the CER calculus.

‘(d)(1) The Secretary shall not use evidence or findings from comparative clinical effectiveness research conducted under section 1181 in determining coverage, reimbursement, or incentive programs under title XVIII in a manner that precludes, or with the intent to discourage, an individual from choosing a health care treatment based on how the individual values the tradeoff between extending the length of their life and the risk of disability.

• TRANSLATION: The Secretary cannot use CER to deny or try to persuade a patient from choosing a treatment that may prolong their life but leave them severely disabled. Alternatively, the Secretary cannot prevent a patient from choosing a treatment which may improve the quality of their life, as opposed to an alternative treatment which may extend the length of life.

‘(2)(A) Paragraph (1) shall not be construed to–

‘(i) limit the application of differential copayments under title XVIII based on factors such as cost or type of service; or

• TRANSLATION: The extant differential copayment guidelines are unaffected. 

‘(ii) prevent the Secretary from using evidence or findings from such comparative clinical effectiveness research in determining coverage, reimbursement, or incentive programs under such title based upon a comparison of the difference in the effectiveness of alternative health care treatments in extending an individual’s life due to that individual’s age, disability, or terminal illness.

• TRANSLATION: See 1182(c)(2) discussed above.

‘(3) Nothing in the provisions of, or amendments made by the Patient Protection and Affordable Care Act, shall be construed to limit comparative clinical effectiveness research or any other research, evaluation, or dissemination of information concerning the likelihood that a health care treatment will result in disability.

• TRANSLATION: This section is straightforward. The Institute can compare various treatments and determine which is more likely to result in a disability, and disseminate those findings.

‘(e) The Patient-Centered Outcomes Research Institute established under section 1181(b)(1) shall not develop or employ a dollars-per-quality adjusted life year (or similar measure that discounts the value of a life because of an individual’s disability) as a threshold to establish what type of health care is cost effective or recommended. The Secretary shall not utilize such an adjusted life year (or such a similar measure) as a threshold to determine coverage, reimbursement, or incentive programs under title XVIII.’

• WHAT IS A QALY?: The Quality-Adjusted Life Year (QALY) is defined by the NIH as:
  • (1) A unit of measure of utility which combine life years gained as a result of health interventions/health care programs with a judgment about the quality of these life years.
    (2) A common measure of health improvement used in cost-utility analysis, it measures life expectancy adjusted for quality of life. (See NIH’s Health Economics Information Resources, Glossary, at http://www.nlm.nih.gov/nichsr/edu/healthecon/glossary.html#QALY)
• The goal of the QALY is to ensure that healthcare resources are allocated in a manner which is most beneficial. Because healthcare resources are scarce, however, the $/QALY looks to allocate those resources economically. The QALY ipso facto discounts the value of life due to a disability. This is because the QALY works by assigning different states of health along a continuum, with perfect health being 1 and death being 0. The QALY is interested in whether different treatments provide more QALYs, In other words, QALYs are interested in whether one treatment provides more years at a better state of health (i.e., closer to 1) than another treatment. See M. Weinstein, Spending Health Care Dollars Wisely: Can Cost-Effectiveness Analysis Help? (2005)

• TRANSLATION: The Institute cannot utilize a $/QALY ( or a similar measure) as a threshold to establish what treatment is cost-effective, recommended or incentivized. (It is, however, noteworthy that in describing “similar measure,” both “age” and “terminal illness” are not expressly excluded as prohibited criteria in the development of a metric, as they are throughout the text of other portions of the provision).

• Note: 1182(c)(2) does allow for a disability to be taken into account when comparing various treatments for an individual. That section must be distinguished from the current section (1182(e)), where the upshot is that the dollar valued QALY cannot be a benchmark by which to allocate resources. If we are only determining which of two resources to a given individual shall be reimbursed, then the individual’s disability may be taken into account, i.e., treatment effectiveness under the individual’s circumstances  is a metric for which CER may be utilized; however, dollar value of life quality is not a permitted metric or criteria for treatment.

Comparative Effectiveness Research Under Health Reform, “The Institute”

“Bend the cost curve” has been the mantra of many students of health care reform. The Dartmouth Health Atlas has shown that up to 1/3 of care may be unnecessary. But how do we find out what care is unnecessary? One tool that holds promise is comparative effectiveness research.   Now that health reform has been signed into law, there is greater certainty as to the future of comparative effectiveness research (CER). The Stimulus bill had already allocated $1.1 billion dollars to investigate CER. The newest health reform law continues to build on that start. So what about HR 3590, also known as the Patient Protection and Affordable Care Act? Will they ration care? Pull the plug on your grandmother? Get between you and your doctor? To start answering these questions, I will provide a brief overview of CER under the new law, and describe the law’s vision for a new institute for CER research.

Part D of  H.R. 3509 is entitled “Comparative Clinical Effectiveness Research.” Section 1181 of  Part D defines CER as: “research evaluating and comparing health outcomes and the clinical effectiveness, risks, and benefits of 2 or more medical treatments, services, and items described in subparagraph (B).” Subparagraph B goes on to describe various services and goods associated with health care.

The Institute
Section (b) of 1181 is where the rubber hits the road. Under this this section, the law creates a nonprofit corporation to be called the “Patient-Centered Research Institute,” known as “the Institute,” which is neither an agency nor establishment of the United States. This is rather interesting, and I did not know that our federal government created such corporations, but I suppose it could be compared to a nonprofit Amtrak.

Funding
The Institute will be backed by a Trust Fund created by money transferred from the Medicare Part A and B trust fund. It will receive, for year 2013, an amount equal to 1$ multiplied by the number of individuals entitled to benefits of Medicare Part A or enrolled under Part B. For years 2014 through 2019 the multiplier is $2.

The Purpose and Duties of the Institute
The purpose of the Institute is stated as what amounts to the typical reason for CER: making better health care decisions based on the evidence.

The duties of the institute are listed as:

1. Identifying and adopting (by majority vote within the Institute) research priorities and establishing research project agenda
2. Carrying out research project agenda by doing
   1. Systematic reviews of previous (and future) research (often known as meta-analysis), and
   2. Primary research including randomized clinical trials. The primary research the Institute conducts can be subcontracted to other institutions, under certain constraints.
3. Data collection from various electronic sources like those at the Center for Medicare and Medicaid Services.
4. Appointing expert advisory panels for clinical trials
5. Supporting patient and consumer representatives
6. Establishing a methodology committee to study new ways to measure and conduct CER.
7. Providing a peer-review process for primary research conducted by the Institute. Notably, if the Institute subcontracts, they can use the peer-review process of the organization to which they contract with.
8. Release of research findings to clinicians, patients, and the general public. The Institute must also release an annual report.

Governing in the Institute
The Institute will be run by a Board of Governors. The breakdown of the Board of Governors is quite interesting, and possibly telling:

• The Director of the Agency for Healthcare Research and Quality
• The Director of the National Institute of Health
• 17 members appointed by the Comptroller General of the U.S. The 17 members must be composed of:
  • 3 members representing patients and health care consumers.
  • 5 members representing physicians and providers, including at least 1 surgeon, nurse, State-licensed integrative health care practitioner, and a representative of a hospital.
  • 3 members representing private payers, of whom at least 1 member shall represent health insurance issuers and at least 1 member shall represent employers who self-insure employee benefits.
  • 3 members representing pharmaceutical, device, and diagnostic manufacturers or developers.
  • 1 member representing quality improvement or independent health service researchers.
  • 2 members representing the Federal Government or the States, including at least 1 member representing a Federal health program or agency.

This very well may be one of the handouts that the Senate provided Big Pharma and device manufacturers to get them on board. Remember that CER may very well show that a drug that a company has invested hundreds of millions of dollars in turns out to be ineffective when compared to its competitor. Thus, it is not surprising, for the cynics among us, that the Board has at minimum 3 industry reps from pharma and devices while there is a minimum of only 1 doctor. You start to wonder why the AMA supported the bill if physicians are only guaranteed 1/17th of the positions. After all, it is undeniable that physicians will be interacting with the CER data more than anyone, and they have on the ground experience using CER and related decision aids like Clinical Practice Guidelines.

Financial Remuneration of Clinical Study Investigators

In November 2009, the Center for Health & Pharmaceutical Law & Policy, in its White Paper, Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight, explored payments to investigators — and other potential motivators — to conduct research.  A study in this month’s IRB: Ethics & Human Research explores the impact payments may have on researchers to conduct and complete studies.  In Motivated by Money? The Impact of Financial Incentive for the Research Team on Study Recruitment, Sharon Unger and her colleagues examine the effect financial remuneration has on researchers in a neonatal intensive care unit (NICU).

Taking advantage of a “fortuitous set of circumstances” in which two separate clinical trials with nearly identical inclusion criteria were conducted simultaneously in an NICU in Canada, the authors looked at two issues: 1) whether financial remuneration impacted the rate at which the research team approached parents about research participation, and 2) whether financial remuneration impacted the rate at which parents provided consent to participate.

In the first study (Study A), a placebo-controlled trial involving a medication that was the standard of care for treatment of newborns nearing extubation to prevent apnea of prematurity, members of the research team were financially compensated for their time if they were successful in obtaining parental consent (parents were unaware of this arrangement).  In the second study (Study B), which involved two different forms of noninvasive respiratory support following extubation, there was no financial compensation of the research team.  Both studies had the same recruiting team.  Study A was federally funded, multicentered and high-profile, while Study B was a single-center, unfunded trial.

The payments in Study A were per capita, which, while creating a direct incentive to recruit individual enrollees, is usually not problematic as long as the payment is not excessive.  The Center recommends “that the benchmark for compensation for physician services for research should be comparable payment for time and services for treatment. This will compensate physicians fairly for their time and services, and will assure that there are no hidden bonuses or incentives for physicians to recruit patients into research or to refer them to research rather than treatment.”  As noted in the study, finder’s fees are increasingly considered “ethically problematic;” the Center recommends a wholesale bar on finder’s fees because they can create conflicts of interest that can incentivize investigators to recruit and retain individuals who do not meet the study’s inclusion and exclusion criteria.

As the authors noted, and as acknowledged in the Center’s White Paper, potential enrollees are increasingly vulnerable as increasing numbers of individuals seek to participate in research either as a primary means of access to treatment or as a form of income.  The results of this study indicate a much higher likelihood of approach when there was a prospect of financial remuneration.  These results are concerning, and were anticipated by the Center’s White Paper, which noted the potential for poor compliance with inclusion and exclusion criteria and pressure to enter or remain in a clinical trial.

However, surprisingly, the authors found that, despite the much higher likelihood of approach for Study A than Study B, parents were much more likely to actually agree to enroll their newborn in Study B — for which there was no financial remuneration of the research team.  The authors explored various explanations for this result, including that the research team was overly cautious about giving the appearance that their approach for consent was motivated by financial compensation, or that parents chose to withhold consent  due to the research team’s  increased pressure.

The authors do acknowledge other potential factors — beyond financial remuneration –  that could have affected the study’s results.  For example, parents’ hesitancy to enroll their newborn in a placebo-controlled drug trial could explain the discrepancy between enrollment in the studies.  Likewise, the authors consider that parents may not have been able to differentiate between the two modes of support being investigated in Study B.  In addition, the recruiting team, when presented with the results of the study, did not recall feeling influenced by the financial arrangement of Study A, but did “recall being highly motivated to ensure the success of Study A as it was part of a high-profile, multicentered trial.”

The authors concluded by noting concerns that “there may be a point at which the amount of the financial remuneration or the manner in which it is assigned could negatively impact the ethical conduct of the researcher,” but cautions that these concerns should be balanced with the value of conducting research in patients’ best interests.  This balancing act is considerably important.  As the Center notes,

Research is critical to the advancement of medical treatment and health. It must be structured to produce high quality data that facilitates the assessment of safety and efficacy in the population for whom the treatment will be used. The good of the enterprise requires that the clinical trial system sufficiently balance the costs and benefits to physicians and prospec­tive trial participants to ensure the continued sufficient supply of researchers and subjects. The system must also be imbued with actual and perceived integrity — so that it produces scientifi­cally reliable results, participants are safe, and people trust the system sufficiently to be willing to participate.

Further Calls for Increased Oversight on Medical Research & Physician Conflitcs of Interest

The Center for Health & Pharmaceutical Law & Policy has continued to focus on the implications of research funding in patients’ decisions to participate in clinical research, as well as the effects such funding can have on researcher behavior and research results.  In January 2009, the Center recommended that all financial relationships between industry and physicians be publicly disclosed by industry.  And just this month, the Center released its most recent White Paper, “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight.”

Similarly, in a November 17 letter to Francis Collins, 100 researchers, academics, and public policy analysts asked the NIH to “fund studies on medical ethics, conflicts of interest in medicine and research, and prescribing behavior” in order to determine the effects of industry-academic relationships on human health.  The letter implores the director of NIH to focus on “the research gap on the effect of conflicts of interest and commercial influence on medical decisionmaking” and to establish a mechanism for funding relevant research.

One of the primary concerns in the researchers’ letter is an issue also identified in a November OIG report, “How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health,” which found that a majority of academic researchers’ conflicts of interest are unreported.   The report flags the potential for extensive conflicts between faculty members and their government-financed research.  In response, the US Senate Finance Committee recently sent letters to several universities requesting such information.  Just yesterday, Northwestern University’s Feinberg School of Medicine, reacting to national concern about physicians’ and researchers’ financial conflicts of interest, began posting external professional and industry relationships for approximately 2000 faculty members — including service on boards of directors, consulting and related activities, ownership or investment interests, royalties and inventor shares, and additional activities such as lectures and participation in scientific advisory boards and professional societies.

Further research is obviously necessary to determine how financial relationships influence — as the authors of the letter to NIH call it — “the beliefs and behaviors of researchers and clinicians, and the effects of industry-academic relationships on the generation and dissemination of medical knowledge.”  In the meantime, increased oversight of physician-industry relationships by the federal government to evaluate and oversee investigator or institutional conflicts of interest, both for research within and without academic medical centers, is necessary.

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy Issues White Paper Calling for Major Reforms in the Financing and Oversight of Clinical Research

Seton Hall University School of Law’s Center for Health & Pharmaceutical Law & Policy has called for major substantive reforms in the financing and oversight of clinical research. In a White Paper entitled “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight,” the Center proposes legal and policy changes to address conflicts of interest in the relationships between industry and doctors that can create unwarranted risks to trial participants and to the scientific integrity of research.

Kathleen Boozang, a dean who oversees the Law School’s Center, explains that “Some of the ways that drug and device trial sponsors pay the physicians who lead clinical trials can tempt them to recruit individuals for clinical trials who would be better off receiving conventional therapy. This is of particular concern if physicians encourage their own patients to enroll in trials that these same physicians are overseeing.”

Over 60% of testing of experimental drugs and medical devices now occurs in physicians’ private offices; unlike years past, industry funds a much higher percent of clinical trials than government, frequently paying researchers significantly more than government does.  For some physician practices, conducting clinical trials represents a significant portion of their income.

According to Carl Coleman, a Seton Hall Law professor who collaborated on the White Paper, “A different kind of problem arises if people are enrolled in trials who don’t meet the criteria for who should participate - these individuals’ health can be put at risk, and their participation can skew the results of the trial, which is bad for everyone.”

Federal regulations in this area have not kept up with the rapid changes in how research occurs, and even those regulations that exist are poorly enforced, according to recent government studies.  Understanding that the collaboration among industry, government, and medicine in the pursuit of clinical research is critical to driving scientific progress, particularly as industry increasingly replaces the government as the primary source of research funding, the Center’s recommendations include:

1) Establishing a norm of financial neutrality between treatment and research. Ensuring that physicians receive comparable compensation for treatment and research will help ensure that their decisions to conduct research, as well as to recommend that a particular individual participate in a clinical trial, are grounded in reasons unrelated to their personal financial interests. This will be best accomplished, in the first instance through regulations that ban certain kinds of research compensation, and provide examples of acceptable payment methodologies that industry can follow. Reform by prosecution signals what practices government dislikes, but does not provide a clear vision of ideal approaches to managing conflicts of interest related to the conduct of research.

2) Establishing federal guidelines as to the principles or methodology by which to determine fair market value of physician time spent in clinical work. Federal regulations should be promulgated that establish a benchmark formula for determining fair market value of physicians’ time, effort and expenses for clinical research. Such regulations would promote the goal of financial neutrality between treatment and research. Physicians cannot be underpaid for research either - compensation for clinical trial work should therefore include reimbursement for any additional expenses that are unique to the research environment.

3) Banning payments with equity interests; disqualification of investigators who hold direct interests in the outcome of the research. Federal regulations should prohibit compensation for research in the form of an equity interest in the sponsor of a clinical trial. The law should preclude researchers who have investments that give them a direct interest in the outcome of the research from leading clinical trials.  Where absolutely necessary, such individuals might appropriately serve as consultants.

4) Banning payments of finder’s fees and bonuses for recruitment and retention of trial subjects. Certain forms of compensation create conflicts of interest that can incentivize investigators to enroll individuals in a clinical trial who are too healthy or too sick to participate, or to deemphasize information that might discourage individuals from consenting to trial enrollment. Federal law should ban such compensation methods, including finder’s fees and bonuses for meeting recruitment and retention goals.

5) Reforming federal regulations to compel and better guide the evaluation of relationships between industry and would-be physician investigators prior to the commencement of research.   The White Paper includes overlapping but sometimes distinctive recommendations for federal regulation to evaluate and oversee investigator or institutional conflicts of interest, both for research within and without academic medical centers.  Specific to research outside of academic medical centers, federal regulations should spell out clearly the obligation of community-based physicians acting as investigators or institutions acting on their behalf to report information about compensation for research and other financial interests to Institutional Review Boards.

Summarizing the importance of this White Paper, Boozang states, “The pharmaceutical and medical device industries save millions of lives each year with their innovations.  It is imperative that we maintain the integrity of research, and the public’s trust in the process.”

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy. The Center is a think tank that fosters dialogue, scholarship, and policy solutions to critical issues in health and pharmaceutical law. As part of its mission, it convenes policymakers, consumer advocates, the medical profession, industry, and government in the search for concrete solutions to the ethical, legal, and social questions presented in the health and pharmaceutical arenas. The Center also runs a compliance training program covering the state and federal laws governing the development and marketing of drugs and medical devices. The White Paper, “Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight,” may be found here.

Seton Hall University School of Law, New Jersey’s only private law school and a leading law school in the New York metropolitan area, is dedicated to preparing students for the practice of law through excellence in scholarship and teaching, with a strong focus on clinical education. The Law School’s health law program has been ranked as one of the top programs in the country. Founded in 1951, Seton Hall Law School is located in Newark and offers both day and evening degree programs. For more information visit law.shu.edu.

Alternative Revenue Stream for Private Practice Physicians – Research Investigator

Clinical research is the only way [for a physician in the managed care era] to make a boat payment, quips David Stark, M.D.

With increasing frequency, pharmaceutical and medical device companies are turning to physicians in private practice, rather than academic medical centers, to serve as investigators overseeing the 60,000-odd clinical trials each year, between 80 and 90% of which are funded by industry as opposed to, say, NIH. Academic medical centers are losing the “business,” having fallen from 63% to 26% as the site for clinical research between 1994 and 2004. While it might be argued that trials in the private practice setting produce superior results because they occur under circumstances that more closely resemble how the drug or device will actually be used if approved by the FDA, there are significant risks attendant to this phenomenon that have received too little attention.

The ultimate question is whether physicians can compartmentalize the competing incentives that exist in advising patients about whether to pursue conventional therapy or participate in a clinical trial. This is especially true if the physician is being handsomely compensated for each patient she recruits into a trial, and is exacerbated when the physician also has other financial relationships with the trial sponsor (the drug or device company) for, say, speaking and consulting gigs. Clinical Research in the Private Office Setting — Ethical Issues The recruitment process for clinical trials is the longest and most costly part of the process - prospective participants have to undergo testing to see if they qualify for the study, and federal law requires that they receive significant amounts of information and have ample opportunity to have their questions answered pre-enrollment. A per capita payment contingent upon successful enrollment of the patient will tempt a physician to fudge on this process and enroll unqualified subjects. This not only may put them at risk because they are too sick, but also skew the research results because they’re not sick enough. Bonuses for meeting enrollment goals only make it worse.

Without impugning physician integrity, how realistic it is for physicians to serve in the dual capacity of treating physician and researcher? Studies have repeatedly confirmed “therapeutic misconception” whereby study participants believe, no matter how clearly told to the contrary, that they are “patients” receiving treatment, rather than “subjects” of research who may be receiving a placebo or an experimental drug. This phenomenon is certainly exacerbated when the patient’s treating physician is doubling as the investigator of the clinical trial. Most patients continue to believe that their own personal physician would be driven solely by their best interests. Ironically, some people have more faith in an experimental intervention when they learn that the investigator has a “piece of the action.”

Obviously, significant policy and legal questions arise from this practice, and a more holistic approach to the question of the best way to encourage clinical trials while safeguarding the interests of trial subjects is beyond what I can attempt here. But one possible approach could be drawn from informed consent law — whether statutory or common law, which should require physician disclosure of conflicts of interest to patients. Imagine the beginning of a conversation between doctor and patient/potential research subject:

Doctor: “Just so you know, if you agree to participate in this clinical trial, I get paid $1000 by the manufacturer of the product being tested, but if you don’t, and you just want regular treatment, I’ll only get paid $60 by your insurance company. But, in fairness, that’s because a clinical trial is a lot more work for me….”

But to be honest, I don’t really believe in this solution either. Most recipients of this information either don’t understand it, or have no idea what to do with it, or both. Some fear that too much confusing information might kill trials altogether, which would be a terrible outcome. And there are certainly reasons to fear that such trials are becoming harder to run, to the point where they’re not worth the money. Ultimately, I guess, I want to control how physicians get paid to serve as investigators — the Goldilocks Solution — not too much, and not too little. I want them to be paid just right, so that they are willing to conduct clinical trials, but aren’t tempted to act other than in the patient’s best interest. Of course, what is just right and how to enforce it poses its own problems.

Seton Hall Law School, the author’s employer, is the recipient of grants, donations and endowments from the pharmaceutical industry. No part of the author’s compensation is funded by these gifts.

x-posted at Concurring Opinions

Drug Study Fails to Mention Risk of Death to Test Subjects

[Ed. Note: Today's Post is by Maansi K. Raswant, a Seton Hall Law student pursuing the Health Law concentration. She is a research assistant to the Center for Health & Pharmaceutical Law & Policy and an intern at the NYC Health and Hospitals Corporation.]

As reported recently in the Boston Globe, a federal probe found that heart attack survivors enrolled in a clinical trial conducted in over 120 sites nationally had not been adequately informed of the safety risks of the study, including the risk of death.

The process under study, chelation, involves “periodic infusions of a drug– in this case, disodium EDTA.” The infusions are being tested in conjunction with the ingestion of high doses of  vitamins and minerals. However, according to the federal probe, “in 2008 FDA removed disodium EDTA from the FDA’s approved list and withdrew of approval of new drug applications for disodium EDTA.” Test subjects were not informed that disdodium EDTA “is no longer FDA approved for any use and has been removed from the market because of safety concerns.”

Funded by the National Heart, Lung and Blood Institute and the National Center for Complementary and Alternative Medicine, the study has over 1,500 subjects. Though researchers suspended enrollment last August due to the investigation, federal officials allowed the study to continue pending further findings of the probe, a decision that has been highly criticized.

In addition to the deficiencies regarding the  informed consent of study participants, the Boston Globe reported that the investigation found that several co-investigators involved in the study had been disciplined for “substandard practices” or had been involved in insurance fraud. Three were convicted felons. Federal officials explained that they found the substandard practices and convictions of the principal investigators “concerning” but not a reason to “automatically preclude an investigator from participating in research.”

The U.S. Office of Human Research Protections detailed the findings of the investigation and required corrective actions in a letter to the three medical institutions heading the study. In response to the investigation’s findings, the study modified the consent form to recognize death as a “rare complication of the EDTA [chelation] infusions.” The Office of Human Research Protections has also requested further modification of the form to disclose that disodium EDTA had been removed from the market.

Despite the change in consent form, questions remain about the acceptability of the risks posed by the study. As the Globe reports, critics of the study, including the head of bioethics at the University of Pennsylvania, Arthur Caplan, have charged that the risks posed by the study are unethical. The complaint against the study filed with the Office of Human Research Protections noted that since “the mid-1970’s court documents and newspapers have reported at least 30 deaths associated with intravenous EDTA.”

The probe is the lastest in a string of major investigations of clinical trials, including the continuing investigation into payments by device maker Medtronic to Dr. Timothy Kulko (who is accused of falsifying author names and  study results), and the Synthes indictment for allegations that its subsidiary, Norian, conspired to conduct unauthorized clinical trials that placed subjects at risk of death without properly informing them of the risks. In the Synthes/Norian matter, three patients are believed to have died as a result of the use of the companies’ bone cement products.