Prosecuting Doctors for Importing IUDs from Canada, but Still No Penalties for Selling Adulterated Heparin from China

Here in Rhode Island, the big health care story recently was the use of unapproved intra-uterine devices (IUDs) by some local obstetrician-gynecologists (OB-GYNs).  The first nuanced summary of the story which just appeared in the Providence Journal, written by Felice Freyer, suggested how the consequences of possible misconduct in health care depend on the clout of those involved.

The Unapproved IUDs

Here are the main points. The issue that caused so much local controversy was the use of unapproved IUDs:

Ten Rhode Island medical groups with 28 doctors told the Health Department that they bought IUDs, a form of birth control, from a foreign source, at prices about half what they had to pay for IUDs approved for use in the United States. Many had stopped using the unapproved devices long before the Health Department began its investigation in June.

Here is what we know about the actual devices they implanted:

An IUD is a T-shaped device that can fit in the palm of a woman’s hand. To prevent pregnancy, doctors insert it into the uterus, where it can stay for years. There are two types available in the United States: the ParaGard copper IUD and the Mirena hormonal IUD. Mirena, the more costly and more popular brand, has a coating of a progesterone-like drug that reduces heavy menstrual bleeding.

Unapproved IUDs Made by an American Company in Finland and Sold in Canada

Most of the "unapproved devices" the doctors were using were apparently made in Finland by an American company.

In most cases, the doctors were using Mirena, which is made at a factory in Finland by an American company, Bayer Healthcare Pharmaceuticals. Only when it comes through approved channels can doctors and patients be assured that a product meets FDA standards. But it is unclear whether Bayer –– or anyone –– makes a version of Mirena that does not meet those standards.

The doctors imported the devices from far-away, exotic Canada.

Most of the devices apparently came from Canada, where the government negotiates with drug and device makers to keep prices low.

There is no reason to suspect the devices were counterfeit, or defective.

'If they’re really from Canada and from a reputable pharmacy, it should be exactly the same thing [as the FDA-approved version],' said Sheryl Ruzek, a retired public health professor at Temple University and vice chair of the board of the ECRI Institute, a nonprofit organization that evaluates medical procedures and products. 'My hunch is the patients were not harmed,' she said.

Potential Negative Consequences for the Physicians

However, the RI physicians are in big trouble for importing them:

In Rhode Island, the state boards that regulate physicians, nurses and nurse-midwives are investigating all those involved. If any are found guilty of unprofessional conduct, they could face disciplinary action such as a reprimand or license suspension. The state attorney general’s office has a Medicaid fraud unit, but declined to comment. The U.S. Attorney also had no comment.

US doctors in other states have also been importing IUDs, and also are in big trouble:

So many doctors were importing IUDs or considering doing so that the American College of Obstetricians and Gynecologists recently took an official stand, issuing an advisory opposing the use of imported devices.

In 2006, the California Department of Health found that eight doctors had used imported IUDs in some 850 women.

In October 2009, an Arkansas doctor was indicted by a federal grand jury for using non-FDA-approved versions of Mirena. He was charged with violation of the Food, Drug & Cosmetic Act, health-care fraud (for allegedly billing Medicaid for the unapproved devices) and money-laundering (for the way he allegedly handled Medicaid reimbursements). The doctor, Kelly Dean Shrum, has not yet come to trial, but potential penalties include fines and imprisonment.

Summary, and the Contrast with the Case of the Adulterated, Fatal Heparin
So to summarize, doctors who imported IUDs from Canada that appeared to be identical to those sold with FDA approval in the US, and were made in Finland by an American company at the same factory in which the US approved IUDs were made have gotten into major trouble with state and federal authorities. There is no clear evidence that the IUDs caused any harm to patients.

I am not defending the doctors' actions. However, contrast the treatment they are likely to receive with another case we have frequently discussed.

We last blogged about the case of Baxter International's adulterated heparin here.  In summary, Baxter International imported the "active pharmaceutical ingredient" (API) of heparin, that is, in plainer language, the drug itself, from China.  That API was then sold, with some minor processing, as a Baxter International product with a Baxter International label.  The drug came from a sketchy supply chain that Baxter did not directly supervise, apparently originating in small "workshops" operating under primitive and unsanitary conditions without any meaningful inspection or supervision by the company, the Chinese government, or the FDA.  The heparin proved to have been adulterated with over-sulfated chondroitin sulfate (OSCS), and many patients who received got seriously ill or died.  While there have been investigations of how the adulteration adversely affected patients, to date, there have been no publicly reported investigations of how the OSCS got into the heparin, and who should have been responsible for overseeing the purity and safety of the product.  Despite the facts that clearly patients died from receiving this adulterated drug, no individual has yet suffered any negative consequence for what amounted to poisoning of patients with a brand-name but adulterated pharmaceutical product.

Yet everyone from state health departments to the federal authorities have jumped into the case of the unapproved IUDs imported, but from Canada, and apparently identical to the IUDs sold in the US.  There is, at least so far, no evidence that the IUDs were defective or dangerous, and no evidence they have harmed patients.  One doctor has been prosecuted for violating the Food, Drug and Cosmetic Act, and for health care fraud and money-laundering.  No one working for Baxter International (or for the identified organizations within its supply chain) has been prosecuted for anything.

What the...?   I do not object to discipline and prosecution of individual doctors who appear to have broken the law.  But why are we so vigorously pursuing individual doctors for an apparently technical violation of laws that did patients no apparent harm, when we are not pursuing health care corporate executives for selling adulterated drugs that likely killed patients? 

F Scott Fitzergald wrote that the "very rich are different from you and me," and it appears that very rich health care leaders have impunity when it comes to conduct that let patients be harmed and die. 

Real health care reform would make top health care leaders as accountable as we now make individual doctors.

BLOGSCAN - Guidelines for Aprotinin

On the GoozNews blog, anonymous blogger "PM" discussed a set of guidelines written last year on the prevention of operative bleeding. The guidelines endorsed aprotinin to reduce bleeding despite concerns raised in a 2006 New England Journal of Medicine article. Subsequently, several studies showing increased risks of mortality for patients receiving the drug, and it is now off the market. PM wondered whether these guidelines enthusiasm related to the financial ties that a majority of authors reported with Bayer, the company that made aprotinin?

Re-Examining the Suppression of the Trasylol Study

We first blogged about allegations that Bayer A.G., the German pharmaceutical company, may have suppressed its own research that showed its drug Trasylol (aprotinin) may have increased risks of severe problems such as congestive heart failure, kidney failure, stroke, and death in 2006 here and here. The St Petersburg (FL) Times just re-examined the story. The new reporting sheds more light on how the research was suppressed, and reactions to the suppression. To summarize....

In 2006, an observational study in the New England Journal of Medicine suggested that Trasylol may have had more adverse effects that previously believed. [ Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-365.] [Free Full Text]

The first author of the study testified at a US Food and Drug Administration (FDA) hearing under adversarial circumstances.

Panelists attacked Mangano's methodology, saying he had not sufficiently accounted for the high-risk nature of patients receiving Trasylol.

In a recent interview, Mangano said he was shocked by the panel's harsh reception of his work.

'The whole thing was a set-up,' he said. 'We did not have anything to gain financially by this. We were making an observation about safety.'

Mangano noted that the chairman of the panel, Dr. William R. Hiatt, has written papers underwritten by Bayer, and that three committee members received waivers to vote because of financial interests in drug companies.

'The system is ridiculous,' he said. 'It's all pro-industry. Who's protecting the patient?'

Only after the meeting was it revealed that Bayer had hidden the results of its own study.

Dr. Alexander Walker, a professor at Harvard School of Public Health, said Bayer hired him six months earlier to review an enormous database of 67,000 bypass patients. The study compared the side effects of Trasylol with those of the two other anti-bleeding drugs.

Walker said his analysis matched Mangano's: Trasylol patients seemed to be at increased risk for death, kidney failure, congestive heart failure and stroke.

When contacted by the FDA, Bayer said it had 'mistakenly' neglected to mention the giant study. The company said the data was "preliminary in nature and raised significant questions on the study population, outcomes and methodology."

That response sounds hollow to several advisory committee members still stung by Bayer's behavior. Dr. Michael Lincoff, vice chairman of cardiovascular research at Cleveland Clinic in Ohio, said that several panelists had commented during the meeting on the need for more data.

'At no point did the Bayer folks say, 'It's on its way,'' he said.

Steve Findlay, a panel member and health care analyst with Consumers Union, said Bayer's actions were 'intentional and very disingenuous.'

'Absolutely no one would say it was in the public interest, or the interest of people having heart surgery, for that information not to be made public.'

'Bayer's action is yet another example, and an egregious one, that shows the lack of transparency regarding important data,' Findlay said. 'We need a system that makes all this publicly available.'

Bayer suspended two unidentified employees following the revelation of Walker's study. It also said it was investigating the incident, a review the company says is still under way.

Mangano's final comments were

You just wonder how many heart failures and strokes are going to happen because this drug is still on the market.

But bringing up drug safety issues is not for the weak-hearted. There are a lot of interested parties that go against you. You just keep moving forward.

We have said it before. We will say it again. To make the best decisions about tests and treatments, patients and physicians need access to the best available data from clinical research. Thus, suppressing research data or results is bad for patients and physicians. It also betrays the patients who originally volunteered to participate based on the understanding that their participation would be used to advance science and health care.

Thus, commercial research sponsors (e.g., drug, biotechnology, or medical device companies) who suppress such data are betraying their public trust. If they cannot be trusted not to suppress data that is unfavorable to their interests, they ought to be banned from sponsoring or controlling research on human beings.

Hat tip to PharmaLot.

Bayer's Attempted Suppression of Trasylol (Aprotinin) Data Makes the New England Journal of Medicine

The latest issue of the New England Journal of Medicine includes an article about Bayer's attempted suppression of data from an observational study of Trasylol (aprotinin). [Avorn J. Dangerous deception - hiding the evidence of adverse drug effects. N Engl J Med 2006; 355: 2169-2171] We had first blogged about this case, based on a story reported in September, 2006 in the New York Times, here. Avorn's comments on the case are notable:

The health care system has a hard time performing drug-safety analyses, in large part because it relies on the pharmaceutical industry to conduct most research on the risks and benefits of medications. It is naive to expect companies to voluntarily fund studies that could sink lucrative products, the FDA lacks the regulatory clout to require them, and despite the $220 billion we spend on drugs each year, we apparently can't find the resources to provide public support for these studies, even if the results could be of great clinical importance and save millions of dollars.

Avorn suggested:

A good start would be to make a national commitment to publicly supported studies of drug risks so that no company could take possession of critical findings for its own purposes. The results of that research could be discussed openly at an annual conference on the risks and benefits of drugs.

In my humble opinion, it does not make sense to let pharmaceutical (and bio-technology and device) companies be responsible for performing relatively unmonitored studies on human subjects to test their own products. One solution would be to put scientists, physicians, and organizations who are not beholden to such companies in charge of such studies. Another would be much more intense regulation of any human studies sponsored by commercial firms.

At least this issue has now come out in the perhaps world's most prestigious medical journal, so it is squarely in front of doctors, other health professionals, and health policy makers.

But I now realize that Avorn's article, and, for that matter, my previous post, both seemed to avoid the issue of accountability of the drug, bio-tech, and device companies who are currently performing (or funding, and then at least partically controlling) studies on humans. So let me correct that omission.

Also in my humble opinion, as long as commercial firms (e.g., pharma, bio-tech, or device) sponsor, and to any extent control studies on human beings, these firms should be held accountable for any failure to disseminate study findings, even if, and maybe especially if the findings are not favorable to their product. Because their products affect peoples' health and safety, suppressing data about their products' adverse effects, or failure to provide beneficial effects is an affront to any patient who might take or be subject to such products. There should be severe negative consequences for any company that withholds such findings.

Another Attempt at Suppression of Medical Research: Bayer and Trasylol

The New York Times reported that "Bayer A.G., the German pharmaceutical giant, failed to reveal to federal drug officials the results of a large study suggesting that a widely used heart surgery medicine might increase the risks of death and stroke, the [US] Food and Drug Administration announced Friday."

Bayer scientists even appeared at a public meeting called by the F.D.A on Sept. 21 to discuss the possibility that the drug, Trasylol, might have serious risks. But they did not mention the study or its worrisome results.

In a highly unusual move, the food and drug agency released a public health advisory saying it had learned of the study's existence only on Wednesday.

A top F.D.A. official said the agency learned of the Trasylol study on Wednesday only after getting a tip from a researcher involved in it.

In a written statement, Bayer said 'that it mistakenly did not inform' the F.D.A. of the study and added, 'This data was not shared immediately with the agency because it was preliminary in nature.'

Bayer's study was performed by a contract research organization [whose name was not disclosed]. But Bayer did not inform the F.D.A. that the study was being done, even though that is routine practice.

It examined hospital record of 67,000 patients, 30,000 of whom received Trasylol. The rest got other drugs. It concluded that patients given Trasylol were at greater risk.

Trasylol is the trade name for aprotinin. It is used to reduce the systemic inflammatory response after cardiac surgery.

This case just seems to be just the latest example of a commercial research sponsor attempting to withold the results of a study which turned out not to be favorable to its interests. We have previously posted on other examples of such research suppression, e.g., see this post for discussion of some classic cases from the 1990s, and this post on the attempted suppression of the Famvir vs Valtrex study.

Each new example raises the worry that the entire clinical research base may be distorted by such witholding.

The Times quoted Senator Charles E. Grassley (R-Iowa), chairman of the Senate Finance Committee, "The remedy is mandatory reporting of all clinical trials and real teeth for the F.D.A to do its job holding drug companies accountable."

The current story, however, is one example of why this would not be complete remedy. The Trasylol study was an observational study, not a clinical trial, and hence would not be included in currently proposed mandatory reporting schemes.

I believe that this is another reason to question whether commercial health care firms should have any role in clinical studies meant to evaluate their products.