The Curious Case of Pfizer's Asbestos Claims

Here is a very strange and long-running story that raises some questions about how health care organizations are lead, but seems to have bee covered only in the business press.

Pfizer Goes Into the Asbestos Business (in 1968), Faced Hundreds of Thousands of Lawsuits (in the 1980s), Promised to Settle (in 2004)

Here is the background, per a 2004 report by the Associated Press, per Fox News:

Pfizer Inc. (PFE) Friday said it has agreed to pay $430 million to settle all lawsuits against it alleging injury from insulation products made by a subsidiary.

Pfizer and its Quigley Co. subsidiary were named, along with several other defendants, in 171,611 lawsuits claiming personal injury caused by exposure to asbestos, silica or mixed dust.


Pfizer acquired Quigley Co. in 1968. It sold some products containing asbestos until the early 1970s.

Pfizer will establish a trust for the payment of pending claims as well as any future claims. It will contribute $405 million to the trust over 40 years through a note, and about $100 million in insurance. Pfizer will also forgive a $30 million loan to Quigley.

Since 1982, Quigley's main business has been to manage the asbestos lawsuits.

As part of the settlement, Quigley will file for Chapter 11 bankruptcy. Its reorganization plan must be approved by the bankruptcy court and confirmed by a vote of 75 percent of the claimants.

That seems like the end of a long story, but it was not.

Bankruptcy Proceedings Go On Through 2009, No Claims Paid

By 2009, nothing had really been settled. Apparently, the bankruptcy of Pfizer's subsidiary, which was set up as if Quigley was an independent corporation, had not resulted in any resolution to the multiple lawsuits and the large claims. As reported in December, 2009, by Bloomberg:

At issue in the trial is whether Quigley, a former maker of asbestos-containing products, can confirm a plan of reorganization, ending more than five years in bankruptcy. The trial pits the U.S. government and asbestos victims against Pfizer, the world’s biggest drugmaker, with claims that its $450 million contribution under a settlement isn’t enough to satisfy its liabilities.

At the trial, the lawyer for the asbestos victims claimed that Pfizer was using the bankruptcy of its subsidiary to avoid liability:

Edward Weisfelner, a lawyer for an ad hoc group of so- called asbestos victims that represents 30,000 individuals, told Bernstein today that the plan can’t be confirmed because the purpose of the bankruptcy law being used to channel asbestos claims is to 'scrub' a viable company of liabilities.

Under bankruptcy law, courts shouldn’t approve Chapter 11 reorganizations where the primary purpose is to shield a third party, such as Pfizer, Weisfelner said.

'Courts are instructed to avoid the possibility that parties use bankruptcy to protect a third party that’s not submitting itself to the jurisdiction of the court, and that’s exactly what’s going on in this case,' Weisfelner said.

The US government also objected to what Pfizer was doing:

Opposition to the plan also comes from the U.S. Trustee, an arm of the Justice Department that monitors bankruptcies, which has said was improperly orchestrated to shield the drugmaker from liability.

t the time, Pfizer (through its Quigley subsidiary) also was attempting to keep the whole thing quiet, but not successfully:

The U.S. Trustee has fought to keep the trial open to the public, and said in court documents that some of Quigley’s requests to keep information confidential failed to meet legal standards for protecting 'commercial' information.

Of course, at that time, the opinions of the plaintiffs' lawyer and the US Trustee were just that, opinions.

By 2010, Judge Found that Pfizer "Manipulated" the Bankruptcy

But by September, 2010, according to Bloomberg then:

Pfizer Inc.’s Quigley unit, a former asbestos maker, was denied permission to exit bankruptcy by a judge who found the world’s largest drug company manipulated the bankruptcy process to benefit itself.

U.S. Bankruptcy Judge Stuart M. Bernstein in New York today rejected Quigley’s fourth reorganization plan and said parties should discuss dismissal of the case. He said the plan was filed in 'bad faith' by Pfizer and cited testimony that asbestos claims directed at Quigley could total $4.45 billion over the next 42 years.

No Progress by the End of 2010

Apparently despite the judge's opinion, the case still remained tied up in court. By December, 2010, no progress had been made. According to Bloomberg then:

Pfizer Inc., the world’s largest drug company, should have the bankruptcy of its Quigley unit which has protected it from asbestos-related health problems since 2004 dismissed, lawyers for the U.S. Trustee said.

While the bankruptcy has been pending, creditors with alleged asbestos-related health problems have been unable to sue New York-based Pfizer, and many have died, wrote lawyers for the U.S. Trustee, an arm of the Justice Department that oversees bankruptcy. A hearing to decide the U.S. Trustee’s request is set for Jan. 13, according to court papers filed Dec. 23.

'The harm in delaying the inevitable dismissal of this case is to the individuals who have filed asbestos claims against the Debtor and Pfizer,' lawyers for acting U.S. Trustee Tracy Hope Davis wrote in court papers. 'For some of those individuals, time may be of the essence.'

So Pfizer had stalled for so long that some of the plaintiffs had died off.

Summary

So let us summarize. For reasons that are unclear, Pfizer Inc, primarily a pharmaceutical company, bought out a company that made asbestos products in 1968. The health hazards of asbestos were soon recognized, and many people filed lawsuits against Pfizer's subsidiary, alleging they had been harmed. Pfizer promised to settle the matter in 2004, about 30 years since the exposures occurred. Yet by setting up a bankruptcy of its subsidiary as if it were an independent company, Pfizer stalled any resolution of the case for at least another six years, using what a Judge termed "manipulation." Now it is 2011, and the cases are still unresolved.

So for a company that claims it is

committed to applying science and our global resources to improve health and well-being at every stage of life.

and boasts

Pfizer Inc: Working Together for a Healthier World

This does not look good.

So question number one is should not the leaders of a company whose main business is ostensibly making people healthier be more sensitive to claims about the health effects of its products? Specifically, why did Pfizer's leaders not try to more speedily come up with a cleaner and more timely solution to this problem that would appear more sensitive to the health problems of the claimants?

It would be interesting if Pfizer's top leaders were to try to answer that question.

My policy observation is now familiar.  As we have said before, far too often the leaders of not-for-profit health care institutions seem more interested in padding their own bottom lines than upholding the institutions' missions. They often seem entirely unaware of their duty to put those missions ahead of their own self-interest. Like the financial services sector in the era of "greed is good," health care too often seems run by "insiders hijacking established institutions for their personal benefit." True health care reform would encourage leadership of health care who understand health care and care about its mission, rather than those who see a quick way to make a small fortune.

Post Title → The Curious Case of Pfizer's Asbestos Claims

What Did Parexel Tell the Participants in the TGN 1412 Trial?

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We recently reported an account of an interview with one of the participants which serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects (see post here).

Bloomberg news just reported on the consent form used in the trial, raising even more issue about what the participants were told or understood about what could happen to them. These issues are summarized below.

Risks Not Revealed - Bloomberg showed the form to several medical ethicists. Michael Goodyear stated, "they [the trial investigators] failed to to adequately disclose the degree of uncertainty around a first-in-man trial. The risks were well known. They were not disclosed in the consent form." Arthur Caplan, of the Center for Bioethics at the University of Pennsylvania, said, "they hid the most serious threats with bland language." Parexel countered only by saying that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) "has done an exhaustive inquiry of Parexel and confirmed that the trial was run according to the approved protocol." However, Bloomberg noted "the agency says its investigation didn't include a review of the consent form."

Participants Questions Deflected - Bloomberg reported that study participant Raste Khan claimed that Parexel staff deflected questions, saying "we're in a bit of a push. Can you sign now, and I'll explain it all to you."

Proportion of Patients to Receive Placebo Not Explained - Khan also said, "They didn't tell us how many placebos there were, so I just thought it was 50/50." Caplan called this a "'major' ethical violation to withhold the actual chance of receiving the drug."

Drug Not Described Clearly in Lay Terms - The drug was described as "a 'monoclonal antibody,' which means that it is an antibody (a naturally produced protein) that has been designed by scientists to target a particular type of cell -- in this case, a type of white blood cell called T-cells.'' Caplan retorted, "I've read a lot of consent forms and I don't understand this." Goodyear noted that the consent form never clearly said what the drug would do, specifically never stating that the drug would stimulate the immune system, and suggested that comparing the drug to aspirin and ibuprofen was also misleading.

Adverse Effects Minimized - "Parexel's consent form says the drug, called TGN 1412, was designed to treat arthritis, other inflammatory illnesses and leukemia. The form says that 'no significant side effects had been seen in the animal studies.' "I think it was misleading not to tell participants that that this drug was genetically engineered from hamster cells and that it was designed to alter their immune system,"' commented Goodyear. "Reasonable people would think twice before allowing an experimental drug to change their immune system.''
Furthermore, the form described a cytokine burst as akin to hives. Goodyear responded, "Since monoclonal antibodies are know to cause Cytokine Release syndrome, which can be fatal, and Parexel was not even planning for this, the subjects should have been warned." Parexel's response, again was "the MHRA found no deficiencies during its inspection of Parexel's Phase I unit at Northwick Park Hospital that would have contributed to the adverse reactions experienced by the study volunteers.''

Possible Coercion - "Ethicists say the consent document exploited the participants' need for cash. The first page of the consent document says participants can leave the trial at 'any time without giving a reason and my rights will not be affected.'' On page 9, the document says, 'If you leave the study and exercise your right not to give a reason or are required to leave the study for non-compliance, no payment need be made to you.'
'That's very coercive language,'' says Greg Koski, 56, a physician and former head of the U.S. Office for Human Subject Protection, interviewed by phone April 5. 'It's a bait and switch.'"

Failure to Identify Ethics Committee Which Approved the Trial - " Parexel's TGN 1412 consent form omitted the name and contact information for the Brent Medical Ethics Committee, which approved the consent form and supervised the trial." Caplan noted, "The participant needs to know who to contact. There has to be a source of independent advice. They are defeating the entire purpose of having an ethics committee if you can't find it.'' The MHRA investigation did not cover the role of the ethics committee.

Referral to an Irrelevant Pamphlet - " Parexel's consent form advised subjects to read a pamphlet published by Consumers for Ethical Research, a London-based advocacy group. Naomi Pfeffer, chair of the organization, says the booklet shouldn't be used for healthy volunteers as it was written as advice to sick people considering treatment through a clinical trial."

Revelations about how Parexel failed to inform, or misinformed subjects in the calamitous TGN 1412 trial, coupled with previous reports about how SFBC International, another contract research organization, treated its trial subjects (most recent post here), suggest that commercial contract research organizations need to be much more closely regulated and supervised than they are now. And it may be time to question the whole notion of commercial firms doing clinical trials of drugs and devices.

Addendum (14 April, 2006): The Lancet just published a lead editorial that summarized the TNG 1412 trial, and concluded, "the TGN 1412 events indicate that urgest change is needed in the approval processes and regulation of phase I trials of biologic agents." [Anonymous. Urgent changes needed for authorisation of phase I trials. Lancet 2006; 367: 1214.]

Post Title → What Did Parexel Tell the Participants in the TGN 1412 Trial?

A Report Leaves Many Questions About TGN 1412 Unanswered

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG,. All six healthy volunteers who got the antibody soon became critically ill.

Our first post noted that little was known about how the trial was designed, and about who had reviewed the ethical aspects of its protocol. A later post summarized questions posed in a BMJ editorial, including how were research subjects recruited and motivated, what were they told about possible risks, why were healthy volunteers rather than patients recruited, and why were all patients given the drug simultaneously? The BMJ editorial, a Lancet editorial, and our first post all called for more openness and transparency in drug research.

Now the UK Medicines and Healthcare Products Regulatory Agency has issued an interim report. (See news articles in the Times [UK], Nature, and the Boston Globe.) Basically, the MHRA "ruled out contamination, overdose, and procedural problems," as per the Globe. But it revealed nothing more about the trial protocol, nor how it was reviewed. For example, the Globe stated that "Parexel spokeswoman Jill Baker said that she couldn't comment on the design of the trial, but it had been approved by health authories and reviewed by an ethics committee in Britain." None of the other news accounts provided any other answers to the questions above.

The main conclusion of the report was that "the drug TGN 1412 caused an unprecedented and unexpected reaction that did not occur in tests on animals," per the Times. This seems to be stating the obvious. The questions remain whether this unprecedented and severe adverse drug reaction could somehow have been anticipated by perusal of animal testing data or understanding of the science behind development of the drug; or whether the adverse drug reaction could have been reduced by a differently designed or implemented trial?

The Telegraph reported that a lawyer for two of the trial participants is not happy. Ms Ann Alexander said "the MHRA's report gives no detailed information about the pre-clinical trials, about which there has been conflicting information since the trial was suspended."

So there is still little transparency to this trial. We still do not know the results of testing the antibody in animals, the design of the trial protocol, the justification for aspects of the trial design, or who reviewed the ethical aspects of the protocol.

This sad case still illustrates how commercially sponsored pharmaceutical research often remains hidden behind the veils of trade secrecy and business confidentiality. If pharmaceutical companies really want patients and physicians to trust them more, they should start making their human research more transparent.

Post Title → A Report Leaves Many Questions About TGN 1412 Unanswered

Advertisers Want to Strip Direct to Consumer Drug Advertisements of Specific Information on Side Effects

The Associated Press reported that the Coalition for Healthcare Communication submitted a petition to the US Food and Drug Administration (FDA) to abolish the requirement that direct to consumer advertising of drugs include information about their specific adverse reactions. Instead, the Coalition suggested that the advertisements "simply carry a boilerplate warning that all perscription drugs have potential risks and benefits." (See an early post on direct to consumer advertising here.) "The Coalition for Healthcare Communication's members include the American Association of Advertising Agencies, Healthcare Marketing and Communications Council and Public Relations Society of America."

Their rationale was, "While some may think it desirable to tell consumers about all side effects and contraindications, no matter how clearly this information is communicated to consumers, a significant number will lack the education or background to comprehend or act on it." [emphasis added]

Of course, this raises the question of whether direct to consumer advertising, which is apparently only allowed in the US and New Zealand, is a good idea at all. Should patients who may not be able to comprehend information about drugs' adverse effects be exposed to sometimes emotionally based advertising designed to promote drugs' supposed benefits?

Post Title → Advertisers Want to Strip Direct to Consumer Drug Advertisements of Specific Information on Side Effects

An Update on the Tragic TGN 1412 Trial

Our most recent post on the lack of transparency in the trial run by Parexel of TGN 1412, a drug developed by TeGenero, which left all six participants in intensive care with multi-organ system failure, was here.

This trial has generated tremendous media attention. Thus, we now know a bit more about it, but still not much.

According to TeGenero's website, the drug TGN 1412 is a monoclonal antibody that targeted the CD28 receptor on T-lymphocytes. The drug is not meant to destroy T-lymphocytes, but rather to activate the CD28 receptor. According to TeGenero, the TGN 1412 leads to "pronounced T-cell activation and expansion." Thus, unlike some other monoclonal antibodies used to treat cancer, this drug was meant to change the settings, as it were, of the patient's immune system. This was thus a novel therapy, and hence one whose results might have been unpredictable.

Furthermore, the Times (UK) reported that before the trial was carried out, there may have been reasons to be concerned that this drug might have had adverse effects. The Times article quoted Angus Dalgleish, (who holds the Foundation Chair of Oncology at St. George's Medical School in London, but is also the Research Director for Onyvax, a company that also is developing cancer treatments based on immunology), "I would have told the people doing this trial [on TGN 1412] not to do it because the dangers were so great." He cited studies of a "similar drug," "They should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways." (I have not yet been able to figure out precisely which studies he meant.) Furthermore, the Times quoted Jorg Schaaber, "a member of the German drug industry monitoring group Buko Pharma" (whose web-site is here, but appears to only be in German), that monoclonal antibodies like TGN 1412 carry "considerable risks." Finally, it quoted Michael Seed, a Senior Research Fellow at the William Harvey Institute at Barts and the London Hospital and the Queen Mary's School of Medicine and Dentistry, "The danger is that they are messing around with T regulator cells and we don't know what all the T regulator subsets do. Some will switch things on and some will switch things off."

Furthermore, newspaper reports hint at irregularities in how the trial was conducted. The Times (UK) article suggested that the fees paid volunteers were sufficient to be inducements, rather than just payments for time and expenses. It also alleged that in other trials, Parexel, the contract research organization conducting the TGN 1412 trial, used consent forms so long as to be unreadable, and "pressured" volunteers to sign the form with reading it, "because I felt like I was slowing everyone down." Also, it noted that some trial participants may have been professional research subjects, e.g., one, referred to as a "serial human guinea pig," had reportedly made 60,000 pounds sterling in four previous years from participating in drug trials.

An article in the Telegraph (UK) cited a review article on the effects of monoclonal antibodies to CD28 (Hunig T, Dennehy K. CD28 superagonists: Mode of action and therapeutic potential. Immunol Letters 2005; 100: 21-28 )which noted "massive expansion and functional activation of regulatory T-cells by in vivo treatment with CD28 superagonists," but also revealed gaps in current knowledge about what CD28 activation does, and then asked "does it even make sense to talk of informed consent when the experts themselves admit to sugh gaps in their knowledge?"

Thus, there are reasons to suspect that this trial had not been fully thought through, and that it it was not optimally implemented.

Once again, while hoping that six participants in this trial get better, I also hope this tragedy prompts a re-evaluation of our drug testing procedures, and particularly more transparency in all phases of the process.

Post Title → An Update on the Tragic TGN 1412 Trial

A Window on Human Research Done by Contract Research Organizations

The recent tragic and unprecedented results of a Phase I clinical trial of a monoclonal antibody known only as TGN 1412 provide a new window into the issues surrounding the now heavily commercialized world of drug testing.

The outcome of the TGN 1412 tests have received global attention. Briefly, TGN 1412 is a monoclonal antibody developed by the German company TeGenero AG. An initial test on six volunteers was arranged by Parexel International at their facility at Northwick Park Hospital in London, UK. Six volunteers received apparently the same initial dose of the drug, while two others received placebo. Within hours of receiving the drug, all six complained of fever, and severe pain in their heads. They apparently developed severe swelling of their heads and upper bodies, and then developed multi-organ system failure. All were rapidly admitted to the hospital's intensive care unit.

The particular symptom complex these patients suffered seems to be unprecedented. Previous instances in which everybody who received a new drug rapidly developed life-threatening illnesses are apparently unheard of.

The media have been doing their best to investigate what happened, while the UK Medical and Healthcare Products Regulatory Agency (MHPRA) suspended the trial and is also investigating. Based on newspaper reports available so far, though it is striking what is not known about this drug trial.

We know the company designation for the drug, and its general type (a monoclonal antibody, or protein developed to bind to a specific molecule), but nothing more specific. We do not know what the target molecule was for the antibody, the rationale for its potential therapeutic usefulness, or the results of its in vitro (test-tube) or animal testing. Some of the news reports suggested conflicting results of animal studies. For example, one report in the Times (UK) quoted the girl-friend of one of the trial subjects , "They [the drug company] said there was an oversensitivity in monkeys...." Furthermore, "a dog and some animals had died." But the Times also reported that the Chief Scientific Officer of TeGenero, Thomas Hanke, "refused at a press conference to say whether animals had died during earlier tests. 'There has been no issue on the safety of the drug oanimalsls. This is not relevant.'" In addition, Bloomberg News reported that the CEO of TeGenero, Benedikte Hatz, said "these events were completely unexpected and do not reflect the results we obtained from initial laboratory studies...." Finally, the Independent reported a claim by a lawyer for one of the research subjects that "there is confusion about whether the drug had been testsuccessfullylly and safely on animals before the tests on these volunteers."

We know very little about how the trial was designed. The Times reported "the trial protocol had been agreed with the MHPRA and was carried out 'according to strict ethical and regulatory requirements,' per Parexel. The MHPRA yesterday refused to give precise details, citing commercial confidentiality, and questions to Parexel went unanswered." Some reports suggested that all six volunteers got doses of the drug simultaneously. The Times noted that this practice was not condoned by a textbook it consulted, which instead suggested sequential dosing.

We do not know what sort of oversight or review this trial had received. The Bloomberg report quoted Parexel's claim that it uses "standardized procedures for testing a drug in humans for the first time, based on a protocol approved by ethics committees and regulatory authorities." What ethics committee approved this protocol is unclear.

We have previously posted about how clinical research on human subjects has become more and more an enterprise done by for-profit commercial contract research organizations, (like Parexel), and supervised (in the US, at least) by commercial institutional review boards (IRBs). We posted (go here and see links) about various questionable practices by US based commercial contract research organization SFBC International, which is now under investigation by a US Senate Committee and the US Security and Exchange Commission (SEC). Furthermore, a trial immunosuppressantresant drug carried out by SFBC International's Canadian subsidiary resulted in 20 patients and staff members contracting latent tuberculosis.

Current regulations of clinical research on humans in the US were developed in the days when most research was carried out and directed by faculty members at academic institutions. Now most research is funded by commercial firms, mainly drug and device companies. When such research is carried out in academic institutions, it is performed often under contracts that give considerable control to the commercial research sponsors, rather than to the faculty ostensibly principal investigators. Furthermore, most such research is now carried out by contract research organizations, under contract to the drug or device company, and supervised by commercial IRBs also paid by the commercial sponsor.

Human clinical research has profound health and safety implications both for its subjects, and for any patients who eventually take the drug or use the device under study. Given that, research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised. Such transparency was obviously not in evidence in the trial of TGN 1412. We need to revise regulation of drug and device testing on human subjects to make it sufficient to protect research subjects and patients in the current era of globalized commercial research.

Post Title → A Window on Human Research Done by Contract Research Organizations