Protocol 126 - was a series of experiments to test whether monoclonal antibodies against T-cells would improve outcomes of bone marrow transplants for patients with leukemia, mainly by preventing graft-versus-host disease (GVHD). The protocol went through several versions over 1981 to 1993.
Genetic Systems Inc. - The monoclonal antibodies came from Genetic Systems. The company was set up by David Blech, a young entrepreneur with little money and no apparent biotechnology background. The company enlisted several researchers at the Fred Hutchinson Cancer Research Center: Dr. Robert Nowinski, who actually ran Genetic Systems; Dr. E. Donnall Thomas, who had won the Noble Prize for the development of bone marrow transplants, who received 100,000 shares of stock and sat on Genetic Systems board; Dr. John Hansen, who got 250,000 shares, and served as the Medical Director of Genetic Systems for an $18,000/year consulting fee; and Dr. Fred Martin, who got 10,000 shares and served as a consultant.
The First Version of the Protocol - This group of scientists submitted a research protocol to the Hutchinson Human Subjects Review Committee. They did not divulge their business relationships with Genetic Systems. The committee initially rejected the protocol for reasons including insufficient prior animal research; choice of good rather than poor prognosis subjects; fears that T-cell depletion might prevent bone marrow grafts from "taking;" and problems with the informed consent document including minimizing the risk of graft failure, and not discussing alternate approaches to GVHD.
The Revised Protocol - After the committee was reconstituted, it approved a revised version of the protocol. The revised committee still did not hear of the investigators' financial relationships with Genetic Systems. Neither did it hear that the company had agreed to give the Hutchinson a share of royalties from the antibodies.
Protocol 126 in Operation - The protocol began with Dr. Martin, then a post-doctoral student, as Principal Investigator. Initial results showed no decline in the rate of GVHD. The protocol was revised in 1983 to increase the potency of the antibodies against T-cells, but the consent form was not revised, even though the Committee wanted it to include "the risk of fatality from an additional malignant process," that had been observed in other studies of anti-T-cell antibodies.
In 1983 the Hutchinson adopted a conflict of interest policy forbidding researchers from working on projects "in which the member has an economic interest." Yet Hansen and Martin continued their work on Protocol 126. Later they claimed not to have heard of the new policy.
The protocol then came under the jurisdiction of the Hutchinson's new Institutional Review Board (IRB), with Dr. Henry Kaplan as chair, and including Dr. John Pesando. "Kaplan wrote to Thomas asking about rumors that researchers had financial intersts in a company that would use the findings from Protocol 126." Thomas denied this, but posited that the IRB had "an obligation to assist us and impede our research." Kaplan then felt "it certainly didn't appear that we had the power to investigate anything once I got that letter from Dr. Thomas." Dr. Pesando heard that "Thomas and others were enraged with the challenge to their research." Kaplan and Pesando continued to have misgivings. Kaplan appealed for help from the NIH but got no response. Kaplan asked Hutchinson President Dr. Robert Day for an independent review of the protocol, but Day refused. Dr. Thomas challenged Pesando in a staff meeting, "who the hell are YOU to question what we do around here?"
The IRB began to receive reports of engraftment failures affecting patients in the then current version of Protocol 126, 7/20 died of graft failure from June 1983 to March 1984, while 5 more suffered leukemia relapse. The consent form was changed to acknowledge the possibility of graft failure, but then only said "a second marrow transplant would be necessary," without acknowledging that a second transplant would be unlikely to succeed.
The Later Stages - The investigators kept making changes to the protocol, but graft failures continued. For the duration of the protocol, the graft failure rate was 24%. The relapse rate overall was also unusually high, 100% for chronic leukemia. Martin eventually said, "a lot of rejection, a lot of recurrent malignancy. And so it didn't work. It was a bad idea." There was no final report from Protocol 126. Martin said he discarded his files in 1998. The Times reported that 80 of 82 patients in the protocol had died by 2001.
Pessando Protests - Dr. Pessando left the Hutchinson in 1987 after his contract was not renewed. He wrote to the Office of Protection from Research Risks (OPRR) in 1991.
Basically, senior clinicians at the Fred Hutchinson Cancer Research Center in Seattle conducted clinical trials with high therapy-induced mortality rates while they were major stockholders in the company with commercialization rights to those therapies.In 1993, OPRR began an investigation. It send questions to the President of the Hutchinson, who sent a written response, which included the assertion that conflict of interest problems were addressed by the organization's new conflict of interest policy in 1983, which "was not enforced and resulted in no changes in Protocol 126," according to the Times. The OPRR investigation was plagued by delays. The OPRR never conducted a site visit, and apparently relied on no documents other than Pessando's initial complaint and the Hutchinson's written reply. The Times stated that internal OPRR emails indicated that the office early on concluded that his complaints were baseless, so then decided on manuevers to "sort of CYA (cover your ass)."
Frustrated by their lack of response, Pesando wrote to Department of Health and Human Services (DHHS) Secretary Donna Shalala and Director of the National Institutes of Health (NIH) Harold Varmus
In late 20th century America, prominent physicians at a major cancercenter knowingly risked the lives of unsuspecting patients in pursuit of financial gain, sucessfully bypassed regulatory bodies, and repeatedly silenced opposition.... Yet there could hardly be less concern if laboratory rats had died instead.Pessando also complained to the State Department of Health, but the investigation was not completed after the staff member who was involved left.
The Fall of Genetic Systems - Genetic Systems went public in 1982, and was eventually bought out by Bristol-Myers-Squibb in 1985 for about $300 million, who in turn, sold part of it for $20 million in 1991, and closed the rest, taking a $274 million loss. Genetic System's' Founder David Blech was involved in many other biotechnology start-up companies, and in 1992 was listed as one of the 400 richest Americans. As his losses mounted in 1993, however, he started executing sham stock transactions to hide them. His firm, D. Blech and Co., closed in 1994. In 1998 he plead guilty to two counts of fraud. He was fined and censured by the Securities and Exchange Commission.
The Aftermath - The Seattle Times series provoked a local uproar. Families of four deceased patients who had participated in Protocol 126 sued the Hutchinson, but a jury found against them in 2004. The Hutchinson developed stringent regulations about conflict of interest in 2002. The Office for Human Research Protections re-reviewed the case, and found that the Hutchinson violated multiple DHHS regulations during the conduct of two protocols, In Protocol 126, violations included enrolling a subject in a revised version prior to IRB approval; and improperly using expedited review of modifications of the protocol.
The Anechoic Effect and Protocol 126 - Several searches (PubMed, Google Scholar, and Web of Science) revealed very little about Protocol 126 in the medical and health care literature. There was a one page news item in Science in 2001, which prominently featured rebuttals by Hutchinson officials. An article in IRB: Ethics & Human Research concentrated on issues relevant to IRB members. I could find no other articles that included more than one sentence on this case, in particular, none in any large circulation medical journals.
Summary - A series of trials, called Protocol 126, at the Hutchinson Cancer Research Center were run by researchers who had extensive, major financial relationships with the the Genetic Systems, the company that developed the treatment used in the protocol. The investigators failed to divulge these relationships, despite institutional rules to the contrary. They are alleged to have intimidated other physicians and IRB members who tried to review questionable elements of their protocol. The patients enrolled in the protocol did very badly, probably worse than had they had conventional treatment. Efforts by Hutchinson physicians to have an on-site local or federal investigation of the conduct of the protocol did not succeed. Even though Protocol 126 ran from 1981 to 1993, the controversy surrounding it was not revealed until the Seattle Times series in 2001, and it has received little attention in the medical and health care literature since.
Comments - This appears to be yet another case involving major conflicts of interest, at least one person who eventually proved to be a criminal, alleged intimidation of whistle-blowers, and patients with poor clinical outcomes. Yet because it took place at a revered institution, it has received less attention than the facts would seemingly demand.
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