Cancer Vaccine Study Subjects File Suit Against University of Oklahoma Researchers

Participants in an investigational cancer vaccine research study at the University of Oklahoma Health Sciences Center in Tulsa have filed a federal lawsuit against the study's lead clinical investigator, its corporate co-sponsor and its institutional review board (IRB) members, citing numerous violations of human subject protection regulations, internationally recognized ethical standards for research conduct and civil rights laws (Robertson v. McGee, N.D. Okla., No. 01CV00G0H(M)).

The lawsuit, which is believed to be one of only a few federal legal actions taken against IRB members in the United States to date, is predicted to stifle voluntary physician participation on institutional review boards (IRBs) and signifies a likely trend toward increased litigation in the clinical research field.

Problems associated with the three-year-old melanoma vaccine study at the Tulsa campus surfaced in March 2000 during an independent audit by a contract research organization, which recommended the study's termination based on serious subject protection violations that allegedly had occurred. Although university researchers halted the study in March, neither subjects nor the FDA were notified of the safety violations that led to the study's cessation, according to the lawsuit filed Jan. 29 in the U.S. District Court in Tulsa.

Prompted by a whistleblower complaint, the Office for Human Research Protections (OHRP) conducted an investigation into the study that resulted in the suspension of all federally funded human research at the Tulsa campus in June 2000 (see "OHRP Halts Human Research at University of Oklahoma ...," September 2000, p. 1). In its suspension letter to the Health Sciences Center, OHRP noted a number of "major findings" of alleged human subject protection violations relating to the vaccine study, including: inadequate procedures for the manufacturing and safety testing of the vaccine; failure to adhere to protocol inclusion/exclusion criteria; incomplete informed consent documents; and a failure by the IRB to meet its federal regulatory obligations.

OHRP lifted its research suspension in July 2000 based on the university's assurances that it would implement a more stringent research review process and overhaul its educational and training program for researchers and IRB members. Since then, the FDA has allowed 10 melanoma patients to re-enroll in the vaccine study.

However, citing many of the allegations made in the OHRP suspension letter as substantiation for their legal action, 19 research participants, family members and the estates of several of those subjects who died while in the study, are seeking undisclosed damages against multiple defendants. Defendants named in the lawsuit are: J. Michael McGee, the study's principal investigator; all members of the university's IRB; other university officials, including the school's president David L. Boren; and Seattle-based Immunex Corp., which co-sponsored the research and supplied the biochemical drug used in combination with the vaccine.

Among the specific allegations made in the 130-page complaint are the following:

* McGee violated federal regulations governing controlled clinical trials in humans both by enrolling more subjects than permitted by the approved protocol and by misrepresenting the experimental nature of the vaccine and its risks to subjects during the consent process;

* The vaccine failed to meet good manufacturing practices and was prepared from "potentially infected cell lines";

* Immunex "knew or should have known" about McGee's alleged failure to meet his regulatory obligations and that no animal studies had been performed using the investigational vaccine; and

* The reviewing IRB: maintained meeting minutes that lacked the detail necessary to document why changes in the study protocol and informed consent documents were made; failed to document the review of investigator brochures, case report forms, or subject recruitment information relating to the study; and conducted expedited review in situations requiring consideration by all review board members.

These alleged "deficiencies and misrepresentations" caused research subjects to believe that the "risks of the trial were minimal and the potential benefits [were] enormous," the complaint states.

There are 91 causes of action cited in defense of the lawsuit. These include violations of: the ethical protections guaranteed in the Nuremberg Code and the Declaration of Helsinki; violations of federal regulations governing the manufacture and control of investigational biological drugs for clinical use (21 CFR Parts 210, 211, 601, 610) and federal human subject protection regulations (45 CFR Part 46); fraud on the FDA with respect to the protocol and conduct of the trial; and civil rights violations.

Additionally, the plaintiffs are seeking damages for: negligence; intentional and negligent infliction of emotional distress; fraud and misrepresentation; assault and battery; lack of informed consent; and strict products liability.

The road to proving charges of wrongdoing in this case will be an uphill one for the research subjects and their families, according to McGee's attorney, Lynn Mattson with Doerner, Saunders, Daniel & Anderson LLP in Tulsa.

"This case rests entirely on a whistleblower's complaint," Mattson told the Monthly Bulletin.

Mattson also is representing McGee in a matter involving employment claims against the university over tenure issues; the former clinical investigator was relieved of all of his clinical research-related duties following the OHRP suspension, but has remained on the faculty of the university's department of surgery pending an administrative hearing. The University of Oklahoma at Tulsa declined to comment for the purposes of this story.

As for the claims made against the study's co-sponsor, Immunex Spokeswoman Robin Shapiro told the Monthly Bulletin that the company "was not aware" that human subject protection regulations were not being adhered to during the study, adding that all study-related information supplied to Immunex "appeared to comply with FDA requirements."

The IRB members named in the lawsuit could not be reached for comment.

The Oklahoma case represents yet another high-profile black eye for a clinical research industry that recently has found itself at the receiving end of growing scrutiny for alleged lapses in human subject protections.

This case also is somewhat unique because individual IRB members are being held accountable for their actions - a situation that has happened in only a handful of federal and state cases. As such, the case may foreshadow a new trend toward naming review board members in research-related lawsuits.

According to John Isidor, chief executive officer for Schulman Associates IRB based in Cincinnati, one likely outcome of the Oklahoma case is that physicians and other professionals will be reluctant to assume roles in IRBs.

However, Alan Milstein, the attorney representing the research participants in the Oklahoma case, argues that the gravity of the IRB's research role dictates that review board participation should not be a voluntary effort.

"IRBs have certain duties under the law that are critical and significant, and they should not be voluntary committee[s] that simply meet once a month," Milstein said in an interview. "If there aren't sufficient resources for IRBs to perform their monitoring responsibilities, then either there need to be fewer clinical trials or more IRBs that are equipped to perform the functions they are obligated to [perform] under the law."

Milstein, an attorney with Sherman, Silverstein, Kohl, Rose & Podolsky in Pennsauken, N.J., also represented the family of Jesse Gelsinger, the 18-year-old man who died in 1999 during an investigational gene therapy study at the University of Pennsylvania (see "University of Pennsylvania Researchers, Bioethicist ...," November 2000, p. 1). The wrongful death lawsuit was settled in late 2000 for an undisclosed amount in the Gelsingers' favor.