When Drug Trials Go Wrong, Patients Have Little Recourse

Despite Consent Forms;
Ms. Davenport's Decline

Thursday, January 31, 2008
By SARAH RUBENSTEIN
The Wall Street Journal Online

COUPEVILLE, Wash. -- Before Suzanne Davenport entered a clinical trial testing a drug for Parkinson's disease, she could drive, cook and care for herself. Within months, she was wheelchair-bound and living in a nursing home.

Ms. Davenport's family says the trial caused her precipitous decline. It is suing the two drug makers that ran the trial and the university that enrolled her in it for compensation to cover her mounting medical bills.

The case highlights one aspect of the legal and regulatory void surrounding clinical trials. Federal law does not require researchers to compensate participants harmed in such trials. It merely requires that their consent forms spell out whether compensation will be available for research-related injuries in trials that involve more than minimal risk.

The prospect of compensation for injuries, of course, encourages volunteers who might otherwise be reluctant. But the wording in these consent forms is often confusing and vague. It can be unclear which research entity is responsible for the cost of subsequent care, how much that entity will pay and under what circumstances it is obligated to pay. One big problem is that it can be difficult to separate what was caused directly by a trial from the natural progression of the participant's disease.

Companies "do not want to end up paying for all of somebody's care when that care may simply be the product of the fact that that person had a grave illness," says Haavi Morreim, a University of Tennessee bioethics professor who has studied clinical-trials lawsuits.

The issue has come into heavier focus as drug companies, under increasing financial pressure to bring drugs to market, have stepped up the pace of clinical trials. World-wide, the number of industry trials rose to 59,000 in 2006 from 40,000 in 2000, according to an estimate from CenterWatch, a clinical-trial listing service. The growth has come in part from a jump in small early-stage trials meant to help drug companies weed out duds quickly. Makers say it is also increasingly common to test a single drug multiple times to see if it can treat different conditions.

There is little definitive data on the number of injuries from clinical trials, partly because there is no one government body that regulates all of them. But the issue is getting more attention following several widely publicized lawsuits, including a suit over the 1999 death of Jesse Gelsinger, an 18-year-old who participated in a gene-therapy trial at the University of Pennsylvania.

Many lawyers had long been reluctant to pursue clinical-trial injury cases because they worried the consent forms protected drug companies and universities from liability, says Alan Milstein, the attorney for Mr. Gelsinger's family. The Gelsinger case, which settled for an undisclosed sum, helped raised public awareness of safety issues with trials. The lawsuits also showed that it was possible to find flaws in the informed-consent process and sufficient maneuvering room in the wording to be successful. Mr. Milstein says he has filed 13 cases involving clinical-trial injuries since then, with 11 involving full or partial settlements.

A Gradual Decline

Suzanne Davenport, a 71-year-old retired kindergarten teacher, was diagnosed with Parkinson's in 1989 after her husband noticed she was inadvertently knocking her hand against posts as they walked their dog.

[Suzanne Davenport]

Her decline was very gradual, her family says. For years, she continued to quilt, an activity that required the sorts of fine motor skills that Parkinson's can ravage. But by 2003, the disease had advanced. Among other things, Ms. Davenport had to keep redoing her stitches to get them right, says her husband, Jim Davenport. She gave up the hobby.

In early 2004, neurologists at the University of California, Los Angeles, where Ms. Davenport was receiving some of her care, discussed with her the idea of participating in a clinical trial. It involved surgically implanting an experimental drug called Spheramine into the brains of Parkinson's patients with the aim of improving their motor skills.

The drug was in mid-stage development. An early-stage study in 2000 involving six trial participants with Parkinson's found that it was "well tolerated without serious adverse events related to the treatment," and patients' motor symptoms improved, according to a 2005 article in the Archives of Neurology.

Spheramine was originally developed by Titan Pharmaceuticals Inc. of South San Francisco, Calif. Titan entered into a partnership to develop the drug with another company, Berlex Inc., which was the U.S. arm of the German drug maker Schering AG. Berlex sponsored the trial and UCLA enrolled patients and evaluated them before and after receiving the treatment.

On June 10, 2004, Ms. Davenport signed a UCLA consent form stating: "If you are injured as a direct result of research procedures, you will receive treatment at no cost. The University of California does not provide any other form of compensation for injury."

Decoding 'Injury Statements'

Consent forms and compensation plans vary by institution. There have been sporadic calls to standardize these programs, but none have been widely adopted. The Institute of Medicine, a nonprofit group that advises the government on health policy, recommended in 2002 the creation of a "no fault" compensation system for injured subjects. The goal was to help trial participants resolve their claims quickly, without having to resort to lawsuits.

Throughout the second half of 2004, Ms. Davenport went through periodic pre-operative tests at UCLA. Shortly before the scheduled operation, the venue for the procedure was switched from Stanford University's medical center to Tampa General Hospital in Florida.

Ms. Davenport signed another consent document, this one from the University of South Florida, which employed the surgeon who would operate on her. The form contained three "injury statements."

The first statement, from USF, said financial damages would be available to her in the event of an injury "to the extent that negligent conduct of a University employee caused your injuries," but such damages could be "limited by law." The second statement, from Tampa General Hospital, said the cost of treatment for any injury "may be the responsibility of you or your insurance company." The third statement, from Berlex, said: "If because of your participation in the study you require additional care that would not ordinarily be necessary for your condition, this will be provided at no additional cost to you."

On Jan. 14, 2005, Ms. Davenport walked into Tampa General Hospital. When she came out of the surgery, she was no longer the same person.

She could no longer stay upright in a chair and could not walk, her husband says. She also needed a diaper and her mouth hung open. On the flight home, Mr. Davenport says he spent about four hours propping his wife's upper body against the back of her seat so she wouldn't fall forward. In the following weeks, Ms. Davenport hallucinated frequently and her cognitive skills had diminished considerably, says her daughter, Julie Languille.

By September 2005, eight months after the surgery, Ms. Davenport required constant monitoring. The family decided to put her in a nursing home outside Seattle, near Ms. Languille's home. There, Ms. Davenport lost her balance and fell a few times. The nurses put her in lap restraints to keep her from getting out of her wheelchair.

Ms. Davenport's neurologist, John Roberts of Virginia Mason Medical Center in Seattle, says he believes Spheramine caused her sudden decline. Dr. Roberts was not involved in the trial, but learned from a UCLA neurologist in early 2006 that Ms. Davenport was among the patients who had received the drug. As is the case in many clinical trials, some patients who were part of a control group had not received the drug.

Dr. Roberts, who had been treating Ms. Davenport for almost a year before she entered the trial, says before the trial, she was able to walk and conduct basic living activities independently. Based on her age and her overall health, he estimates she could have gone another 10 years before needing to move into a nursing home had she not taken part in the trial.

[Julie Languille]

Ms. Languille says Medicaid, the government health-insurance program for the poor, has paid for most of Ms. Davenport's care since the surgery, more than $100,000 to date. Mr. Davenport, a retired aerospace engineer, is required to contribute $700 a month. So far, the family says it has spent more than $28,000 on her care.

In March 2006, Ms. Languille decided to seek compensation. She started with Jeff Bronstein, the neurologist who was the lead investigator at UCLA. Based on conversations with clinicians at other trial sites where patients received Spheramine, Dr. Bronstein says Ms. Davenport's condition after the trial was unusual. He says it was also not typical of Parkinson's patients, which indicated to him that the drug was likely a contributing factor.

Dr. Bronstein referred Ms. Languille to an official at Titan who was his main contact for the trial. He says he thought the companies were responsible for compensation. "I thought it was going to be the best way to help the family, and the fastest way," he says.

A contract between Berlex and the Regents of the University of California, obtained by The Wall Street Journal through a public-records request, says Berlex would reimburse the university for "reasonable" costs for treatment needed as a result of the trial, assuming the study was conducted according to its rules and the university wasn't negligent.

Ms. Languille spoke with Dmitri Lissin, a clinical-development director at Titan. He asked her to send him the nursing-home bills so he could submit them for payment. In a subsequent letter, Dr. Lissin wrote that Titan had initiated a legal review of her mother's case. Ms. Davenport's decline "can possibly be attributed to the natural course [of her disease] or experimental treatment, or both," he wrote.

In an interview, Dr. Lissin, who no longer works for Titan, said responsibility ultimately rested with Berlex, and he was helping them to review the case.

Titan declined to comment on its role in Ms. Davenport's case but said in written a statement that all trials of Spheramine have been monitored for patient safety. It added that it is "committed to the...continued development of Spheramine as a potential new treatment option for patients suffering with Parkinson's disease."

Ms. Languille says she was next contacted by Berlex. In an email, Walter Hong, a Berlex medical-development director who was following up on her case, asked whether Ms. Davenport received any state aid, whether she would qualify for Medicaid, and whether the family had "a plan in place for spending down" its income and savings. The company says it was trying to determine whether any settlement would damage Ms. Davenport's eligibility for insurance from the government or another provider.

She was contacted next by a Berlex attorney, Eric Threadgold. She says he told her over the phone that if the company were to pay, it would prefer to do so in one lump sum rather than in monthly payments as bills arose. He also said since Ms. Davenport would have required nursing-home care at some point anyway, Berlex would only be accountable for the extra care required as a direct result of the trial. He asked for an estimate of those costs. Mr. Threadgold would not comment on the case.

Ms. Languille wanted to move her mother back home and hire live-in aids to help take care of her. She calculated the cost over 20 years, including equipping the house and providing 24-hour nursing care. Her calculation, which also included reimbursement for prior costs, came to $3,429,248.

According to court documents, Mr. Threadgold wrote in an email to Ms. Languille a month later that the company was willing to try to resolve her mother's situation in a "mutually acceptable manner." He cited "Medicare, tax and projected nursing-home expenses" as some issues that needed to be addressed.

Fearing that the company was dragging its feet, Ms. Languille hired a lawyer, Stephen Pappas. Mr. Pappas took over conversations with Berlex in the fall of 2006.

In 2007, the family decided to sue Titan, Berlex and the regents of the University of California, seeking more than $5 million for damages, medical expenses and attorney's fees. Mr. Pappas says he sued the California regents rather than Tampa General Hospital or the University of South Florida in part because the UCLA consent form offered the broadest description of compensation for medical care.

The University of California declined to comment on the substance of Ms. Davenport's case because of the pending litigation. A spokeswoman for the university said in a written statement that the university "takes these matters very seriously" and that the parties "are working to determine a satisfactory resolution."

[Testing, Testing]

In a response to the Davenports' complaint filed in Alameda County Superior Court in California, the regents said, among other things, that the university had fulfilled its informed-consent obligation to Ms. Davenport. It added that the university wasn't liable for an alleged "defectively manufactured medical product."

Since testing of Spheramine began, Schering AG was acquired by Bayer AG, and Berlex was renamed Bayer HealthCare Pharmaceuticals Inc. A spokeswoman for Bayer said in a written statement that the company "has undertaken efforts to try to agree on some type of compensation for Ms. Davenport's care" even though "it has not been established" that her "current symptoms" were related to the trial. She also said, "We sympathize with Ms. Davenport and her family, and remain committed to resolving this matter as soon as possible," adding that the parties are close to a legal settlement.

'Great Promise'

Bayer says Ms. Davenport was one of 71 patients enrolled in this stage of the drug trial. It says the study is being monitored by an independent board which has not reported a safety concern. Because the research is ongoing, Bayer says results from the trial are not yet available, but says "early research has shown great promise." It expects late-stage testing of Spheramine will begin in the second half of 2009.

During a visit to her nursing home this past fall, Ms. Davenport rambled mostly incoherently. At one point, she said she had been in the nursing home "almost three years," prompting Ms. Languille to correct her. She had been there two years, Ms. Languille reminded her. "But I bet it feels like three," she added.

"Yes, it does," her mother responded.

 

KEY DOCUMENTS
 
[pdf]
•  The consent form Ms. Davenport signed to enter the trial at UCLA. Language about compensation for injury is on page 14.
•  The consent form Ms. Davenport signed before undergoing the surgery in Florida. Language about compensation for injury is on pages 14-15.
•  A contract between the Regents of the University of California and Berlex. The agreement contains information (highlighted in yellow) about what happens if a patient is injured in the trial.
• Ms. Languille wrote to Dmitri Lissin of Titan Pharmaceuticals after she spoke with him and requested compensation for her mother's care. This is Dr. Lissin's response.
• A Berlex official sent Ms. Languille 10 questions about the family's finances and her mother's situation. This document shows Ms. Languille's email in response , as well as her answers to the questions.
•  A letter from the Davenports' attorney to Berlex demanding compensation for Ms. Davenport's past and future medical expenses.