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Experiments on Humans Business of clinical trials soars, but risks unknown Medical studies give new hope to patients, yet Originally Posted At:http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2002/08/04/MN178017.DTL
SPECIAL REPORT Experiments on Humans Business of clinical trials soars, but risks unknown Medical studies give new hope to patients, yet Tom Abate, Chronicle Staff WriterSunday, August 4, 2002 ©2003 San Francisco Chronicle
At Children's Hospital in Oakland, nurses poked Kendra Gottsleben's arm, looking for a vein to deliver an experimental enzyme that's designed to tame the toxins ravaging her body.
Gottsleben, 17, suffers from a rare disease that has left her just 39 inches tall, and unless medical researchers can devise a treatment, chances are she could be dead in a few years.
No one would fault this experiment. But clinical trials are not always so ethically straightforward.
Three years ago at San Francisco General Hospital, doctors gave patients with acute respiratory distress different levels of oxygen as part of a test of whether this would improve survival rates.
The change proved beneficial. But researchers ran into trouble when federal regulators determined that they failed to obtain the proper consent before putting patients through the experiment.
This year, an estimated 20 million Americans will take part in more than 41, 000 clinical trials and uncounted more federally funded experiments. And even though few would argue the necessity of these life-and-death tests, the process of human experimentation is coming under a microscope.
With billions of dollars swelling the coffers of medical research, a spate of tragic deaths has revealed cracks in regulatory safeguards and raised concerns that scientists in a rush to discover new treatments may not be doing enough to ensure safety.
The problem is that these experiments, which range from tightly supervised drug studies like Gottsleben's to triage situations like the UCSF case, defy simple safety prescriptions.
"I do support research with human beings and I think we can do it without slowing down (progress), but I am also an advocate for greater human research protections," said Adil Shamoo, a professor at the University of Maryland at Baltimore and a longtime critic of the current systems of oversight for human clinical trials.
But clinical trial insiders say concern about safety risks have been overblown by prominent coverage of a few incidents, like the deaths of Jesse Gelsinger at the University of Pennsylvania in 1999 and Ellen Roche at Johns Hopkins in 2001.
"It is not a patient-beware situation," said Ken Getz, president of CenterWatch, the Boston publishing firm that tracks the clinical trials industry. "The vast, vast majority of clinical trial participants have very positive experiences."
But even those who run the regulatory systems designed to police the booming medical trials industry don't have a firm grasp on how many volunteers are taking part in experiments -- much less whether they face greater or lesser risks.
"The numbers quite frankly have been hard to pin down because various agencies have parts of the puzzle," said Greg Koski, director of the Office of Human Research Protections, the federal agency that polices federally funded academic research and that recently scolded UCSF for its emergency room trial.
But Koski's counterpart at the U.S. Food & Drug Administration, the agency that regulates clinical trials by drug and biotech firms, said that clinical trials are so different that their risks cannot be analyzed or regulated in some blanket fashion.
"How do you compare deaths in an AIDS trial to deaths in a sinusitis trial?" asked David Lepay, the FDA's director of clinical trial safety.
And that brings the debate full circle to the difference between the UCSF experiments and Gottsleben's -- there is no one-size-fits-all description of the nature or the risks of clinical trials.
For life and death conditions like heart disease or cancer, for example, volunteers have almost nothing to lose.
Arthur Kaye, a 70-year-old San Franciscan, took part in a clinical trial in 1999, taking infusions of a biotech medicine designed to grow new blood vessels to his ailing heart. It didn't work, but Kaye says he's no worse off for having volunteered and would take part in research again.
"When you're sick and in a life-threatening situation, if you can do anything that could solve the problem, why not?" Kaye asked. "It'll either help you or help the general public."
Although Kaye suffered no side effects, he did take a novel medicine and was therefore at some possible risk. At the opposite end of the safety spectrum, some studies require no more than answering questions and giving blood.
For instance, Kaiser and UCSF are collaborating to determine whether there are genetic differences that make some people respond to antidepressant drugs, while others suffer side effects.
There are several antidepressants on the market, but 30 to 40 percent of patients don't respond to the first type of pill they're prescribed, said Kaiser's principal investigator Catherine Schaefer.
Kaiser researcher Nancy Rieser is helping recruit 1,500 volunteers from Kaiser clinics. She enlists patients who have just started taking drugs for depression and conducts a 90-minute interview to establish their mood when treatment begins. Shorter follow-up interviews are conducted at four and eight weeks to gauge any responses to the medication. Kaiser technicians also draw a blood sample.
The blood work is sent to UCSF, where scientists Kathleen Giacomini and Ira Herskowitz are looking for genetic variations among the volunteers. By correlating the interviews with the DNA profiles, researchers hope to spot any differences that could be diagnosed in advance so each patient gets the right pill.
"Once you explain the purpose of the study, most people are willing to take part," Rieser said. "They want us to find these answers."
And then there's the Kendra Gottsleben experiment, which involves a disease,
MPS VI, that is so rare that BioMarin Pharmaceuticals of Novato had to scour the world for volunteers on whom to test its enzyme treatment.
Gottsleben and her mother only recently went home to South Dakota after spending four months living in an Emeryville hotel. BioMarin paid for their room, and extended the same courtesy to three other youths with MPS VI, and their moms, from Portugal, Brazil and France.
Sitting around the hotel pool with the other moms last month, watching all four young volunteers splash off the heat of an East Bay afternoon, Betsy Gottsleben nodded in Kendra's direction.
"The enzyme has to be doing something -- she hasn't walked this well in three years," she said.
Of course, that could be just a mother's wishful thinking, and the whole reason for doing clinical trials is to get the proof that drug companies, biotech firms and academic researchers all need to determine whether their experimental treatments are safe and effective.
In fact, the surge in medical experimentation, powered by advances in genetics and other fields, continues to fuel demand for volunteers and poses new challenges for scientists trying to recruit them -- and for regulators who want to make sure subjects aren't being pressured into taking unnecessary risks.
Safety questions aside, there are already signs that a steady increase in the number of human experiments is butting up against the finite supply of potential volunteers. For instance, CenterWatch has reported that 52 percent of drug trials were delayed up to six months by recruitment difficulties in 2001.
With the safety debate compounding the troubles with recruitment, it's clear that researchers will have to settle questions about risks and regulations.
"One of the reasons for taking a look at the rules is that more and more individuals are losing faith in their safety if they participate in a trial," said Heidi Wagner, a Washington, D.C., lobbyist for Genentech, the biotech giant in South San Francisco.
"It hasn't affected Genentech yet, but it's a general concern."
--------------------------------------------------------------------------------The series With clinical trials a booming business, The Chronicle explores the concerns about human safety.
-- Today: The risks The growth in clinical trials puts pressure on researchers, participants.
-- Monday: The rules Fragmented regulations may leave some volunteers unprotected.
-- Tuesday: The reality What every participant in a medical research study should know.
--------------------------------------------------------------------------------
E-mail Tom Abate at tabate@sfchronicle.com.
Clinical trial deaths Year Research center/Patient Type Funding sourceof trial1991 UCLA / Tony LaMadrid Schizophrenia Government1993 Hutchinson Cancer Institute / Kathryn Hamilton Breast cancer Industry1996 University of Rochester / Nicole Wan Airborne Government chemicals1998 St. Jude's Children's Hospital, Memphis / Three children Leukemia Government1999 Children's Hospital, Pittsburgh Gage Stevens Acid reflux Government1999 University of Pennsylvania Jesse Gelsinger Gene therapy Government2001 Johns Hopkins Ellen Roche Asthma Independent Source: Centerwatch.com Chronicle Graphic