August 14, 2007

Nationwide this year, charitable foundations such as the Cystic Fibrosis Foundation, Juvenile Diabetes Research Foundation, Michael J. Fox Foundation for Parkinson's Research, Multiple Myeloma Research Foundation, and Muscular Dystrophy Association will pump about $75 million into drug-development research by biotechnology firms, according to CenterWatch Monthly, an newsletter that covers the pharma and biotech industries.

Source: The Boston Globe

Stricter rules for clinical studies sought to protect patients

By Naomi Aoki, Globe Staff, 6/12/2002

TORONTO - Jesse Gelsinger was 18 when he volunteered to be part of a clinical trial for gene therapy at the University of Pennsylvania. Within hours of the treatment, his organs began to fail, and three days later he was dead. An investigation later revealed that the university and lead researcher in the trial stood to gain millions from the drug being tested and had ignored early warning signs.

The 1999 case shocked the public and the research community, and along with a handful of other highly publicized deaths in clinical trials, it cast grave doubt on the ability of the existing system to protect patients. As a result, federal legislators and regulators are considering stricter regulation of clinical trials. And in a somewhat surprising twist, the pharmaceutical industry - the chief sponsor of such research - also is calling for tougher rules.

''Patients are our business,'' Heidi Wagner, head of government affairs for California biotechnology giant Genentech Inc., said during a panel discussion this week on protecting people in clinical trials, at the annual meeting of the Biotechnology Industry Organization here. ''We wouldn't be anywhere without the patients who volunteer for these trials.''

Biotech and pharmaceutical companies depend on volunteers for clinical studies of their drugs to prove that they are safe and effective and to bring the drugs to market. More than 3,000 trials were taking place in Boston-area hospitals and clinics at any given time last year. If patients lose faith in the system meant to protect them, industry officials said, they will shy away from clinical trials. And this is a risk the industry simply cannot afford to take.

More than 80 percent of biotech and pharmaceutical companies already miss their deadlines for enrolling patients, in some cases by more than a year. And every day a trial is delayed costs an estimated $1.3 million in direct and lost opportunity costs, according to CenterWatch Inc., a Boston publishing company that focuses on clinical trials.

The stakes only promise to get higher as the pace of scientific research continues to accelerate. Since 1993, the number of drugs in company pipelines has doubled. Innovations in technology and the mapping of the human genome are expected to herald an unprecedented age of discovery, meaning more drugs, more trials, more competition for study volunteers, and more money to lose.

''In the past, we've responded when there's been a problem,'' said Dr. Greg Koski, head of the Office of Human Research Protection, the agency that oversees all federally funded research. ''We've got to move to a more proactive system, one that will prevent harm, because that's what will build the public trust.''

After Jesse Gelsinger's death, the gene therapy study at Penn was shut down. Federal investigators found that researchers had violated their own protocol and federal safety rules, ignoring signs seen in earlier patients that the treatment could be harmful and failing to disclose financial conflicts. Penn set up a $1.5 million, 13-member Office of Human Research to train, assist, and monitor researchers. The lead researcher quit in April as head of Penn's gene-therapy institute, and the FDA has begun a process that could bar him from human research overseen by the agency.

Though the Gelsinger case is certainly cause for concern, Koski and industry officials said, such cases remain the exceptions. By and large, they said, the system does protect patients. Deaths are rare - only about 1 in 10,000 subjects die. But the system has become bogged down in procedural and bureaucratic complexities that don't necessarily protect study volunteers. Koski said the system needs to be streamlined; protections must focus on protecting people in clinical trials rather than the institutions running them, and on preventing lapses rather than reacting to them.

Informed consent must go beyond getting a person's signature on a form, said Koski, who prefers the term ''informed participation.'' Study volunteers need to understand the risks and benefits of the clinical trial. They should be informed about the study's goals and results from earlier trials, and be told of any developments as the study progresses.

Koski favors a more centralized system of third-party review. Currently, all research centers that conduct clinical trials must have institutional review boards, or IRBs, that oversee a study to ensure it follows standard protections established for human research. The boards are generally made up of volunteers from the institution.

The system leads to redundancies, especially in cases where many different institutions are involved in a single trial, Koski said. Rather than having IRBs from every institution review the same study, a single IRB could oversee the entire trial.

He also supports a voluntary accreditation system for IRBs that would encourage them to go beyond what is legally mandated and strive for a standard of excellence. And he believes separate boards should be established to review potential conflicts of interest, monitor trials for any safety concerns, and watch for any violations of protocol.

Koski's office and industry leaders disagree on relatively few points. One key point of dissension, however, is in dealing with financial conflicts. Genentech's Wagner supports full disclosure of all potential conflicts - financial or otherwise - to IRB members and study volunteers but does not believe such relationships should automatically disqualify a researcher from participating in a study. Koski believes there should be a presumption against a scientist who stands to gain significantly from the success of a drug being involved in its development.

''No matter how well intended people are, bias creeps in,'' he said.

At the panel discussion Monday, Genentech's Wagner, the sole industry representative, was the most vocal in support of strong federal legislation. Companies navigate an increasingly layered system to run clinical trials, she said. The industry is regulated primarily by the Food and Drug Administration, while many of the academic researchers with whom the industry collaborates on trials are regulated by Koski's office. Yet other laws regulate the privacy of patient information in clinical trials.

Many states also have their own sets of regulations that companies must meet. And when working with 50 different academic research centers, Wagner said, companies are often left negotiating the details of informed consent and study protocols with 50 different IRBs - a task that greatly adds to the time and complexity of managing clinical trials.

''It's adding burdens and costs to the system that don't necessarily add to the safety of patients,'' she said.

Wagner said the industry wants one set of rules to extend to all researchers - regardless of whether they are funded by industry or government and regardless of the state in which they are conducting research. She would like to see a move toward a more centralized review process, encouraging institutions to work with a single independent IRB that oversees and monitors large, multisite trials.

''Strong federal legislation is the only way to get that kind of unified system,'' Wagner said, ''because it's the only way to preempt state law.''

Wagner believes that a bill, proposed by US Representatives Diana DeGette, Democrat of Colorado, and Jim Greenwood, Republican of Pennsylvania, to extend protections under federal law to all human-research subjects would be a giant step in the right direction. US Senator Edward M. Kennedy also is drafting a bill to increase protections for people who volunteer for clinical trials.

''Right now, there is growing public distrust,'' said Ken Getz, president of CenterWatch. ''If some of the regulations being considered are passed, it may be another way for industry and legislators to signal that they are doing as much as they can.''

Audits of both federally funded and industry-sponsored clinical research have found that the most common problems are failing to comply with study protocols, falsifying data, and failing to properly comply with informed-consent rules. But, Getz said, historically less than 3 percent of those cases are serious violations that put patients at significant risk.

Nonetheless, Getz said, patients need to feel confident they are being protected. They need to be treated as partners in the research, rather than as subjects of study. And critical to that endeavor is to educate people about the importance of clinical research for medical progress as well as to be brutally honest about the risks involved.

Although Wagner believes that streamlining clinical trials could reduce their time and costs, Getz said other measures may increase their cost and length, driving up prescription drug prices. But he believes the trade-off is worth it. Better research means better protection for volunteers in studies, and also for the public at large because the more that is learned in clinical trials, the better equipped regulators and physicians are to decide whether to approve or prescribe a drug.

''At the end of the day, what matters most is the protection of patients and study volunteers,'' Getz said. ''It benefits all of us if research is safer and has better oversight.''

Should you enroll in a clinical trial? New book offers guidance

By Carol Cruzan Morton, Globe Correspondent, 5/14/2002

Clinical trials attract sick people seeking novel lifesaving therapies and healthy volunteers with an altruistic desire to help the sick. After all, clinical trials are the source of the latest breakthrough miracles and incremental advances in medicine - from new drugs that treat AIDS to innovative chemicals to tame cancer.

Despite their hopes, most of the estimated 2 million sick and healthy volunteers in clinical trials will be given drugs that eventually flunk their tests. For one in 30 volunteers, experimental treatments will cause serious side effects that may be fatal, life-threatening, permanently disabling, or result in hospitalization.

Last year, for example, Ellen Roches, a healthy volunteer, died in an asthma study under the supervision of Johns Hopkins Medical Institutions in Baltimore. Three years ago, Jesse Gelsinger, 18, died in a gene-transfer experiment at the University of Pennsylvania.

What you don't know about clinical trials can hurt you, say the authors of a new book, ''Informed Consent: The Consumer's Guide to Volunteering for Clinical Trials.'' The book comes from the Boston-based CenterWatch, which publishes newsletters for the clinical trials industry and for volunteers who participate as research subjects.

''In some cases, clinical trials may offer access to treatments that can dramatically improve and extend lives of people suffering from severe and chronic illnesses,'' write coauthors Ken Getz and Deborah Borfitz. ''But along with promise and hope, there are also numerous risks.''

More than 120 new remedies each year emerge from rigorous tests, thanks to thousands of volunteers during the average 15-year testing cycle for each drug, the authors say. Some people volunteer in hopes of a few more years of life. Others, such as Gelsinger, want to help scientists understand and treat others with similar conditions. One in five drugs is ultimately approved by federal regulators. Side effects suffered by research volunteers will be described in the packaging material that comes with the drug - if it makes it all the way through testing.

For some people with advanced cancer, heart disease and AIDS, the risks of participating in a clinical trial may be better than the worse alternative of imminent death after the failure of inadequate but tested treatments. But healthy people also volunteer for clinical trials that prove risky.

Two recent deaths, as well as allegations that financial conflicts of interest have caused ethical lapses, have prompted some reforms in agencies and institutions. Senator Edward M. Kennedy and US Representative Diana DeGette, a Democrat from Colorado, are circulating drafts of legislation to better inform potential volunteers about risks, to reduce financial conflicts of interest, to expand the scope of protection beyond federally funded research, and to improve the institutional oversight of research trials.

Even with proposed reforms, the key safety feature in clinical trials rests with the individual judgment of a research volunteer.

The most important principle in well-established international standards in clinical trials is ''informed consent based on full disclosure of potential risks and benefits,'' said former Health and Human Services Secretary Donna Shalala.

''While everyone focuses on the deaths, it is the wrong focus,'' said Leonard Glanz, professor of health law at Boston University's School of Public Health. ''People need to understand that research is not treatment. Research is designed to find out if something is a treatment. People in research projects are subjects, not patients. They are there to benefit the research. It's not like a doctor-patient relationship.''

Many people, however, don't see it that way. In a recent survey of people who had volunteered for a clinical trial within the last six months, CenterWatch found that 74 percent still knew ''little to nothing'' about the clinical trial industry, and nearly one-third said they didn't understand all the risks.

Scientists conduct experiments on people to answer five basic questions about new drugs or devices, say the book's authors. Is it safe? Is it effective? Is it better than or equivalent to other available treatments? What side effects does it produce? What dosage works best?

Clinical trials may test different combinations of old drugs, or they may test new ideas from a research laboratory. Human testing begins after promising tests in animals. Some volunteers in clinical trials may receive toxic doses of a drug. Others may be in a comparison arm of the study that doesn't receive the experimental drug. About 2 percent of Americans participate in clinical research, according to the book, but the figure jumps to 6 percent among people who have severe, chronic illnesses.

The riskiest testing happens in the first two rounds of testing, known as phase I and phase II, where scientists are still figuring out how much of a drug to give, what side effects it might cause, and whether it shows any sign of doing what it's supposed to be doing. By the third round of testing, two-thirds of the drugs in testing have already flunked out, and scientists have some idea about how they might work and what problems they might cause. Phase III studies involve several hundred to several thousand patients, or about six out of every 10 people who volunteer for experimental treatments.

''When it comes to study risk, in particular, you may have to dig for the full story,'' Getz and Borfitz state in their book. ''FDA's guidelines don't require a drug's complete track record be shared. If you want to know details, such as the number of deaths and serious side effects observed in earlier clinical trials, even if the study drug was not implicated, you have to make a point to request that information.''

After his teenage son, Jesse, died, Paul Gelsinger learned that adverse events in animals and other people were missing from the informed consent document. His son was far from being on the brink of death: Thanks to improved medications for his metabolic disorder, he was asymptomatic at the time he entered the clinical trial aimed eventually at newborns with a more severe form of the same disorder.

As advised in the book, Gelsinger asked about financial ties of the researcher to the company and was told that he was an unpaid consultant. After his son's death, he learned the researcher had a 30 percent vested interest in the company that stood to gain the most from this research and that he received $13.5 million in stock for his share in the company. Gelsinger advocates reform in the system and better informed consent for research volunteers.

George Annas, professor of health law at Boston University School of Public Health, adds another piece of advice missing from the book.

''Your doctor should never do research on you,'' Annas said. ''The patient makes the final go, no-go decision, but they can't make that decision unless they have reasonable information and they understand that research is not therapy. The doctor running the clinical trial is not working for the patient; his loyalty is to the research protocol.''

Source: The Boston Globe

The word on clinical trials There is widespread public interest in taking part in clinical drug trials, but researchers often find it hard to get the word out to potentially interested volunteers.

Radio spots, newspaper advertisements, and television commercials are expensive and don't always clearly convey the message. Postings in hospitals never seem to reach a wide enough audience.

That's why there's CenterWatch, a Website that offers more information on trials in all of the major disease areas than any other on-line destination. The site, based in Boston, enables electronic visitors to research more than 5,000 ongoing trials seeking participants. More than 80,000 individuals - patients and others - log on to the site every month, and site coordinators expect to have counted more than a million total visitors by year's end.

Those numbers aren't too shappy for a site that has yet to celebrate its third birthday. Founded in June 1995, CenterWatch has established a virtual forum through which pharmaceutical companies, contract research organizations, and individual investigators post trials and solicit participants from across the country. Interested individuals can contact the professionals directly, via email, or access telephone numbers and mail addresses to inquire about a trial.

The site organizes information into 20 areas, from gastroenterology to cardiology to emergency medicine. The information is updated three times each week. Thousands of industry-sponsored trials are conducted in the United States every year, says Kenneth Getz, the site's publisher. "CenterWatch views each of these trials as an opportunity for patients to gain access to promising new techniques. [We] really keep [our] finger on the pulse of new clinical trial developments," he said.

It is still free to electronic visitors, but CenterWatch charges health professionals a low monthly rate to post their trials. Because of this arrangement, it does not necessarily list every trial that might interest a visitor. Site manager Ann Kennon says the fees, even though low, sometimes deter health professionals from organizations with little money to establish an Internet connection or to register online. In these cases, she adds, those studies don't get listed.

More than 25 percent of the visitors are cancer patients, while a significant number of others are seeking information on diabetes, heart disease, AIDS, and skin disease. Visitors log on from every corner of the country, Kennon says, and nearly half of them have been recently diagnosed with an illness.

Of the site's highpoints, perhaps the best is its e-mail notification service. Electronic visitors can register to receive an e-mail every time a new trial is entered in a specified field. More than 15,000 users have joined the e-mail notification program in the last year.

The site is also organized fairly well. There's other information, as well: background information on clinical research, links to other important health-related sites and a list of new drugs approved by the Food and Drug Administration.

On the downside, however, finding the information CenterWatch offers can be frustrating for some users. The site lacks a search engine; to search it, visitors must scroll through endless pages of trial categories. And because of the length of the trial lists, some of the topic pages are impossible to download in a timely manner, making the site's most useful portion difficult for visitors with slower modems to navigate.

CenterWatch is attracting some impressive clients. For example, the National Institutes of Health currently is advertising for volunteers for "ALLHAT," a study on treatment of hypertension. Kennon says two of her goals for next year are to make the site more accessible for patients and cheaper for professionals to list trials. She expects to have a site redesign by the end of the year.

The Boston Globe, Monday June 1, 1998