Although there are cases where things have gone wrong during clinical trials, the majority of clinical trials are conducted safely and ethically. There are many professionals and procedures in place to ensure that your rights are protected and that the risk of participation is minimized. However, some violations still occur. The responsibilities of research center personnel, the institutional review board (IRB) and the study sponsor are mandated by federal guidelines. A review of these responsibilities shows a number of checks and balances designed to protect study volunteers:
Study Coordinator responsibilities include among other things:
- Managing daily study tasks
- Educating research center personnel about study requirements
- Submitting documents to the IRB
- Screening and enrolling study volunteers
- Collecting data and recording information on the study report forms
- Coordinating volunteer visits
- Following up and periodically touching base with study volunteers
- Storing, maintaining and dispensing investigational drugs
- Collecting and processing lab samples
- Maintaining volunteer and data confidentiality
- Communicating with the investigator, sponsor and study monitor
Investigator responsibilities include among other things:
- Instructing and supervising staff compliance with the study protocol
- Submitting protocol, amendments, consent forms and advertising material to the IRB
- Obtaining IRB approval
- Ensuring that volunteers meet eligibility criteria
- Adhering to study randomization and blinding requirements
- Maintaining patient case records and ensuring their completion
- Ensuring that data are complete and accurate
- Responding to data queries
- Documenting, conducting and delegating study tasks
- Notifying the IRB of serious adverse events (SAEs)
- Providing periodic progress reports to the IRB
IRB responsibilities include among other things:
- Ensuring that study risks to volunteers are minimized and reasonable in relation to the anticipated benefits
- Reviewing, approving/rejecting research studies and related activities
- Requiring modification of research activities
- Ensuring and documenting that volunteers have provided their informed consent
- Providing investigators and research center personnel with written documentation of approval, disapproval and modifications of research activities
- Ensuring that IRB committee membership complies with regulations
- Maintaining complete records of IRB activities (e.g., meeting minutes, correspondences with research center personnel and statements of significant new study findings communicated to volunteers during the study)
Sponsor responsibilities include among other things:
- Selecting qualified investigators and research centers
- Providing investigators and study staff with information to conduct the protocol
- Ensuring proper and effective study monitoring
- Ensuring that the study follows the protocol and plans in the Investigational New Drug (IND) application
- Providing prompt information about serious adverse events to the FDA and participating investigators
- Disclosing to the FDA the financial interests of participating investigators
Most offenses are minor, so they result in a warning letter from the FDA’s Division of Scientific Investigations, which instructs them to take certain corrective actions. The FDA then monitors research investigators to make sure the proper corrective steps were implemented. Most of the 100 or so complaints the FDA investigates each year result from careless – though potentially dangerous – mistakes. Every last pill could not be accounted for, or a 72-year-old is enrolled in a study when the cut off age is 69. The opposite is also true – some investigations will not turn up even a single minor violation.
Fewer than 3% of unsolicited FDA audits uncover serious violations. However, in cases where inspections were solicited due to complaints filed against research centers, more than one-quarter of them received serious violations of good clinical practices (GCPs). These violations included falsification of records or the failure to report adverse events. When serious violations are cited, the FDA must suspend and even consider disqualifying the investigator from conducting future research. One or two investigators are actually disqualified each year and a few others “voluntarily” remove themselves from conducting clinical research. Sometimes, investigators instead consent to having restrictions placed on how they conduct future studies – to perform no more than two studies simultaneously, for example, or to participate in trials only as a sub-investigator.
Today, more than 50,000 clinical investigators are conducting at least one clinical trial every year. Since 1964, the FDA has disqualified 100 investigators for failing to comply with Good Clinical Practice guidelines. Another 29 have had restrictions placed on them by consent. Twenty have been prosecuted criminally. As a result of more “for-cause” – or solicited – inspections conducted annually by the FDA, the agency is finding more serious problems are being uncovered now than in the past. Given the large increase in the number of investigators and trials being conducted today, there are proportionately fewer violations than in the past.
The Office for Human Research Protections (OHRP) also uncovers a handful of serious violations from the more than 100 complaints it receives each year alleging misconduct by federally funded university-affiliated institutions. The percentage is small compared to the number of clinical trials conducted at these institutions. As many as 3,000 protocols are conducted annually at each of our nation’s top 130 academic medical centers. Permanent suspension of studies or federal funding because of wrongdoing is rare. But when it does happen, it is quite serious.
In situations where you feel that your safety and ethical treatment are in jeopardy, your best guide is the informed consent form. It is your bill of rights. If you feel, for example, that you have been subjected to unreasonable risk, that your concerns and wishes are not being respected or that you have witnessed unethical behavior, you need to contact the IRB immediately. A contact number for the IRB or patient advocate is provided with your informed consent form. The study staff can also provide this information for you at any time.
If you are not satisfied after talking with your IRB or patient advocate, or if it appears that the IRB and the study staff are unable to help, then you need to file a complaint directly with the FDA or OHRP.
To lodge a complaint with the FDA
For studies of biologics, including gene therapy and vaccine studies, you should contact the Division of Communication and Consumer Affairs in the Center for Biologics Evaluation and Research.
- Telephone (301) 827-2000
- Fax (301) 827-3843
For drug studies, the FDA contact is the Division of Scientific Investigations in the Office of Medical Policy at the Center for Drug Evaluation and Research.
- Telephone (301) 594-0020
- Fax (301) 594-1204
For medical device studies, the contact is the Division of Bioresearch Monitoring in the Office of Compliance at the Center for Devices and Radiological Health.
- Telephone (301) 594-4718
- Fax (301) 594-4731
To lodge a complaint with the Office of Human Research Protection
- Telephone (301) 496-7005
- Mailing Address
Office for Human Research Protections
Department of Health and Human Services
The Tower Building
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
- Email ohrp@osophs.dhhs.gov
You might also try the Office of Inspector General, Department of Health and Human Services (HHS).
- Telephone (202) 619-0257 or (877) 696-6775 (toll-free)
- Mailing Address
The U.S. Department of Health and Human Services
200 Independence Avenue, SW
Washington, D.C. 20201
It usually does not make sense to file a complaint with the pharmaceutical company sponsoring the research, although you can try. Most pharmaceutical companies have limited resources established to handle direct contact with study volunteers. This is changing, however. A growing number of companies – particularly the largest ones – do offer toll-free hotlines that you can call to report an emergency. We have provided contact information for pharmaceutical and biotechnology companies in the appendix.
Self-help and various advocacy groups – health and medical associations – may be of some assistance in handling your reports and complaints. Associations that set national and local health policies may also be good contacts. These groups may be better equipped to help you locate and choose clinical trials than to help you deal with misconduct issues. Still, they can help you better understand your rights as a volunteer, and they may help you contact other more helpful organizations and institutions. A list of some of these associations and groups are also included in the appendix.
It’s impossible to test the safety of a drug in people with every conceivable combination of disease, drug interaction, age and genetic predisposition. Therefore, some general, and all long-term, side effects aren’t discovered until after a drug has been on the market and used by millions.
Physicians, pharmacists and even patients themselves routinely report adverse events to the FDA through an ongoing drug-safety program known as MedWatch. A drug causing an adverse event in sufficient frequency, relative to how often it’s prescribed, will usually have its label changed so that doctors are informed about the new information and about what, if anything, they can do to minimize the risk. Many safety-related labeling changes are made every year. Side effects are dangerous enough to take two or three prescription drugs off the market each year. There are a number of web sites that post MedWatch information online for you to refer to.
Although this may not address immediate concerns about safety and ethical treatment, you can play a more active role in the future by joining or participating in an IRB. This experience will help you increase your network of support. Motivated parents – especially those who have had a child in a clinical trial – make ideal IRB members.
Being involved on an IRB is no small task. Members often have to do a lot of reading and attend numerous meetings. It depends on the IRB. Some have a fixed number of members who look over, and comment on, every protocol. Others have a pool of members from which they draw, based on their area of interest and expertise.
CenterWatch estimates that there are approximately 3,000 IRBs operating within the United States that oversee government- and industry-funded clinical trials. Boards are established, trained and licensed differently from place to place. The OHRP offers general IRB training that focuses on research ethics (http://ohrp.osophs.dhhs.gov).
Steve Hirschfeld, M.D., Ph.D., medical officer with the FDA, said his hope is that people will start demanding quality in clinical trials as they do in most everything else – including their automobiles, food and regular medical care. Joining an IRB is a good starting point. Even people who are completely untrained in science and statistics can make substantial contributions to discussions about studies after only a few hours of training, he said.
The incidence of misconduct and noncompliance is rare. When these acts are uncovered, the government and industry typically respond by modifying practices and adding new policies and procedures.
There are a lot of pressures placed on researchers today to enroll patients quickly, to conduct clinical trials faster, to review and approve study protocols in less time, and to compete against other research centers for new studies from industry and government study sponsors. Some research professionals are tempted, for example, by the potential to increase their salaries by doing more and larger clinical trials. Despite these pressures and temptations, history has shown that a very small number of investigators, coordinators and IRB personnel have been led astray. What follows are a few examples of their misconduct that have helped to shape new policies and legislation.
In 1999, California physician Robert Fiddes was disqualified as a clinical investigator and sent to prison for 15 months after he and two of his study coordinators conspired to falsify drug trial results by “inventing” patients and medical data. He also lost his medical license. The whistleblower was one of Dr. Fiddes’ employees.
Similarly, a disgruntled employee tipped off the Medical College of Georgia in Augusta that Drs. Richard Borison and Bruce Diamond – a prominent psychiatrist and pharmacologist – were secretly conducting schizophrenia drug trials for eight years using university resources and pocketing the proceeds. They “coaxed” psychotic patients into trials with money and cigarettes, but gave scant attention to their care. Untrained staff took blood draws and adjusted doses of study drugs. The two were finally put behind bars in 1997, fined $125,000 a piece, and ordered to pay millions of dollars back to the college.
Jesse Gelsinger’s Story
One of the largest concerns today relates to conflicts of interest. Investigators and universities that have an economic interest in the drug they’re investigating tend to be less vigilant – consciously or unconsciously – about patient safety and ethical treatment. This is considered one of the many factors associated with the death of 18-year-old Jesse Gelsinger in a 1999 gene therapy experiment at the University of Pennsylvania. Jesse had a massive and fatal immune system reaction to a common-cold virus used to deliver a particular gene to his liver. (See Chapter Five, under “The Most Responsible Party” for more on financial conflicts of interest in research.)
Jesse had an inherited metabolic disorder that had landed him in a coma several times. But he was doing relatively well on medications before entering the trial. The university and principal investigator wanted to test a treatment for newborn babies, but they first needed adults to participate in a clinical trial focusing on how suitable the common-cold virus was for gene transport delivery. They also stood to profit if the drug worked. But the Gelsinger family was not informed about this conflict of interest – or all of the drug’s dangers. Questions were raised later about whether Jesse fit the inclusion criteria and even whether federal regulators were notified of adverse events during earlier studies of the experimental intervention.
A subsequent investigation by the FDA revealed that established safety rules were not followed and that the study should have ended months earlier than it did. It ordered a halt to nine clinical research projects at the university’s Institute of Human Gene Therapy. The family ultimately sued and won an out-of-court settlement. The university wrote a letter of apology to Jesse’s family and was determined thereafter to make itself a model for human subject protection.
“Jesse just wanted to help,” said his father, Paul. “There was nothing in it for him – no money and no treatment that was even applicable to him. His heart was totally in this, and it really impressed me. It was his chance to make a difference. When he died, I tried to adopt some of the heart he had and befriended the doctors. They were not bad men. They had simply become blind to the real purpose of what they were doing.”
It was only when he became aware of lapses in the protocol that he sued. “Litigation was the only way to get their attention. The clinical trial should never have taken place,” said Gelsinger. “It was too dangerous and of no benefit to those who participated.”
Perhaps most disturbing, said Gelsinger, is that Jesse would probably still be alive today if a gene therapy information network had been set up. The FDA and National Institutes of Health (NIH) were discussing the idea back in 1995 but later dropped it. The reason, an FDA official confided in him, was because his supervisors “answered to industry.” And industry fears that sharing information – including adverse events and deaths associated with certain types of trials – will cost them their competitive edge.
After examining close to 100 other gene therapy protocols, the FDA determined that gene therapy trials are no better or worse than standard drug trials in complying with federal research rules. “What happened in the Gelsinger case, and other serious cases we’ve had, is that the system was compromised in more than one area,” commented David Lepay, the FDA’s senior advisor for clinical science. Of greatest concern are uninformed IRBs, inadequate adverse event reporting and clinical investigators who double as study sponsors and thus conduct trials shy of a critical “control point.” Education, and a special monitoring unit, may present at least a partial solution. Integrity in the doctor-patient relationship – something regulators can’t control – also has to be there.
Another Case of Conflict of Interest
Allegations similar to those in the Gelsinger case have been reported at other universities and research centers since Jesse’s death. These include an alleged breach of trust by the Fred Hutchinson Cancer Research Center, a top bone marrow transplant center in Seattle. The center’s principal investigators – including a Nobel Prize winner – received consulting fees from the firm producing the drug for leukemia trials conducted there in the 1980s and 1990s. The center was given shares of stock in the company and rights to study drugs owned by the company for 20 years. Nearly all of the study’s 82 participants have since died. A quarter of them would still be alive, family members believe, had they received an alternative therapy. But the doctors never fully informed them about the dangers of the experimental drug or other available treatments, they say. So they’ve filed a lawsuit against the center.
The “whistleblower,” in this case, was a member of the research center’s IRB. An independent review of patient protection practices, coordinated by the Hutchinson Center, suggested a host of changes be made. One major recommendation was that all individuals involved in human subject trials be prohibited from having a financial interest in for-profit corporations that may benefit from the result of such trials.
There is now growing concern among regulators, professionals and the public that financial conflict of interest – including stock ownership in the sponsoring drug company – are biasing the way studies are designed and conducted. There is also growing concern that conflicts of interest are biasing the way study findings are written up in prestigious medical journals. These kinds of influences are potentially harmful both to human research subjects and those who use the drugs once they’re approved for sale. The U.S. General Accounting Office, in its November 2001 report on financial conflicts of interest in research, found that editors of major medical journals were concerned about the “competitive economic environment” in which some clinical research is conceived and conducted. In response, the International Committee of Medical Journal Editors has “revised and strengthened” the section of publication ethics in the reference that many medical journals use as the basis for their editorial policies. As part of the revised reporting requirements, authors will need to disclose details of their own and the sponsor’s role in the study.
Another Recent Case Involving Misconduct
Participants in a clinical trial for a melanoma vaccine are suing the IRB at the University of Oklahoma Health Sciences Center for failure to adequately protect them. The lawsuit alleges that the IRB was negligent in its duties, including stopping the center from conducting the trial. The IRB is faulted for not reviewing the conduct of the trial, the informed consent documents that understated risks to subjects and the recruitment advertisements that falsely represented the vaccine as a “cure for cancer.” When the trial closed prematurely in the spring of 2000, the IRB permitted researchers to tell participants that the reason was a shortage of the vaccine rather than safety violations discovered by the FDA. The university dismissed everyone involved in the alleged wrongdoing. The suspension has been lifted.
In a report issued in 1998, the inspector general of the U.S. Department of Health and Human Services concluded that many IRBs were operating over capacity. Following that report, OHRP has suspended research programs at a number of institutions. In 1999, it briefly shut down all 2,000 medical experiments at Duke University because of safety concerns – including inadequate informed consent procedures. In recent years, research has also been temporarily suspended at a number of university-affiliated sites because of human subject safety concerns. Violations have been made across several areas including informed consent noncompliance, poor record keeping, and poor reporting of serious adverse events.
One of the most recent suspensions was at Johns Hopkins University School of Medicine and its affiliated institutions following the death of Ellen Roche, a healthy 24-year-old woman, during an asthma experiment. She died of adult respiratory distress syndrome not long after being given an inhaled dosage of a non-marketed drug known as hexamethonium. The principal investigator said he could find no recent articles in the medical literature associating the drug with severe pulmonary disease, and no articles at all connecting it to pulmonary toxicity when delivered by inhalation. And researchers on the 1978 study attesting to the drug’s safety failed to report that two of five volunteers in the study became sick.
An OHRP investigation found that Johns Hopkins’ IRBs weren’t providing adequate review of many new research programs and, when they did, the deliberations included board members with financial conflicts of interest. The OHRP briefly took away Johns Hopkins’ Multiple Project Assurance – the permit needed to conduct federally funded research that holds institutions responsible for all trials involving human participants. Previously enrolled subjects were allowed to continue in a trial only if it was in their best interests. After four days, with a new plan in place to correct deficiencies, all research in which there was no more than a minimal risk to volunteers was allowed to resume.
Regulatory scrutiny of Johns Hopkins has changed the clinical trial process there in several potentially significant ways. Informed consent documents have been simplified and better cover key points. IRBs seek to be more ethnically diverse and have been tasked with more closely scrutinizing studies that don’t involve the FDA. Investigators are also routinely reminded that changes in study protocols require IRB review and approval and that unanticipated problems involving risks to subjects must be promptly reported.
Reform is not always prompted by a complete suspension of research. An OHRP investigation, for example, led the University of Arkansas and Arkansas Children’s Hospital to expand its IRB staff and require its investigators to be educated about their responsibilities to protect the safety of study volunteers. The move followed the death of a 3-year-old boy who had been placed in the wrong arm of a kidney cancer trial.
Other academic institutions and federal research agencies have undertaken similar reforms when OHRP has investigated alleged violations or suspended trials due to poor investigator compliance or IRB judgment.
Citizens for Responsible Care and Research advocates that 51% of IRB membership come from – and be selected by someone – outside research institutions. Gelsinger proposes that the NIH establish a user-fee program to fund the establishment of IRBs independent of institutional influence.
Unintended harm might sometimes occur from a drug long after it has been approved for sale on the open market. The incidence of these occurrences is extremely rare. Recently, the FDA shelved the popular cholesterol-lowering drug Baycol (cerivastatin) after linking it to 31 deaths in the United States from a rare muscle-destroying side effect. Volunteers involved in clinical trials for the popular diet pill “fen-phen” were informed years after the trials ended, and the drug had been prescribed to more than 7 million patients, that it was causing heart and lung problems in some patients who took it. By then, the drug had caused problems in 45,000 patients and approximately 300 deaths. People who took the drug and survived were compensated, but the damage to their health was permanent.
Many of these cases show what can happen when things go wrong. Every accident and death is significant, but the likelihood of their occurring is rare. Recent responses by regulatory agencies, sponsor companies and research centers suggest that measures are being taken to help prevent these accidents from happening again. For example, during 2000 and 2001, institutional and independent IRBs have been implementing initiatives designed to improve IRB effectiveness. These initiatives involve increasing IRB headcount, creating toll-free numbers for volunteers, providing more training and education and improving standard operating procedures.
Some suggested steps that you can take to better protect yourself
- Ask who wrote the study protocol and what qualified that person to do so.
- Call the IRB to learn about how much time was spent reviewing the study protocol and what specific areas, if any, gave members cause for discussion or concern.
- Find out if there is or has been professional debate about the risks associated with the study drug. If so, ask for referrals to medical publications where these risks are discussed.
- Request that the study staff speak to you in plain English (or Spanish, French, sign language, etc.) – or find someone who can.
- Quiz the researcher and study coordinator about how many adverse events and deaths have been reported during trials of this study drug – whether or not they were actually attributed to the drug. If they don’t know, call the IRB. If the IRB doesn’t know, call the pharmaceutical company.
- Ask the researchers if they would advise you to enroll in the trial if you were a member of their family.
- Gather as much information as you can from published reports and news coverage about your study medication.
- If possible, go to another research center conducting the same clinical trial. Go through the same set of questions and see if you get the same answers. Seek explanations for inconsistencies.
- Share everything you learned with your family doctor and other friends and family within your support network before enrolling.
The danger of sharing these examples of misconduct is that they can increase your fears and anxieties about participating in clinical trials. But, the danger of not sharing these examples is more serious. They illustrate the worst cases and the responses they prompted from the government, the public, academic institutions and from industry. This chapter is intended to help you avoid these worst case situations.
As in all things, knowledge is power. Whereas reading this chapter, or this book, is no guarantee that you will be protected from all the potential risks associated with a clinical trial, reading it does give you the knowledge and the power to recognize when your rights and your health are at risk and to take steps to protect yourself from these risks.
Next Chapter: Finding Clinical Trials
Introduction