Speeches & Testimony

Senate Help Committe
Human Research Subject
Written Comments for the Hearing Record

Abbey S. Meyers
President
National Organization for Rare Disorders (NORD)
55 Kenosia Avenue
Danbury, Ct 06813-1968
Phone: (203) 746-6518
Fax: (203) 746-8728
Email: orphan@rarediseases.org

May 14, 2002

Mr. Chairman, Members of the Committee, we are grateful that you are examining the human research subject protection system in the United States. Senator Kennedy was responsible for the last major revision of patient protection legislation in the United States, and it is appropriate at this critical juncture in history Senator Kennedy will again lend his wisdom to the restructure of a system that needs reform. Research relies on public trust, and public trust has greatly eroded in the wake of recent revelations.

It is time for the federal government to enhance human research protection rules because the American research enterprise has greatly changed, biomedical technology has profoundly changed, and in light of highly publicized recent research tragedies, public trust in our current human protection system has been seriously undermined. In fact, the federal law that protects the welfare of animals in research is far superior to our nation’s patchwork of human protection rules. It is time to protect people at least as much as we protect animals in research.

I am Abbey Meyers, President of the National Organization for Rare Disorders (NORD). I am a former member of the National Commission on Orphan Diseases (1986-89), the NIH Human Gene Therapy Subcommittee (1989-92), the NIH Recombinant DNA Advisory Committee (RAC) (1993-96), the FDA Biological Response Modifiers Committee (1995-99), and I am a current member of the HHS National Human Research Protection Advisory Committee (NHRPAC). I am speaking now on behalf of NORD, and not on behalf of NHRPAC. Most importantly, I am speaking as a person who has participated in medical research, along with my three children who have a rare genetic disease. I can tell you from personal experience that public trust in the human research protection system is critically important to the future of research. Without confidence that the welfare of research volunteers overrides the interests of investigators and institutions, patients will not volunteer for research, and the system will implode.

The Evolution of Human Protection Rules

The history of human research protection rules began with Hippocrates who advised physicians, “First, do no harm.” Unfortunately, despite the Hippocratic oath taken by countless generations of physicians, increasingly rigid rules have evolved as a direct result of serious ethical violations. Many of these ethical lapses were by well-meaning scientists who felt the value of their scientific discoveries outweighed the suffering that would be imposed on individuals. In fact, each major enhancement of human protection rules has been precipitated by serious and tragic research events that were repulsive to the public.

During the past half-century, numerous government committees and commissions have issued recommendations for fine-tuning the rules, but little has actually been done. Some lament that our system is based on local control by Institutional Review Boards (IRBs) which are underfunded, overburdened, understaffed, and riddled with conflicts-of-interest. No government agency knows how many IRBs there are in the United States, nor how many clinical trials there are, how many volunteers are participating in research, how many are hurt each year, nor how many die. Nevertheless, the future of medicine relies on research advances, and it is incumbent on all of us to perfect the system and propel it forward.

Historically, research was done on the poorest and most vulnerable populations (e.g., institutionalized people, prisoners, mentally impaired individuals, etc.). Then, during World War II, there were terrible infractions that shook the civilized world when Nazi physicians pursued blatantly unethical experiments in the name of science. When the allies wanted to put 23 Nazi doctors on trial for war crimes, they defended themselves by claiming the experiments were valid medical “research”. It thus became necessary for the court to create a common-sense code of ethics for judging what “unethical” research is. Those principles became known as “The Nuremberg Code”. The most important principle of the code was the basic tenet that people who participate in research must do so voluntarily; they must not be forced to participate against their will, nor without knowledge of potential risks and benefits.

In 1953, the National Institutes of Health (NIH) issued rules based on The Nuremberg Code requiring all federally-funded research to be independently reviewed by local ethics panels called “Institutional Review Boards” (IRBs), and requiring people who volunteer for clinical research to give their “informed consent”, indicating that they understand the possible risks and benefits of the experiment. Unfortunately, the federal government did not enforce the rules until 1961, and the rules did not apply to privately funded research. Amazingly, even today they do not apply to privately-funded human research.

During the 1960s, stories about horrendous birth defects in Europe led to the discovery that a tranquilizer, Thalidomide, was at fault. The drug was not approved for sale in the United States because FDA had not approved it, but the manufacturer had nevertheless distributed the experimental drug to American doctors for use by patients. The patients were not told that the drug was experimental.

As a result of the Thalidomide tragedy, in 1963 Congress enacted the Kefauver-Harris Amendments to the Food, Drug and Cosmetics Act. The law requires pharmaceutical manufacturers to prove that a drug is safe and effective before it is approved for distribution in the United States. While a drug is being tested, volunteers must be fully informed about the possible risks and benefits of the proposed treatment, and they must give their informed consent before they participate in the experiment. These rules apply to publicly and privately-funded research only if an FDA-regulated product is being studied. Interestingly, in the recent tragic Johns Hopkins asthma study, the investigator did not seek FDA’s permission to use the drug implicated in the patient’s death.

In 1964, newspaper reports about an NIH-funded trial at a Brooklyn, New York hospital shocked the nation. Elderly frail people were being injected with live cancer cells because doctors wanted to monitor the reaction of their immune system. When reporters asked the doctors if they had obtained informed consent from the patients, they insisted that they had. But many of the patients were fully incapacitated by Alzheimer’s disease, and many did not speak English.

Then later in the decade investigative reporters revealed shocking stories about Willowbrook, a New York state institution for people with mental retardation. Even though Willowbrook had an Institutional Review Board, they had allowed a clearly unethical experiment to be pursued by injecting residents with live hepatitis virus. Those people remained contagious for the rest of their lives.

These two New York experiments clearly illustrated that special rules were needed to protect people who are not capable of giving their consent: the frail elderly, people with mental retardation, children, prisoners, etc., were “vulnerable populations” and therefore needed extra protections.

In 1971, the Department of Health, Education and Welfare (DHEW) issued detailed guidance to IRBs for protection of human subjects in research. Then in 1972 the New York Times printed a story that even today represents one of the cruelest medical experiments known. Doctors who wanted to study the natural history of syphilis had tracked African American men from a poor rural area of Alabama, and had denied them treatment even after antibiotics were available to cure the disease. The men were lured to the clinic with promises of free medical care, but they were not treated. The “Tuskegee Experiment” had been going on for 40 years when the Times exposed it.

In response to revelations about the Tuskegee Experiment at Senator Kennedy’s behest, in 1973 Congress attempted to enact a law creating a national research oversight body. There was much opposition and the law failed to pass Congress. Instead, the administration created new human protection regulations to govern all federally funded (not privately-funded) research, and in 1974 Congress passed the National Research Act, which established a National Commission for the Protection of Human Subjects. The Commission pursued an ethical and policy analysis of research related issues. It eventually issued ten reports, the most important of which was the Belmont Report of 1979. This report explained the purpose of bioethical principles and how to apply them to research projects.

The Belmont Report lays out three basic ethical principles: 1) Respect for persons, which requires that people should be treated as autonomous individuals, and that people with diminished autonomy (e.g., vulnerable populations) are entitled to extra protection. 2) Beneficence, meaning that people must be respected for their decisions, and protected from harm. 3) Justice, such as finding fair ways to distribute burdens and benefits. Justice requires that the needy and vulnerable (e.g., welfare recipients, mentally infirm, institutionalized people, minorities, etc.) should not be used for research simply because they are available or can be easily manipulated. Research should never involve groups unlikely to be the direct beneficiaries of the research.

Because of the Belmont Report, the new Department of Health and Human Services (DHHS) issued revised human protection regulations in 1981. It took ten years for all other federal agencies to adopt these rules, which are now known as The Common Rule. The Common Rule is 15 sets of regulations, covering 18 federal agencies that conduct or have responsibility for research involving humans. Privately funded research is not obliged to obey The Common Rule unless the research is carried out in a facility that receives federal funds. If the research involves a product that is regulated by the FDA (e.g., a drug or a medical device), the manufacturer must conform to FDA’s own ethical standards, not The Common Rule. In fact, the FDA has no bioethicists on staff, and they do not police their own human protection rules. They leave it up to commercial sponsors to vouch for the fact they have complied with the rules. The FDA is not even empowered to demand changes to inadequate informed consent documents.

In 1994, another major research scandal was revealed, and this time the federal government was the culprit. Between 1944 and 1973, American soldiers and civilians had been unknowingly exposed to radiation and other dangerous drugs and hazards for Department of Defense research programs. Another federal committee was created: The Advisory Committee on Human Radiation Experiments. In 1994, the Committee recommended that major changes in the Institutional Review Board (IRB) system needed to be made, and that a “National Advisory Group for Human Subject Protection” was needed. This is the concept that Senator Kennedy proposed in 1973, but had been defeated.

In 1995, President Clinton established the National Bioethics Advisory Commission, which issued a series of reports and recommendations about various aspects of research. In December 2000, former HHS Secretary Donna Shalala created the National Human Research Subject Advisory Committee. Despite numerous federal committees and commissions, however, the IRB system has not yet been restructured, and the human research protection system has not been significantly overhauled since 1981. In fact, we do not have a federal law to protect research volunteers; we have many regulations issued by various departments.

Research Today

The substance of biomedical research has changed significantly since 1981. Today most clinical research is pursued simultaneously at several different institutions, instead of just one (multi-site clinical trials). Yet each institution’s IRB has its own unique interpretation of the Common Rule, and they vary widely across the country. It is possible for thousands of patients in the same clinical trial to sign completely different informed consent documents even though they are all participating in the same experiment.

Today there are also many groundbreaking new technologies such as gene therapy, xenotransplantation, cloning, stem cell research, etc., which raise new ethical questions and are very controversial. It has been estimated that as much as 60 percent of clinical research today is being conducted in private doctor’s offices, not federally-funded institutions, and some clinical research is moving overseas to third-world countries where there is little ethical oversight. There are also new questions about conflicts-of-interest because it is not unusual for a scientist today, and/or their institution, to have a patent or to own stock in the company that is sponsoring the research. Does conflict-of-interest compromise the integrity of research data? Can scientists be unbiased if they have a financial interest in the outcome of a study?

The history of bioethics proves that every major improvement of the human protection system has been spurred by a catastrophic violation of basic decency; situations when humans have been treated as objects, not people. Yet our lives depend on the advancements of medical research, and it is wrong to assume that others will volunteer to participate in research from which we will benefit. Ethical scientists who are closely monitored by institutional oversight panels perform the vast majority of research. But current rules are not strong enough to prevent more serious violations from recurring. The fact is we have no comprehensive federal law to protect human research volunteers, but we do have a federal law protecting animals in research. Additionally, the regulations that we do have are aimed at biomedical research, and they do not adequately address social and behavioral research involving humans.

Since the death of 19-year old Jesse Gelsinger in a 1999 gene therapy trial, the field of medical research has been profoundly shaken, and the system of patient protections is being more closely scrutinized than ever before. But any attempt to tighten the rules continues to meet with resistance. For example, both the FDA and the NIH are beginning to understand that the public’s mistrust of controversial new scientific technologies (e.g., gene therapy, xenotransplantation, stem cell research, etc.) is rooted in the secrecy surrounding these experiments, and this “Frankenstein Syndrome” can no longer be tolerated.

Despite the ethical questions raised by the deaths of Jesse Gelsinger at the University of Pennsylvania, and Ellen Roche at Johns Hopkins, appalling violations of ethic rules continue. An astonishing study of lead poisoning in children living in the slums of Baltimore was compared by judges of a Maryland appeals court to the infamous Tuskegee Experiment. In this study, perfectly healthy children were purposely placed in homes with toxic lead levels, and many are now brain damaged. The court called the Johns Hopkins IRB “a non-objective house organ.” Just as we had convinced ourselves that the Tuskegee Experiment could never happen again in America, it did! The basic elements of the experiment were in violation of human protection rules that prohibit exposure of healthy children to more than minimal risks, especially vulnerable children who live in poverty. Yet the IRB endorsed the protocol with no dissention.

How Can Congress Enhance Human Research Protections?

For decades committees and commissions have studied these problems. It is now time for Congress to discard our current patchwork oversight system, and enact a federal law that will ensure the explicit rights of human research volunteers. The disparate rules and regulations that exist today are insufficient to restore trust in the human research protection system. Since the death of Jesse Gelsinger, more and more patients are saying, “Let someone else be the guinea pig”. This mindset threatens the foundation of biomedical research and creates serious obstacles in the path of bringing important scientific discoveries from the laboratory to the bedside of ailing patients.

We fully endorse the recommendations of the National Bioethics Advisory Commission in its May 2001 report, “Ethical and Policy Issues in Research Involving Human Participants.” It is critically important to restore confidence in our human research protection system quickly so that waning public trust will not lead to diminished scientific advancements. We suggest the following principles should be included in federal human subject protection legislation:

1. Two years ago the HHS Office of Human Research Protection (OHRP) was very wisely moved from NIH to the Department of HHS, but we believe it should be made a totally independent agency with regulatory authority over all human research programs, both medical and non-medical, federally funded and privately funded. Currently, 18 federal agencies are signatories to the Common Rule, but at least 69 other federal departments that are responsible for conducting or supporting human research programs are NOT signatories to the Common Rule, and are not under the authority of HHS. OHRP must be given sufficient resources and authority to police all publicly AND privately funded human research in the United States.
   
   
2. There should be a single set of human protection rules that all researchers must comply with, with minimal room for misinterpretation. Non-medical research (e.g., social, anthropological and behavioral research) should be reviewed by non-medical experts. Today many universities require all research to go through IRBs that are composed of biomedical scientists who are not experts in the appropriate discipline. Thus, federal law should ensure that research protocols are reviewed by IRB members who are knowledgeable about the discipline and technology that they review.
   
   
3. NBAC has suggested, and we fervently endorse, a formula for composition of IRBs that stipulates the majority of IRB members must not be employees of the institution. A basic weakness of existing IRBs is that they have evolved into institutional protection bodies instead of a patient protection oversight system. Furthermore, IRBs should be required by law to call in experts for review of protocols for unusual diseases and new technologies. I have always wondered, for example, how an IRB with no expertise in gene therapy, can review and approve a gene therapy experiment. NBAC proposes at least 25 percent of IRB members should be non-scientists, and another 25 percent should represent the “perspective of research participants”.
   
   
4. All IRB members should be required to participate in ethics training and should be certified to participate in IRB deliberations. IRBs have no such requirements at the current time, and professional societies are beginning to develop certification systems.
   
   
5. Most importantly, our current research protection system does not work adequately because there are no realistic penalties for non-compliance. The government’s only remedy is to shut down research at the entire research facility, which punishes the innocent as well as the guilty. In fact, it is the patients who suffer most from this remedy. OHRP should be given authority to impose civil monetary penalties for scientists and institutions, and possibly prison for the most egregious violations of the law.
   
   
6. Conflicts of interest, by researchers and by universities, must be addressed in the new law. We suggest that such conflicts should be revealed to research volunteers in informed consent documents. Additionally, institutions should create conflict-of-interest panels to determine whether specific conflicts may jeopardize the validity of the study.
   
   
7. Adverse events in clinical trials should be reported to a single government agency and shared with other investigators so they will not repeat the same mistakes in similar protocols.

Mr. Chairman, the most important goal of a new human protection law should be to change the mindset of the research enterprise and restore its integrity. Right now too many scientists and universities see the human protection system simply as a logjam of red tape, and IRBs have become liability protection watchdogs for the institutions themselves. They see human protection oversight as a barrier to research, not a safeguard. In the 21st century it is incredible that a study like the Baltimore lead paint study would be approved by an IRB when they knew that at least some of the healthy children would become permanently brain damaged. Instead of safeguards getting better, they appear to be getting worse.

The recommendations of the National Bioethics Advisory Commission (NBAC) echo the recommendations of numerous other committees and commissions over the past 50 years. We do not need any more committees to study the matter and provide reports that collect dust on a government shelf. We need action now because the public has lost its trust in the system, and without trust research will slow to a crawl. Patients are afraid that they will not be protected, and they will have no rights if they are harmed in a research study. Institutional oversight is inadequate, conflict-of-interest is rampant, and FDA can only respond after a violation occurs rather than doing something to prevent new tragedies. Professional medical societies say they will create their own voluntary standards, and they do not want more regulation. But it will be impossible for them to police themselves. OHRP is underfunded and it doesn’t have adequate resources nor authority to do its job. We must have an independent federal human research protection office.

Thank you, Mr. Chairman.

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