Abstract Research disasters have been noted for years. In the early years, the reasons for these disasters was that there were no regulations governing the protection of human beings; and there were no guidelines for safety and efficacy of a new medication or treatment prior to the use in humans. Now regulations and guidelines are in effect for the protection of human subjects. These guidelines and regulations also protect the researchers. These regulations have enabled the researchers to further scientific knowledge of diseases and the etiology, along with the bioavailability, toxicology, and pharmacology of the new medication or treatment.
Even with all of these regulations and guidelines, still researchers perform unethical research on human subjects. This could be attributed to several factors: One is the financial gain; second, is the need to be the best; and third, the professional and academic pressure put on the researchers. Although there are these pressures, the research subject should still be aware of the research at hand and the qualifications of the researchers. Clinical Research Past and Present Imagine living in the early twentieth century and suffering from chronic headaches.
A physician suggests trying something different, a medication not approved by the Food and Drug Administration (FDA) for chronic headaches. The medication is taken at the physician’s request and the result is death. This kind of pre-clinical research actually did happen and still does today. There are regulations today that govern clinical research in humans because of this type of disregard for human life. These regulations enable healthcare providers to enhance scientific development and to minimize risks involved with participation in a clinical research trial.
The need for current and accurate information concerning the proper conduct of clinical research has never been greater than it is today. Researchers are aware of the vulnerability of the data supporting research trials today; this is why properly conducted randomized clinical trials have profound effects on the advancement of medicine. Research involving human patients can be performed in unethical manners. More importantly, if it is not conducted under stringent standards there is a potential for criminal deviations.
That is why there is a need for the potential research subject to select ethical sites to ensure their regard for safety and moral conduct. History of Clinical Research In the year 1780, Benjamin Franklin said, (Shryock-1947) “The rapid true science now makes occasion, my regretting sometimes that I was born so soon. It is impossible to imagine the height to which maybe carried, in a thousand years, the power of man over matter all diseases maybe prevented or cured, not even expecting even that of old age, and our lives lengthened at pleasure beyond the anti-diluvium standard. “
The history of medical science in the United States falls into four epochs; the first era began early in the 18th century and ended approximately in 1820. The second era falls in the year 1820 and ended around 1860; the third era started in 1860 and ended around 1895. Finally, the last era began in 1895 and has proceeded to the present era. During this time, American medicine surpassed a long persisting colonial status and emerged on a level of cultural independence. Physicians have for years attempted to understand diseases, to use the knowledge to cure and relieve suffering in the ill.
There is a sense of the term “experimentation” in which it would be true to say that physicians have been experimenting on their patients since a time beyond memory, record or knowledge. From earliest times when a patient presented with unusual symptoms or a condition that failed to response to usual treatment, doctors have experimented with new therapies. “This approach to medical knowledge, trying out new treatments and procedures and then carefully observing the results, was the dominant method in Western medical science until well into the present century” (Schafer, Vol.307, P 719-724).
Therapies were not based on observational studies but on the authority of tradition. For instance, take the great cough medicine; people were sold the recipe of whiskey, honey, and lemon to quiet the cough. Recipes similar to these were sold to the public without any evidence of safety and efficacy. The products that were non-effective; most of them were 99% water. In the words of Oliver Wendell Holmes, M. D. , “If all of these patent medications were thrown into the ocean it would be good for the population, but bad for the fish in the ocean” (Parasandola, 1999).
“The history of medicine is abundantly endowed with therapies that were widely used and then were shown ineffective or deadly” (Passamani, 1991). For instance, radiation therapy was used on patients between 1940 and 1968 for the treatment of acne. The radiation treatment was found later to lead to a high incidence of thyroid cancer in the treated patients. The thalidomide disaster was another treatment found to be toxic. Thalidomide was used in pregnant women for morning sickness in the early 1950’s. This led to birth defects in hundreds of babies. Because of the birth defects in infants, the drug was banned from use in the United States.
In 1906 a law was passed to set standards for drug purity and quality through the United States Pharmacopoeia and the National Formulary; however, there still was not a law regulating the safety profile of drugs at this time. Disasters of Clinical Research “Research was not as it is today” (Code of Federal Regulations, 1999). For instance, a study that was performed in 1937 involved the death of 107 Americans, most of whom were children. The deaths occurred after taking Elixir Sulfanilamide, a medicine used to treat bacterial infections. The drug Sulfanilamide itself was safe, but the solvent dethylene glycol added made the elixir deadly.
The incident received major media coverage, which led to the 1938 Food, Drug and Cosmetic Act. “The most important outcome of the disaster was that new drugs had to be tested and proven safe before marketing” (Parascandola, 1999). Another disaster of medical research occurred during World War II. The public views doctors as some of the most respected and intelligent individuals in our society. So how can doctors be transformed from healers into systematic killers? Human beings, who put their utmost trust in physicians, were exposed to unthinkable research.
“Nazi doctors conducted research that was not only unethical in nature, but they did not add anything of significance to medical knowledge” (Scott, 1998). The Nazi researchers exposed a number of prisoners to freezing conditions and experimented with various methods of reviving the prisoners. These doctors also had prisoners involved in the drinking of seawater to determine how long pilots could survive once drifting in the ocean. (Moreno, 1997) The doctors involved in the unthinkable research projects were able to maintain some sense that they were not murderers, because they were able to hide behind the idea that they were doctors.
These experiments that were done on prisoners led to regulations for human research. “The trials of these doctors raised issues that were problematic. Prosecutors realized the lack of internationally recognized medical ethics by which the Nazi doctors could be judged” (Moreno, 1997). The “Nuremburg Code” was created for the ability to judge physicians and researchers who do unethical research on human beings. This code was adopted to enable the classifying of rules that would govern the participation of human beings in all medical research worlds wide.
The Declaration of Helsinki was adopted in 1964 by the World Medical Association to aid in the guidance of ethics in human research. These are principles (Appendix A) that are to be followed by physicians and others involved in human research. Of these principles, one states, “It is the duty of the physician to promote and safeguard the health of the people. The physicians’ knowledge and conscience are dedicated to the fulfillment of this duty” (World Medical Association, 1964). In 1966, the Surgeon General announced a policy to govern human subjects participating in research supported by Public Health Service grants.
This policy required institutions receiving Public Health Service support to create an Institutional Review Board to oversee research involving human subjects and require that researchers obtain informed consent from subjects. With this policy in effect since 1966, the following disaster leaves questions on how the Public Health Service could not follow the policy themselves. In 1972, Jean Heller of the Associated Press broke the story of the Tuskegee Trials. “The United States Public Health Service had been conducting a study on the effects of untreated syphilis in black men in Tuskegee, Alabama for 40 years” (Jones, 1981).
Syphilis is a disease that can end in death if left untreated. In the latter stages of syphilis, it affects the brain and impairs one’s mental faculties. These men were not told that they had syphilis. Instead, they were told they had “bad blood”. These men thought they were being treated for their bad blood. However in reality they were being studied to see how syphilis affected them. Once this story broke, an investigation was launched against the United States Public Health Service. The investigation uncovered that there never was a protocol created to be followed for this trial.
The tragedy of this trial was, not only did men die at the hands of these unethical physicians, but they also lost the ability for self-care and independence. When this study took place there was an approved treatment available for syphilis that would have saved the lives of these men. This type of research brought forth even more strict guidelines for the protection of human subjects in research. The Code of Federal Regulations is an important part of clinical research today. These regulations guide all researchers involved in clinical research.
Section 50. 20 states, “No investigator may involve a human being as a subject in research covered by those regulations unless the investigator has obtained the legally effective informed consent of the subject or subject’s legal authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence” (Code of Federal Regulations).
For example, if a patient is approached to participate in a clinical trial, they are to be given enough time and information to decide if that is what they want to participate in the trial. An investigator or an associate with the research site must inform the subject that they can take the informed consent home and talk it over with their family, or research the information without feeling pressured to participate in the trial. The section 50. 25 gives the information on the elements of the informed consent (Appendix B).
This section in the Code of Federal Regulations must be present in every informed consent prior to an Institutional Review Board approval of the consent for the subjects to read. Clinical Research Today “Research today is referred to as medical experimentation, and involves the designing of procedures that systematically manipulates subjects and the use of controls for gaining knowledge” (Schafer, 1982 p 719-724). Properly performed randomized clinical trials are essential to the medical world of today. There are many advantages to randomized clinical trial.
Randomized clinical trials are necessary for valid assessment of therapeutic efficacy. Secondly, they remain the most reliable method for evaluating the efficacy of therapies. Thirdly, they are important in the advancement of medical knowledge. Clinical research today is the scientific study of new medications, treatments, or devices in human subjects. “Professionals who conduct research typically have advance degrees, such as M. D. ‘s, Ph. D. ‘s. These professionals work in research centers, universities, or for pharmaceutical companies” (Dunkin, 2000).
“What these professionals have in common is inquiring minds; they have the patience to probe into the mechanics of diseases and the desire to help their fellow man” (Dunkin, 2000). Researchers work together to better understand a disease and the process it takes on within a subject’s body and why a disease may affect a certain population. However, for advancements to occur basic research and clinical research are necessary. The clinical research phase begins after scientific research has been done on animals.
The findings in the animal studies must have shown that the results are promising to be able to conduct research in humans. The research that is done on animals gives important information on toxicology, pharmacology, and bioavailability of the new medication or treatment. Once scientists have all of the information on these animal studies, scientists present the data to another group of scientists to start the clinical phase. The second group of scientists complies all of the data from the animal studies and begin writing a protocol for the clinical research phase.
A clinical trial is a research study that sets out to answer specific questions about a new treatment or medication. These trials are used to determine whether a new treatment or medication is safe and effective for use in humans. A protocol serves as the basic criteria for all clinical trials. Protocols consist of several steps (Appendix C). It is imperative that these protocols have all of the steps included for the FDA to approve that the clinical trial is acceptable for human subjects. Prior to the research trial beginning the pharmaceutical company has to present the protocol and expected outcomes to the FDA for approval.
There are times where the FDA will turn down the protocol and the scientists must start all over with a new protocol and outcomes. The FDA has also been known to add specific tests to be performed in a protocol due to previous information on the chemical background of the drug. If this happens, then the pharmaceutical company will do what is called an amendment to the protocol to include what the FDA has requested. The IRB must approve the protocol, informed consent, amendment and the investigator to prior to the start of the clinical trial.
The IRB can request that certain information be put in the informed consent for subjects to read. The informed consent must be written on an eighth grade level; this is to ensure that the information provided in the informed consent can be understood by the lay subjects. There are four phases of clinical research. Phase I is the initial introduction of an investigational new medication in humans. Phase I studies are typically closely monitored and may be conducted in patients or normal healthy volunteers. The Phase I studies are designed to determine the metabolism and pharmacologic actions of the drug in humans.
Phase II include controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the new drug. Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained. These studies are conducted to gather additional information about the effectiveness and safety that is needed to evaluate the overall benefit to risk relationship of the drug.
This phase can take years to complete and is done on patients with a certain disease. Phase IV is completed after the FDA has given approval for “post marketing”. The post marketing phase reflects the FDA’s approval of the drug or drugs in question. This phase is used specifically for testing efficacy of one approved drug to another with the same indication. This type of research is commonly referred to as a head to head comparison. The FDA conducts audits at clinical research sites based on for cause audits or on regular audits.
The chart below shows the total audits that have been conducted by the FDA to date along with the findings of these audits. NAI = No action indicated VAI = Voluntary action indicated OAI = Official action indicated Based on the chart it should be noted that the official action indicated means that the site must respond to the findings in writing to the FDA within a specific time period. If a site does not respond to the FDA’s findings, the site can be shut down from conducting research any further. There are many sites that receive a voluntary action indicated. This usually means that the site did not follow the protocol as it was written.
The FDA requires that the site responds to the findings, however, the FDA does not stop the site from conducting research if they do not respond. With the no action indicated the FDA has found no deviations from the protocol. This finding is not usually the case in audits performed by the FDA. Ethics in Clinical Research The financial stakes are high in modern pharmaceutical research, and there is concern that researchers maybe tempted to commit fraud for personal financial gain. The problems with fraud in clinical research are brought to the attention of the public and many people have a negative perception about clinical research.
The reason for this negative perception is caused by the deception that researchers have committed on behalf of their greed. “Scientists have traditionally assumed that research fraud is a rare event, believing that peer review and replication of experiments uncover most attempts at deception” (Parascandola, 1999). A well known case of deception happening has been documented, and was noted as happening in California in the late 1990’s. A physician was asking his staff and family members to donate their biological samples for falsifying research subjects.
The investigator actually was taking samples from his employees and family, storing the samples in a refrigerator at his office. The physician was entering ghost patients into the studies and using the samples from the employees and family members for visits that required lab samples to be collected. It was not until a staff member turned the physician in to the FDA that he was caught for falsifying data on several clinical trials. It was noted that this physician had been committing fraud for over two years. He was given a federal prison term and a hefty fine for the falsifying of data.
Another trial that is recently noted for deception is the one in which Jesse Gelsinger participated in for a disease that he had since he was born. Jesse was an eighteen-year-old with a terrible disease called OTC deficiency. This disease interfered with Jesse’s liver being able to metabolize ammonia. There is a fatal form of this disease; however, Jesse did not have the fatal form. Jesse was able to manage the disease with medications. Jesse took 32 pills a day by mouth to manage the disease. Jesse was a somewhat normal teenager with a terrible disease; until Jesse stopped taking the medication and ended up very sick and in a coma.
Jesse did recover from the coma and went on to graduate high school like most teenagers. Then Jesse learned about a clinical trial being done in Philadelphia for the disease. The trial was looking for a cure of the fatal type of this disease that strikes babies. The clinical trial which involved gene therapy was a hope in the future for the babies in Jesses’ eyes. Jesse flew to Philadelphia to inquire about the study and to see if he qualified to participate in the trial. Jesse underwent the screening process for the study. This process is done to ensure that subject is a good a candidate and qualify for participating in the trial.
Jesse was informed by the researchers that he did meet the inclusion criteria to be enrolled into the clinical trial. Jesse was scheduled to return for the treatment phase of the research trial in the near future. Jesse stated to a friend before the treatment, “The worst thing that could happen to me is that I die; however, it is for the babies” (Helms, 2000). At the treatment visit Jesse had labs collected along with other study specific procedures to ensure that he still met the criteria for participating. Jesse did in one respect qualify; however, he had a high blood level of ammonia. Jesse’s level was 90 mmol.
This level was exclusionary for the treatment phase of the research trial. In order to be able to participate in the trial, the subject could have a level up to 75 mmol of ammonia and still qualify. The researchers at the site blatantly ignored the protocol specifics. Not only did the researchers ignore the elevated ammonia level, the researchers skipped the order in which the assigned treatment should have been given. The researchers did not follow the protocol as written. The results of the ignorance, human error, or sloppiness on behalf of these researchers resulted in the death of Jesse.
Risks are involved in all types of clinical research. “There maybe side effects or adverse reactions to medications or treatments. The treatment may not be effective for the research subject. The protocol may require a lot of the research subjects’ time for trips to the study site, treatments, hospital stays, or complex dosage requirements” (National Institute of Health, 2007). The risks that are involved in participating in a clinical research trial are put into the informed consent for the potential subjects to read.
This information gives in detail the possible side effects with the medication or treatment being studied. The informed consent also gives detailed information about the possible side effects not yet known with the medication or treatment being studied. The information about every possible side effect that has been reported in previous studies is also stated in the informed consent. This information is essential for the protection of the potential research subject that has been asked to participate in the clinical trial. With all the information included in the informed consent, the subjects have the right to decline participation in the clinical trial if they wish.
Along with the risks involved in the research, the benefits are also included in the informed consent. “In many cases the patient himself is intended to benefit directly from the experiment. That is part of its purpose, but not the study’s whole purpose” (Schafer, 1982, p 719-724). For example, by agreeing to participate in an experiment, a patient may gain access to a new and promising medication or treatment that is being tried in a limited way. “Alternatively, or additionally, the patient may benefit indirectly by receiving especially careful attention and care from an elite group of highly trained specialist” (Schafer, 1982, p 719-724).
Subjects who agree to participate in a clinical trial will be able to take an active role in their healthcare. Subjects may have the benefit of putting their disease in remission through clinical research and subjects will be helping others by contributing to medical research. Another benefit is if a subject is unable to afford up-to-date medical care, the subject is able to receive medical care and medications or treatments at no cost. Research can be helpful for more expensive diagnostic procedures that need to be done to find the medical problem that the subject maybe having.
The other side to this is the subject may have something serious going on medically and will have the capability to find out the medical condition. Another, benefit to the subject is they maybe paid for participating in a clinical trial. With this in mind the subjects who have no insurance coverage and cannot afford to take off from work for the necessary medical care, maybe given a stipend to help with the financial burdens of missing work. Without medical research there would be no cures today. Take the treatment for polio; a research trial provided the information for the prevention of polio.
Many research trials in the past have given the knowledge for today’s medicine. Ethical Research Sites How does a subject know if a site is an ethical research site? Is the research site reputable? A subject who is contemplating participation in a clinical trial can look for standards in a research site. A subject can ask questions, such as how long has the research site been doing clinical trials? Most reputable sites have been doing clinical research for more than two years. The subject can ask if the employees are familiar with the regulations and the protection of human beings participating in a clinical trial.
Research coordinators who are well versed in research will inform the subject of the Nuremberg Code, Code of Federal Regulations, and the Declaration of Helsinki. The site has the obligation to read these regulations to the subject. The regulations have been put into effect for the protection of the subject considering participation in a research trial. The subject can ask if the research coordinator is certified in research. Research sites are requiring that the coordinators get certified by the Association of Clinical Research Professionals (ACRP).
Pharmaceutical companies also look for this certification when considering a site to conduct a protocol. The certification is a test asking questions of the coordinator regarding the FDA regulations, good clinical practices, Code of Federal Regulations, and basic knowledge of performing research on subjects. This certification is currently the only means of knowing that the coordinator is knowledgeable in clinical research. The ACRP requires re-certification every two years with the coordinator having to complete 24 hours of continuing education hours.
Since the requirement of coordinators to be certified in clinical research, the ACRP has created a certification test for potential investigators. Even though there is a test for the investigators to take it is not mandatory for an investigator to take this test. With this in mind if there was an increase in expected accountability on the investigators, this would solve a lot of the problems with investigators not doing research for the advancement of medicine and knowledge of disease, but for the greed of the money.
This certification may also help in detouring physicians from performing unethical research. A subject should always be aware of the actions of the research staff. If the subject feels uneasy about the research site, the subject should ask to see the credentials of the research staff. This would include the physicians’ degrees and certifications along with the site staff. More than likely if a subject is at a reputable research site the subject will feel comfortable in the surrounding.
The subject should always remember that withdraw from a study is allowed without any prejudice toward the subject. With all of this information a potential research subject should be able to judge a site’s capabilities and ethics. References Byar, M. D. , David P. , et al “Randomized Clinical Trials. ” The New England Journal of Medicine. Vol 295 No. 2 (1976): p 74-80 Code of Federal Regulations. Illinois: TAP 1999 Helms, Robert. “No Charges Filed: The Manslaughter of Jesse Gilsinger” March 2000. Retrieved November 10, 2000, from http://www. geocities.
com Jones, J. Bad Blood: The Tuskegee Syphilis Experiment: A tragedy of race and medicine. NY: The Free Press, 1981 Moreno, Jonathan D. “The Dilemmas of Experimenting on People” July 1997. Retrieved November 10, 2000, from http://www. techreview. com/articles/july97/Moreno. html> National Institute of Health “Understanding Clinical Trials” Retrieved December 12,2006,from http://www. clinicaltrials. gov Parasandola Ph. D. , Mark. “The History of Medical Research in the United States” Journal of Clinical Research Practice 1:1 (1999): 7-20 Parascandola, Ph. D. , Mark.
“Investigator Fraud in Clinical Research” Mar/Apr 1999. Retrieved December 12, 2006, from http://www. researchpractice. com Passamini, M. D. , Eugene. “Clinical Trials are they Ethical? The New England Journal of Medicine. Vol 324 No. 22 (1991) : 1589-1592 Scott, Stephen. “Nazi Experimentation” April 1998. Retrieved December 14, 2006, from http://www2kenyon. edu Shyrock, R. : American Medical Research Past and Present. NY: The Common Wealth Fund, 1947 World Medical Association “The Declaration of Helsinki” June 1964, Retrieved December 14, 2006, from.
http://www.wma. net Appendix A DECLATATION OF HELSINKI Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects: It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission. 1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately preformed laboratory and animal experimentation and on a thorough knowledge of the scientific literature. 2.
The design and performance of each experimental procedure involving human subject should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed. 3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person.
The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent. 4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. 5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others.
Concern for the interests of the subject must always prevail over the interests of science and society. 6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject. 7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable.
Physicians should cease any investigation if the hazards are found to outweigh the potential benefits. 8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. 9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort that it may entail.
He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject’s freely-given informed consent, preferably in writing. 10. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress.
In that case the informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship. 11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation.