Understanding Research Ethics and Clinical Trials in the Context of Stem Cell Research


Definition of research ethics

Research ethics is the field of bioethics that has codified safeguards and investigated ethical and medical problems that arise from human participation in clinical trials as well as other forms of medical and scientific research. Research ethics involves the application of fundamental ethical principles that include:
  • the design and implementation of research involving human and animal experimentation
  • drafting institutional and governmental regulations and guidances
  • protecting against possible academic abuse or scandal, including scientific misconduct (defined as falsification or fabrication of data or plagiarism)
  • appropriately investigating charges brought by whistleblowers.

Origins of research ethics


Research ethics arose from the ashes of the Holocaust. This racially motivated mass genocide by the Nazi regime included the systematic and brutal torture and murder of millions of people. The Nazi doctors also conducted notorious and sadistic medical experiments, characterized by a total lack of voluntary consent and ethical practice as well as a pervasive pseudo-science. These murderous experiments were intended only to help the German race and German soldiers. Many experiments intentionally ended with the death of the research subject (See Nova Online: Holocaust on Trial - The Experiments).

YadVashemFreezingExperiment.jpg
Nazi doctors overseeing a medical experiment being performed on a prisoner immersed ice cold water. (Image courtesy of Yad Vashem)



This experiment, with a concentration camp inmate as the involuntary subject, tested the limits of human endurance to withstand prolonged submersion in ice water. Many physiological measurements were taken as the subject slowly succumbed. Death was the end point of the experiment. The Nazi experimenters – many among them noted physicians - always carefully documented their research activities, which provided compelling evidence at the Nuremberg Trial.







The Doctors Trial



At the Doctors’ Trial, American medical expert Dr. Leo Alexander points to scars on the leg of Jadwiga Dzido. Dzido, a member of the Polish underground, was a victim of medical experiments at the Ravensbrueck Concentration Camp. Nuremberg, Germany, December 22, 1946.
(Source: United States Memorial Holocaust Museum)

The need was paramount in the years following the revelations of the Nuremberg trials to detach medicine from these
NaziDoctorsNuremburgCode.jpg
(Source: Oxford University Press)

horrors. Guidance and regulations to establish legitimate clinical medical studies with appropriately consented human volunteers would emerge in the aftermath of Nuremberg (Reitz, 2008).

In response to the Nazi atrocities, the Nuremberg Code (1948) was drafted by the judges who participated in the Nuremberg Trial of 23 of the Nazi physicians who were charged with crimes against humanity. This document outlined some of the fundamental legal guidelines involving voluntary informed consent that subsequently have influenced U.S. regulations governing informed consent (see http://www.ushmm.org/research/doctors/Nuremberg_Code.htm for more information).

The Declaration of Helsinki of 1964, written by a group of physicians from the World Medical Association (WMA) provided specific guidelines to physicians conducting international biomedical research involving human subjects that included specific recommendations for obtaining voluntary consent. (See "WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects". See also Module 2 and Legal History of Stem Cell Science).

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Brief review of past U.S. abuses in clinical research


The ethical mandates and procedures currently in place are still evolving. They will always be needed to protect the rights and promote the welfare of research participants in clinical research. Often they emerged as a consequence of a signal abuse or egregious failure to protect patients or study participants (see Module 2). Sometimes scientific research can be overzealous, particularly given the highly-competitive scientific research arena and may even cause harm to human volunteers who participate in such research.

This supplement focuses on why ethical standards and protections are needed to ensure the scientific validity, appropriateness, and ethical conduct of essential clinical research and its sequelae.

After the revelations of Nuremberg and the issuance of both the Nuremberg Code and Helsinki Declaration, Americans believed that we had learned important lessons in ensuring the protection of research participants so that ethical abuses would never occur in the US.

But the US, after WWII, was deeply engaged in what is known as “the Cold War” with Russia. In this climate of intense fear about a possible takeover by world communism, scientific secrecy was common and areas of investigation funded by the US government that today we find ethically and scientifically very problematic could be initiated without publicity or disclosure.

In general, secrecy is the enemy of good science: as with medicine during the Nazi era, there was much research practiced that could never be conducted by today’s standards

A major consequence of this Cold War environment was the federal funding of numerous trials that breached the public trust due to their abusive or negligent procedures. Many of these studies inappropriately used vulnerable or captive populations living in prisons, mental institutions, or nursing homes. Almost all the problematic studies involved flagrant violations of failure to obtain informed consent. A few well known examples include:

  • mentally compromised children at the Willowbrook State School in New York City who were purposely exposed to hepatitis virus (Rothman 1984)
  • elderly, cognitively impaired nursing home residents in Brooklyn, NY who were injected with live cancer cells (High and Doole, 1995; Katz, 1972)
  • over 7000 U.S. military personnel were given LSD or other mind altering drugs in the course of the CIA’s Project Bluebird (Otterman, 2007)
  • various vulnerable groups were exposed to diverse forms of intense radiation (Faden and Lederer, 1996).


These studies are just a few examples of unethical and illegal experimentation in 20th century America that have been well documented (see Module 2; also see Rothman 1992; Moreno and Grodin 2002; and Stobbe 2011).

When Dr. Henry Beecher published his landmark article of 1966, Ethics and Clinical Research, in The New England Journal of Medicine, it was so shocking and unexpected. Dr. Beecher had combed through scores of clinical studies published in the best medical journals and identified more than 100 in which he documented numerous ethical abuses and scientific problems. Focusing on approximately 20 of these studies, his terse descriptions of their shortcomings had enormous impact on the medical and scientific communities, and soon after, on the public discussion of research ethics. His revelations set the stage for more stringent ethical standards, just as the growth of the clinical trial enterprise really began in the United States and elsewhere.

Henry K. Beecher (1904-1976)


Henry K. Beecher, MD had a scientifically significant career in anesthesiology and medicine at Harvard Medical School. Beginning in the early 1960s, Dr. Beecher, who was present at the Nuremberg Trials, became better known to the wider scientific and lay public after the appearance of his articles on unethical practices in medical experimentation (Beecher 1966). His revelations of clinical research abuses in the United States - where many believed that after Nuremberg the US would know how to be ethical and incapable of allowing dangerous and unethical research – were striking and a wake-up call for the research community that there were indeed abuses occurring and that we needed to formulate protections for research participants. His ethical investigations and publications influenced the content of the Belmont Report and led to the implementation of federal rules governing human experimentation and informed consent. (Also see the OHRP Archive: the Belmont Report).

An entire, very interesting issue of a 2008 journal was devoted to the legacy of H.K. Beecher; see Winter 2008, International Anesthesiology Clinics, 46(1).

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Tuskegee and Guatemala


Two of the most egregious trials that were federally funded and NOT documented by Beecher were The Tuskegee Study of Syphilis in the Negro Male, a natural history study designed to follow the course of untreated syphilis, and The Guatemala Syphilis Studies, intended to determine the efficacy of penicillin in the treatment and even prophylaxis of syphilis.

Funded by the US Public Health Service, the Tuskegee Study ran for 40 years (1933-1973) and is infamous for its deception, for its failure to provide informed consent, and especially for its failure to treat the participants with penicillin when this antibiotic became available in 1942.



Tuskegee-syphilis-study.jpg
A doctor draws blood from one of the Tuskegee test subjects. (Source: Wikimedia Commons)


"At the time of the project, African Americans has almost no access to medical care.For many participants, the examination by the PHS [Public Health Service] physician was the first health examination they had ever received." (Source: Thibodeau 2010)


Recent scholarly investigations by Professor Susan Reverby (Reverby 2011) led to revelations concerning the U.S.-led Guatemala Syphilis Studies (1946-1948) where, unlike Tuskegee, many participants WERE purposely exposed by US doctors to syphilis and other sexually transmitted diseases.

These ethically flawed studies underscored that lessons of the Nuremberg Trials were not universally learned in the post-war U.S. Sadly, these abuses show that it is all too easy to be blind to the conduct of morally failed studies all in the name of advancing scientific knowledge.

Professor Susan Reverby ( b. 1946)


Professor Susan Reverby, PhD, Wellesley College, who uncovered documents describing egregious experiments carried out in Guatemala. Prostitutes, patients in mental institutions, and prisoners were deliberately infected with syphilis and other sexually transmitted diseases to determine if penicillin would be effective in treating the disease or could even be used as a prophylactic.

Also see this video interview with Professor Susan Reverby, Wellesley College, and Professor Alondra Nelson, Columbia University, moderated by Gabriel Sanders, Director of Public Programs for the Museum of Jewish Heritage.



A cautionary tale from gene therapy: the case of Jesse Gelsinger


“Gene therapy was the embryonic stem cell research of the 1990s; its ability to cure was thought to be boundless and the hype was astronomical. Its promise was both therapeutic and financial: billions of dollars stood to be made from curing diseases as rare as OTCD [orinthine transcarbamylase deficiency] and as common as cancer, leading several companies to invest millions in the technology.” (Source: the Hastings Center)

JesseGelsingerCropped.jpgJesse Gelsinger (1981- 1999) died in a gene “therapy” clinical trial at the age of 18 after suffering a massive toxic shock reaction to an injected viral vector. He was the first publicly identified fatality due to a gene therapy intervention. Jesse had a mild form of OTCD, a rare, debilitating metabolic disorder that prevents the body from breaking down ammonia, and that appeared might respond to a new gene therapy. While he did not think the new therapy necessarily would improve his own health, Jesse wanted to help those with a more severe form of the disorder and to contribute to science.

A subsequent Food and Drug Administration (FDA) investigation concluded that the study involved serious ethical problems that the University of Pennsylvania, the sponsor of this trial, later attempted to rebut (University of Pennsylvania, 2000). The study’s lead scientist, Dr. James Wilson, and the University were reported to have a conflict of interest as they had a financial stake in the research outcome. The study led to the closure of gene therapy trials at the University and the censure of the principal investigator.

Aftermath and implications of the Jesse Gelsinger Case


The Gelsinger tragedy dealt a severe blow to clinical trials of gene therapies, and revealed how little we knew of the potential consequences of such interventions.

The National Institutes of Health (NIH) held a formal inquiry into the Gelsinger tragedy in which they polled gene therapy researchers all over the U.S. The researchers revealed they had witnessed more than 600 serious adverse events they had not previously reported, including several deaths (see the Institute of Science in Society; Ho, 2005; and the National Institute of Health; Pollner 2000).

Ultimately, the Gelsinger case led to significant responses:
  • The Food and Drug Administration (FDA) put all gene therapy trials at the University of Pennsylvania on hold, as well as other trials ongoing at several other institutions.
  • President Bill Clinton demanded improvements in patient consent procedures and access to information about gene therapy research across the board.

Having the adverse events and questionable practices come to light brought a modicum of benefit to the tragedy. The Gelsinger case was a definite turning point of great relevance today, as we stand on the brink of far more extensive human stem cell research and applications. We are reminded that not only desperate patients, but also those who want to be altruistic and give hope to others may sign up for trials with good and mostly well-informed intentions. And while even the most scrupulous medical scientists cannot foresee all possible risks, both scientists and research institutions must ensure that the ethical and scientific flaws that characterized the Gelsinger case should never be repeated.

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Review of the basic elements of clinical trials


What follows is a review of the basic elements of clinical trials and of the institutional bodies and regulations that guide approval of clinical trial protocols along with how trials are monitored. This review is meant to underscore why “treatments” that have not been studied in this rigorous manner should be viewed with much skepticism.

What is a clinical trial?


A clinical trial (also called clinical research or experimentation) is defined by the National Institutes of Health as a research study involving human volunteers that is designed to answer specific health questions (See: NIH glossary).

All clinical trials involve highly structured clinical interventions with human participants. Protocols are carefully designed to yield explicit and valid data in response to specific questions of interest. While some trials involve healthy volunteers as a comparison or control group, most clinical studies of an experimental drug or device, for obvious scientific and ethical reasons, involve participants who all have the medical condition being studied.

The randomized, double-blind, placebo-controlled clinical trial (randomized controlled trial or RCT) is frequently referred to as the “gold standard” for clinical research. Other trial designs are less stringent, such as:
  • open-label drug or device study (no blinding)
  • single blind trial (study participants are blinded, but investigators are not)
  • uncontrolled study (various intervention paradigms)
  • no placebo or other control group (no active experimental intervention).

High-quality clinical trials of a drug, device, or other intervention will include:
  • screening of potential participants to see if they meet study criteria (both inclusion and exclusion) that can be quite extensive and detailed
  • randomized assignment of included subjects to one of several experimental “arms” or sub-conditions of the trial
  • randomization decided on by chance, as with a flip of a coin or via a computer-generated random number assignment
  • assignment of one group of participants to the placebo arm. This control or comparison group is exposed to all study conditions except the active drug or device, or more rarely, to a sham treatment. Sometimes, trials are designed to compare a new drug with an existing FDA-approved drug and in those trials one group is assigned to receive the approved drug.

"Two and a Half Men"


In this clip from CBS's "Two and a Half Men," Alan tests a new medication as a clinical trial participant in an experiment. Note that this is broad satire! Hopefully this study experience would never happen in real life.



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What are Phase I, II, III, and IV clinical trials?


Clinical trials are conducted in stages, often referred to as Phase I, II, III, or IV clinical trials.

Phase I trials: test safety and efficacy. Researchers test an experimental drug or device in a small group of people (n=20-80) for the first time to evaluate its safety, escalate the dose to determine a safe dosage range, and identify preliminary side effects and adverse events. No clinical benefit is anticipated. Typically those who volunteer for Phase 1 trials are those with a terminal illness or a chronic disease who are apprised of all known risks and are aware that they are not likely to experience any clinical or survival benefit. The goal of Phase I trials is primarily safety and not to determine whether the treatment is efficacious.

Phase II trials: the experimental study drug or device is studied in a larger group of people (n=100-300) to see if it is effective and to further evaluate its safety.

Phase III trials: the experimental study drug or device is given to large groups of people (n=1,000-3,000) to confirm its effectiveness, monitor side effects and adverse events, compare it to commonly used and proven (standard) therapies, and to collect information that will allow the experimental drug or device to be used safely, and go to market. A RCT design is commonly used to compare the different arms of the trial for safety and efficacy.

Phase IV post-marketing: delineates additional information including the risks, benefits, and optimal use of the drug or device over several years accruing reports from patients and their physicians. These marketing studies are especially important in collecting data about adverse events experienced by large numbers of users.
(Source: ClinicalTrials.org)

Clinical trials are expected to take approximately three to six years with costs estimated between hundreds of thousands of dollars to as high as 1.5 billion dollars, depending on the size and scope of the trial. In recent years, given the tight US economy where we have seen a flat NIH budget, less than 10% of proposals submitted to the NIH annually are likely to be funded. Pharmaceutical companies, therefore, have become the major funders of clinical trials.

The path from (laboratory) bench to (clinical) bedside is long and expensive. To justify a new clinical trial there should be sufficient positive data from in vitro and simulation studies, animal trials, and/or extrapolations from human clinical data. All must contribute solid converging evidence to support the investigator’s hypothesis. Detailed review of this justification is a major role of NIH peer review study groups composed of researchers in the field.
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ClinicalTrials.gov


ClinicalTrials.gov is the federal government Web site designed to list all U.S. and foreign clinical trials, active and inactive, which are conducted by for-profit as well as not-for-profit entities. Created by an act of Congress in 1997, ClinicalTrials.gov was expanded in 2007 to include a summary of results for each trial. This site provides extensive information about the clinical trials and participation for clinical investigators, patients and their families, and for the general public.
  • ClinicalTrials.gov (as of winter 2012) documents almost 122,000 trials sponsored by the National Institutes of Health, other federal agencies, and private industry
  • studies listed in the database are conducted in all 50 states and in 179 countries
  • ClinicalTrials.gov receives over 50 million page views per month; 65,000 visitors daily.

More on ClinicalTrials.gov


For an interesting interview on the mission and evolution of ClinicalTrails.gov since its creation in 1997, with its Director Dr. Deborah Zarin, see Marshall E (2011). Unseen world of clinical trials emerges from U.S. database. Science 8 July 333:145 and go to, for example, Understanding Clinical Trials, and About ClinicalTrials.gov.

Registry of all clinical trials


The Registry of all trials at ClinicalTrials.gov is much needed and valuable, scientifically and ethically, for numerous reasons.
  • Many patients participate in clinical trials hoping to contribute to advancing science and medicine for their illness or condition, whether or not they will be helped. They need information listed in the Registry to become informed, to decide if they would like to participate, and to assess whether they possibly might benefit from the listed trial. Encouraging clinical trial participation is central to clinical scientific advancement.
  • The Registry helps patients and families become informed about potential clinical trials of interest before they actually meet with investigators, and if deciding to participate, go through the Informed Consent process
  • The Registry helps to insure that all trials, including industry-sponsored trials that are part of a self-protective, for-profit culture, are transparent with results that are to be openly shared.
  • Scientists tend to publish their positive results more often than their negative findings; this publication bias can damage the research enterprise. As the Registry documents all trials, and informs reviewers, physicians, patients, and the public about current as well as past trials, both positive and negative outcomes are revealed. Trial results are supposed to be updated ensuring that current information is available. This transparency is important to reinforce trust among patients, investigators, and research ethics review boards.

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Informed consent


When designing a clinical research protocol, insuring the protection of the volunteers who agree to participate in these trials is of paramount importance. Before the trial can begin, careful review of the research protocol, and especially the informed consent form, is conducted by university, medical center, or commercial Institutional Review Boards (IRBs).
OPRR.png
(Source: OPRR Reports)

Preparing an informed consent document that describes to potential trial participants what they need to know in order to give or withhold consent is a daunting process. Investigators must summarize often highly complex information in an understandable way that leaves out nothing essential (see Text Box below for a summary of the eight required elements). Yet, at the same time, informed consent documents should not be overly long or complex because then they will not be read. In addition IRBs stress to investigators that the wording of the consent form must be understandable at the 8th grade level or below. Given that informing patients accurately is required, it can be very challenging to explain complex research in very basic terms.

Beginning in 1981, regulations were published to provide researchers with guidance on how to conduct clinical trials, and specifically what elements were required for informed consent. In 1991, all federal agencies that conduct research with human participants adopted the regulations that are now known as The Common Rule (Title 45 Code of Federal Regulations Part 46).

Required elements of informed consent


(Source: 45 Code of Federal Regulations (CFR) 46.116.)

An informed consent form follows a set format including 8 specific areas that must be addressed:

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
2. A description of any reasonably foreseeable risks or discomforts to the subject.
3. A description of any benefits to the subject or to others which may reasonably be expected from the research.
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject including the alternative not to participate.
5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.
6. An explanation as to whether any compensation is provided and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights and whom to contact in the event of a research-related injury to the subject.
8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

Additional elements to insert when appropriate

1. A statement that the particular treatment or procedure may involve risks to the subject (or embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.
2. Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.
3. Any additional costs to the subject that may result from participation in the research.
4. The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject.
5. A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject.
6. The approximate number of subjects involved in the study.

For more information on the construction of Informed Consent Forms, see the Course Resources.

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Henrietta Lacks, the unethical origin of HeLa cells, and the question of who may profit from patients' tissues


The Immortal Life of Henrietta Lacks


Readers of this Supplement are encouraged to read this book, which provides a very engrossing view of research and medical care in the mid-20th century, particularly concerning research involving women and African-Americans.

Source: Skloot, R (2010). The Immortal Life of Henrietta Lacks. New York: Crown Publishing Group, Random House

Rebecca Skloot, the author of this recent interesting book, has donated profits from the sale of the book to be placed in a foundation to benefit the Lacks family.
In 1951, Henrietta Lacks, at age 31, was found to have a virulently malignant cervical cancer. A patient at Johns Hopkins, her cancerous cells were surgically removed without her consent, and with no intent to benefit her medically. The cells were found to have the unusual property of growing aggressively and reproducing eternally, and therefore became an extremely important cell culture tool for scientists. So-called “HeLa” cells since have been grown by the ton, generating great profit for companies but none of the profits made their way to the Lacks family. HeLa cells have been used in thousands of experiments around the world, for example, by Dr. Jonas Salk to develop his polio vaccine, and they accompanied a mission to the moon to test the effects of weightlessness.



Tissue samples from millions of people are obtained during both routine and more specialized medical procedures, a practice that began many decades ago. Both the legal ownership of tissues donated by individuals that are obtained in most medical contexts, and the right to profit from them, were clarified in the Moore case, when the court ruled against the tissue donor profiting from the commercial development of his/her cells and tissues. (Potts, 1992; Devine, 2010).

Moore v. Regents of the University of California (51 Cal. 3d 120; 271 Cal. Rptr. 146; 793 P.2d 479) was a landmark Supreme Court of California decision filed on July 9, 1990, concerning property rights over an individual's tissues or body parts. John Moore had undergone treatment at the UCLA Medical Center for hairy cell leukemia. His cancer cells later were developed into a cell line that was commercialized. The California Supreme Court ruled that Moore had no right to any share of profits from commercialization of anything developed from his discarded body parts. Ruling in favor of the donor could have had costly implications for medical research.

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Institutional Review Boards (IRBs)


Before research protocols can be approved and the study submitted for possible funding, the submitting university or medical center IRB examines the protocol extremely carefully. The fundamental purpose of this examination is to ensure the protection of the participating human subjects and to make sure the study details and informed consent documents are all written with this protection in mind. Exercising care in both the preparation and review of research protocols protect the potential participants first and foremost, as well as the researchers, the institution, and ultimately the wider community and the scientific enterprise.

The IRB of a research university or company is charged with oversight of all research protocols, to insure that they conform to ethical and safety standards. Researchers must submit their complete protocols, with every detail specified, for comprehensive review by an IRB panel comprised of scientists, experts in bioethics, IRB administrative specialists, community, and other members.

The functioning of well-established IRBs continues to raise questions that must be addressed. We know, for example, that there is local variation when protocols are reviewed by different IRBs. This becomes particularly troublesome when a large multi-site study is to be conducted and all sites must approve the research protocol (e.g., Stair et al., 2001). Clearing a complex protocol, often with multiple revisions, at multiple research sites, adds greatly to the time and expense of these very large multi-center trials. These costs add to the difficulty of funding and conducting high quality, large-scale research. Stair and colleagues found that: “The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form.” They further concluded that: “A national, multicenter IRB process might streamline ethical review and warrants further consideration.” In fact, many are now in favor of having a central or single IRB review multi-site trials to reduce variation and time needed for approval.

Institutional Review Board (IRB) Meeting


IRB Committees include a diverse group of faculty members, university staff members and members of the community at large. They must review and debate in great detail hundreds of lengthy documents every year.


A more recent review of IRB issues by the director of the Office for Human Research Protections of the NIH, Dr. Jerry Menikoff (2010) also documented great IRB variation, and diffusion of responsibility, leading to frequent ethical dangers.

IRBs are a crucial partner in the research enterprise, and therefore improving as much as possible the clarity and efficiency of their function is in the interest of all.

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Data Safety and Monitoring Board


Once a phase III clinical trial has been funded, a Data and Safety Monitoring Board (DSMB), composed of statisticians, independent researchers, and bioethicists is set up. The DSMB will periodically review the study data to see if the data demonstrate either sufficient efficacy or serious harms including failure in the experimental arms. All reports of unanticipated side effects and serious adverse events are statistically evaluated. The DSMB has access to the placement of all participants in the various arms of the trial, and adheres to a series of “stopping rules.” If it is clear that more harms are associated with the experimental arm or there is no apparent benefit to the experimental intervention, the DSMB will halt the study. This ability to terminate a trial provides a safety net to ensure that a harmful trial is ended before other subjects may be harmed. Concomitantly, an apparently effective trial can be ended early, sparing subjects from further participation.

At the conclusion of the trial when the data are analyzed, investigators are unblinded to the participants’ study placement, allowing further examination of the findings. Research participants are rarely informed into what arm they were assigned.

These features of a randomized double blinded clinical trial are designed to maximize the collection of valid and unbiased data from closely matched groups. Study groups typically are matched for age, gender, and specific medical characteristics that are scientifically relevant or needing to be controlled, to try to insure the most objective evaluation of the study hypotheses (see section entitled "Review of the basic elements clinical trials" above).

Conclusion


In this supplement, we briefly review how the conduct of medical research over the past 75 years has impacted how we currently regulate clinical trials in an ethical manner. Clinical trials using stem cell technology are beginning to take place around the globe. While stem cell science holds enormous promise for regenerative medicine of the future, the public must be strongly reminded that scientific studies of stem cell protocols are in their infancy. These are exciting times, with the promise of new therapies temptingly close. Yet, safe stem cell experimental therapies that will receive FDA approval and that could be offered to patients routinely still are years off.

The long history of medical and ethical error and abuse, often despite well-meaning professionals being involved, must never be forgotten. Tragic cases such as Jessie Gelsinger’s gene therapy trial must serve as a cautionary tale so that we will conduct current and future stem cell trials with extreme care. Given the intensity of the basic and animal research being carried out, with ever increasing attention to both valid clinical applications and ethical issues, we can be hopeful that the early promise of stem cell science and medicine soon will become a reality.

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References

  • Beecher HK (1966). "Ethics and Clinical Research." N Engl J Med 274(24): 1354-1360.
  • Devine, C. (2010). Tissue rights and ownership: Is a cell line a research tool or a person? The Columbia Science and Technology Law Review. March 9. http://www.stlr.org/2010/03/tissue-rights-and-ownership-is-a-cell-line-a-research-tool-or-a-person/ Accessed May 16, 2012.
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  • High, DM, Doole, MM (1995). Ethical and legal issues in conducting research with elderly subjects. Behavioral Science and the Law 13:319-335.
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