SAFETY IN CLINICAL TRIALS: WHO IS RESPONSIBLE?

SAFETY IN CLINICAL TRIALS: WHO IS RESPONSIBLE?

Ariel E. Quinio, Ph.D. candidate
Abstract
The philosophical and ethical principles that guide modern clinical trials centered on the voluntary nature of human subjects, protection of patients rights to consent, safety, autonomy, dignity and inviolability. Reports of serious adverse events resulting in deaths of volunteers have been a phenomena in recent years. A literature on selected cases of serious adverse events were reviewed for the purpose of identifying parties responsible for the occurrences of such unlikely situations. It is difficult to identify a single entity who can be accounted for any of these serious adverse events considering that clinical trial is a shared responsibility. Although substantial responsibility for ensuring the protection of human subjects is vested in Institutional Review Boards (IRBs), in all trials, ensuring the safety of participants is not solely the responsibility of IRBs, but also significant others including clinical investigators, sponsors, FDA, the Office for Human Research Protection from Research Risks ,and data monitoring committees (DMCs). Responsibilities and roles expected of each entity were discussed and recommended that better interaction and effective communication among various groups be established to improve clinical trials and enhance patientsâ?T safety.

Introduction

The advancement of knowledge in scientific disciplines has been phenomenal in recent years. New therapeutic discoveries for various types of illnesses emerged as a result of continuous research and development efforts in the medical arena. Scientific investigations has remarkably improved the quality of modern life and broaden human perspective by acquiring a deeper understanding of ourselves, the society, and the world we live in. Undeniably, modern advances in science and technology now serves as essential foundations of our societyâ?Ts material, intellectual, and social progress. For some members of the society, scientific discoveries have alleviated the degree of human agony caused by disease and disability. Notwithstanding these tremendous benefits that can be derived from medical research, the pursuit of scientific knowledge through experimentation should not compromise the rights and dignity of human subjects.

Clearly, therapeutic advances for present diseases are by-products of experimentation. The proliferation of powerful drugs and therapies, the range of options in treatments, and the idiosyncracies of patientâ?Ts reactions make it imperative that sound medical practice be supported by scientific evidence. The interrelationship between therapy and scientific investigation of a systematic kind has become the embodiment of current medical practice. The physician being knowledgeable about research uses his best efforts to alleviate the patients disease. The patientâ?Ts duty to participate in research depends larlgely on the assumption that the potential social benefit significantly outweighs the hazards posed by experimentation. Thus, the responsibility for achieving the right balance between conservation and innovation as well as between benefit and risk represents the necessary calculus for conducting research involving human subjects (Feund, 1972).
Philosophical Controversies and Ethical Principles on Research
Involving Human Subjects

The moral justification for involving human subjects in research has not been thoroughly discussed in the literature on human research and codes of research ethics. The major controversy that underlie the subject of human research appeals to the principle of beneficence. It asserts that the social benefits to be gained from such research are substantial and the harms resulting from the cessation of such investigations would be exceedingly grave (Beauchamp & Walters, 1989). Corollary, Eisenberg (1977) supported such claim by pointing out that the only alternative to a perpetual plague of medically induced illness is the vigorous pursuit of biomedical research specifically research involving human subjects.

Beauchamp and Walters (1989) proposed that a second approach to the justification of human research is based on a joint appeal to the principle of beneficence and justice. According to this principle, beneficence requires that each individual should make a modest positive contribution to the society as a whole. If our participation in research offered significant benefit to others, at little or no risk to ourselves, then such participation may become a duty of beneficence. Furthermore, if we fail to fulfill this modest duty while most of our contemporaries make it, we may be acting unjustly, since we are not performing a fair share of a communal task. This only follows that every person currently alive is the beneficiary of earlier subjects involvement in research. To be specific, the willingness of past human volunteers to take part in studies of antibiotics and vaccines has contributed to the health of the whole society . This can be interpreted to mean that it seems unfair for us to reap the benefits of researches without making a reciprocal contribution to the alleviation of disability and disease.

Jonas (1969) contradicted both the principles of beneficence and justice that explained the general justification of human research. In response to the consequential argument advanced by Eisenberg (1977), Jonas asserted that while human research generally contributes to medical progress, most research involving human subjects is not essential to the well-being or survival of the human species. Jonas emphasized further that medical progress to be specific, is â?oan optional goal, not an unconditional commitment.â?ť In this regard, only a national health emergency or similar â?oclear and present dangerâ?ť would provide a sufficient justification for non-therapeutic human research.

The voluntary nature of human research as explicitly characterized by Jonas is an exact contradiction of the central focus of the moral justification to participate in research. The manner in which present-day clinical trials are conducted have been influenced largely by philosophical thought and ethical principles set forth by Jonas. Thus, there is no injustice involved in not volunteering to take part in clinical trials. In Jonasâ?T view, most volunteer of the past including investigators involved in clinical research, performed acts of altruism and moral heroism. Should man of the contemporary society owe debt of the past, it is a debt of gratitude to these bygone heroes, and not an obligation required by a reciprocity of principle of justice (Beauchamps & Walters, 1989). It is evident that Jonasâ?T propositions on the general justification of human research primarily centered on protecting the rights, safety, autonomy, dignity, and inviolability of patients in clinical research.

Review of Selected Serious Adverse Events (SAEs) in Clinical Trials
The ethical principles as previously presented provided insights on how patients should be dealt with in clinical trials. The succeeding parts highlight a review of literature on selected cases of serious adverse events and the controversies, actions and recommendations that ensue towards determining whether a violation of ethical principles has occurred as well as identifying parties responsible for patientsâ?T safety.
Jesse Gelsinger
The most controversial SAE in clinical trials was reported by Thompson (2000) about the death of a patient from a reaction to gene therapy treatment in September 1999 at the University of Pennsylvaniaâ?Ts Institute of Human Gene Therapy, Philadelphia. Jesse Gelsinger was an exuberant 18-year old from Tucson, Arizona who suffered from a broken gene that causes one of the puzzling metabolic diseases of genetic medicine. He went to Philadelphia to participate in clinical research hoping to find a cure for his type of illness. On the contrary, the experiment killed him. The aftermath of his death created a concerted actions among various groups to minimize the occurrence of related incidents in the future. The Food and Drug Administration (FDA) and the National Institute of Health (NIH) conducted a series of investigations of the University of Pennsylvania studies. Findings revealed that gene therapy researchers at the University of Pennsylvania committed violations with federal rules which include failure to report unexpected adverse events associated with the gene therapy trials. The report also mentioned that scientists were even asking that this incident not be made public. The worst case scenario was that only 35 to 37 of 970 serious adverse events from a common type of gene therapy trials were reported to NIH. Results indicated clearly that the system of protecting the safety of research subjects is not properly working.

The investigation of this incident by FDA revealed serious deficiencies in the way how the University of Pennsylvania conducted the ornithine transcarboxylase deficiency (OTCD) gene therapy trials. This was evident when researchers entered Gelsinger into the trial as substitute for another volunteer who dropped out. It was reported that Gelsinger should have excluded from the study because of his high ammonia levels during the time of his treatment. Moreover, the university failed to immediately report that two patients had already experienced serious side effects from gene therapy which was required in the study design, and that the deaths of monkeys who were given a similar treatment were never included in the informed consent decision.

As a result, the Department of Health and Human Services in collaboration with FDA and NIH initiated the Gene Therapy Clinical Trial Monitoring Plan designed to strengthen the level of scrutiny for study sponsors with additional reporting requirements. A series of Gene Transfer Safety Symposia were conducted to provide a means of communication among researchers to share their results about unexpected problems and to increase their awareness about rules and regulations. In addition, the FDA conducted a random inspections of 70 clinical trials in various gene therapy programs across the United States and instituted new reporting requirements for serious adverse events.
Hoiyan Wan
Steinbrook (2002) reported a case of a healthy 19-year old nursing student, Hoiyan Wan who volunteered in March 1996 for a study at the University of Rochester. As part of the study, she underwent bronchoscopy, and then she died two days after. The report mentioned that she received a fatal dose of lidocaine. This tragedy created so much finger-pointing on the part of concerned authorities in their effort to identify who were primarily responsible for this unlikely event. The report pointed out the state investigations criticizing the researchers, the institutional review board (IRB), and the university. In response to this, the University of Rochester instituted several changes which include the establishment of training programs for investigators and the overhaul and expansion of the universityâ?Ts IRBs.
Holden-Able
In the same article, Steinbrook (2002) cited another serious adverse event concerning a nurse, Holden-Able, who enrolled in a study of the metabolism of the amino acids methionine and homocysteine in people with Alzheimerâ?Ts disease. She was a part of the age-matched healthy controls study to test the hypothesis that amino acids are metabolized differently in the two groups. On April 4, 2001, several hours after drinking a mixture of methionine, which is sold over the counter as a nutritional supplement, orange juice, Holden-Able became severely ill. She became confused and vomited repeatedly. Severe respiratory distress developed, and died on May 6. The cause of Holden-Ableâ?Ts death was not accurately determined but an internal investigation could not rule out an accidental overdose of methionine. This was believed to be the most reasonable explanation considering that she had a very high blood levels of methionine. As a result, the medical center implemented new procedures for dispensing nutritional supplements.
Ms. Roche
The John Hopkins University External Review Committee (2001) reported a case of a healthy volunteer named, Ms. Roche for a clinical research on mechanism of deep inspiration airway relaxation conducted by Dr. Alkis Togias, Principal Investigator at the John Hopkins University. The facts and chain of event as outline in the internal committee report are not in dispute. Accordingly, Ms. Roche received inhaled substances in Dr. Togiasâ?T laboratory. Within 48 hours, she developed a cough, fever, rhinorea and myalgia. This illness progressed to ARDS and she died of this illness on June 2, 2001. This unlikely incident had set a stage among responsible entities to review the initiation, evaluation, conduct and oversight of clinical research at John Hopkins University at various levels including the principal investigator, the preparation of pharmaceutical materials, scientific internal peer review at the departmental or research center level, and the IRB.
Reflections on Cases of SAEs
In Gelsingerâ?Ts case, the problem was apparently resulted from investigatorâ?Ts failure to report unexpected adverse events associated with the gene therapy trials. The presence of data safety monitoring committee is also necessary in order to examine the accruing data for indications that clear benefits or harm may be occurring. Moreover, this serious adverse event could have been prevented should the IRB and other regulatory agencies conduct a regular monitoring on clinical trial. IRBs are responsible for conducting regular independent reviews of research. The problem with the system is that the IRB have been criticized for reviewing too many protocols, reviewing too quickly, having insufficient expertise, and providing too little training for investigators and board members (Steinbrook, 2002).

The case of Ms. Roche provided meaningful insights and suggestions that served as catalyst for John Hopkins University towards further improving and strengthening their research endeavors. The John Hopkins External Review Committee (2001) identified specific areas of concerns that constituted limitations of their system with the end in view that these suggestions will be relevant to improving clinical research in other academic medical centers. Suggestions for improvement were directed towards the role of principal investigator; protocol review by the department, IRB and pharmacological review; consent form; and the culture of possible coercion.

Findings revealed that the Principal Investigator with Ms. Rocheâ?Ts case did not report an adverse event in the first patient, performed an adequate but not outstanding toxicology literature review, and changed the protocol without notifying the IRB. In addition, the committee report specified that the informed consent was misleading such that it suggests more assurance of safety with hexamethonium than was known, and suggested that the agent is a medicine in use in anesthesia. It did not mention its limited use as an inhalant. Moreover, inhalant preparation was not sterile. It was not analyzed, and it was not prepared in a fashion appropriate for medical use.

With regards to protocol review by the department, there was no identifiable expert internal peer review or discussion conducted at the level of the whole Asthma and Allergy Center. It was discovered that the protocol review process was grossly inadequate and it did not conform to current standards. The interview conducted by the review committee suggested that there appears to have a possible subtle coercion in the solicitation and recruitment of volunteers to the Asthma Center Studies.

The John Hopkins University External Review Committee (2001) recommended that an oversight at their institution must be significantly strengthened. There should be an institutional requirement of expert internal review and discussions of every protocol at the department or research center level before a proposal is forwarded to the IRB. The IRB must be recognized and expanded as necessary so that each proposal has a full discussion at a meeting of the whole committee. Special care must be taken to ensure the safety of volunteers in studies which have no therapeutic potential. In addition, there must be greater sensitivity to possible subtle coercion of volunteers. Participation by staff in studies within an academic units should be prohibited . Time spent in study should be separated from regular working hours. Lastly, the quality of the substance and integrity of the preparation should be ensured by an institutionâ?Ts research pharmacy or its equivalent.

Responsibility for Patients Safety in Clinical Trials

The tragic case of Gelsinger, Wan, Holden-Able, and Ms. Roche are few selected SAEs that brought tremendous challenges on various research entities involving human subjects. It is difficult to pinpoint a single entity who can be accounted for any of these serious adverse events considering that clinical trial is a shared responsibility (Steinman, 2001). Although substantial responsibility for ensuring the protection of human subjects is now vested in institutional review boards (IRBs), in all trials, ensuring the safety of participants is not solely the responsibility of IRBs, but also of significant others: clinical investigators, sponsors, FDA, the Office for Human Research Protection from Research Risks (formerly Office for Protection from Research Risks), and data monitoring committees (DMCs) also called data safety and monitoring committees. A federal regulations or â?ocommon ruleâ?ť has been provided to govern the conduct of studies among investigators by obtaining voluntary and informed consent from subjects, protecting patients safety, and ensuring that the risk of their participation is reasonable in relation to anticipated benefits (45 CFR Part 46, 1991). Protecting the rights and safety of participants in research is an ethical mandate. Considering that risk is inevitable in clinical research, it is essential that this risk is minimized and that any unanticipated harm be rapidly detected and contained (Califf, et al., 2003).

The preceeding reports of SAEs is ethically indefensible reflecting a fundamental flaw in the current oversight system (NBAC, 2001). For the purpose of improving the conduct of clinical trial, what follows are discussions designed to clarify important roles of those who are primarily responsible in protecting, monitoring, and ensuring patients safety in clinical trials.

Clinical Investigator(s)

The safety of patients is best served by clinical investigators and their staff who have a systematic approach to collecting and reporting study data and are attentive to details of study conducted such as strict adherence to inclusion and exclusion criteria and stopping rules, accuracy in collecting and recording data, expeditiously report adverse events (AEs) to RERBs and study sponsors, and obtaining valid informed consent. An investigator is also responsible in maintaing as well as ascertaining all relevant data regarding the agent or procedure under study, to rigorously assess AEs and to minimize conflicts of interests. An example of a systematic approach to collecting and reporting data is adherence to Good Clinical Practice (GCP). The GCP standards were developed to provide guidance to clinical investigators that would result in common approaches that are consistent with scientific, legal and ethical imperatives to clinical trials performed in different countries (Califf, et al., 2001). Adherence to GCP standards or to another rigorous standard should help ensure that the trial data and recorded study results are credible and accurate, and that the rights, health and confidentiality of participants are protected.

Research Ethics Review Board (RERBs)

This term is used to include groups such as Institutional Review Boards (IRBs), Research Ethics Boards and Institutional Ethics Committee (IEC) who are empowered to protect trial participants by reviewing initial research plans and providing continuous review of approved research (21 CFR 56, 1981). They are responsible for reviewing the protocol and its informed consent document and make an initial judgment about the potential risks relative to the potential benefits of the proposed study as well as benefits to potential participants (OIG, 1998). Many institutions that have corrected serious problems with their programs for protecting research subjects such as those mentioned earlier including John Hopkins University have markedly increased their spending and increased the number of IRBs.

Current federal regulations require that each IRB have â?oat least one member who is not otherwise affiliated with the institutionâ?ť and â?oat least one member whose primary concerns are not in scientific areasâ?ť (45 CFR 46, 1991). In particular, RERBs have generally been provided with safety data in AE reports from several sources, usually with little explanation of their significance. However, they do not typically receive aggregated data on AEs nor are they aware of the number of participants currently enrolled in the clinical trial as a whole which would provide denominator for calculating the incidence. In this context, RERBs functions are limited to the extent that they are not capable of unveiling the data to find out whether a reported event has occurred in the trialâ?Ts experimental or control arm. In addition, RERB cannot determine the potential causality of an AE occurring after administration of an investigational agent. Consequently, RERBs in general cannot use reports of AEs for reliable, ongoing assessments of changes to determine balance between risks and benefits for trial participants, making it impractical for them to have sole responsibility for protecting the ongoing safety of participants.

Data Safety and Monitoring Committee (DSMC)

The data monitoring committees or otherwise known as â?odata safety and monitoring committeesâ?ť are primarily responsible for assessing the appropriateness of continuing clinical trials based on the evolving data. They are typically composed of experts in the disease or condition under study, biostatisticians, ethicists, and patient representatives. In order not to bias the conduct of the trial by revealing early the data, DSMCs act independently of the sponsor and the study investigators (Morse, et al. 2001). The sponsor or steering committee normally charges the DSMC to protect the patients safety by examining the accruing data for indication that clear benefits or harm maybe occurring for individuals participating in the trials (Gordon, 1998).

Corollary, Cairns (2001) cited that a DSMC shares responsibility with the IRBs, government agencies, and with individual investigators who are responsible for ensuring that the trial appropriately balances the risks and rewards for individual subjects. The DSMC also works with the Steering Committee and the trial sponsor who altogether have the operational responsibility for the trial.

Sponsors

A sponsor takes responsibility for initiating the clinical research study (21 CFR Part 312.3b, 1999). These include any entity that funds the research including the medical products (pharmaceutical and medical devices) industry, foundations, governmental agencies and institutions conducting the research study (Califf, 2001). At the outset of human testing of new interventions, sponsors must be able to show that a particular product or behavioral interventions will likely be safe enough to justify such research. Although this determination is always fraught with some uncertainty, it is typically based on the results of preclinical testing (Newell, et al., 1999).

Sponsors have the responsibility to design trials in line with the principle of Good Clinical Practices (GCP) which were developed by ICH to address the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials (GCP, 2002). The sponsor should also ensure that research personnel at clinical research sites are knowledgeable about these practices and how to implement them for a clinical trial. Furthermore, it is the responsibility of the sponsor to review and interpret initial adverse events.

Clinical Research Sites

The site of the clinical trial serves as a venue to conduct primary observations that ensures patients safety. In addition to the clinical investigator and study coordinator, the clinical research sites may be composed of various entities that participate in the clinical trials including local scientific reviewers, pharmacy staff, and grants contract personnel. It is normally expected that each clinical trial has a detailed set of standard operating procedures that promote adherence to the specifics of how study protocols are to be executed according to the principles of GCP (Califf, 2001).
Regulators
These consist of federal agencies including FDA and the Office for Human Research Protections who are responsible for ensuring that products that come out in the market are safe and effective for public consumption. The FDA is also tasked to ensure that human participants in research have been protected (21 CFR Part 50, 1980). The FDA in collaboration with the Office for Human Research Protections regulate the conduct of clinical trials including the testing of new drugs and medical devices. The latter has greater authority over research entities through their written assurances that they will comply with the federal regulations. So that research entities will ensure compliance with federal regulations, fines are imposed on clinical investigators or institutions found to be in violations.
Conclusion and Recommendation
The major players in clinical trials such as investigators, research ethics review board, data safety monitoring committee, sponsors, research sites, and regulators should be guided by philosophical viewpoints and ethical principles in conducting research involving human subjects. In recent years, the moral justification of human research not to mention the principles of beneficence and justice have paved the way towards medical progress. It was not until Hans Jonasâ?T philosophical thoughts that laid much of the ground work for ethical principles governing the present-day clinical trials. A review of four selected serious adverse events from the literature revealed their own stories to tell and the fundamental flaws that led to an inquiry into the issues and the programmatic suggestions that ensue to protect safety of human subjects.

The Jesse Gelsingerâ?Ts case pointed the blame on investigatorâ?Ts failure to report unexpected adverse events associated with the gene therapy trials; state investigation results criticized the role of researchers, the institutional review board (IRB), and the university on Hoiyan Wanâ?Ts death from fatal dose of lidocaine; investigatorâ?Ts and the multitude of others were held responsible for Holden-Ableâ?Ts death from accidental overdose of methionine; and Ms. Rocheâ?T death was likewise accounted for several factors ranging from principal investigatorâ?Ts inability to report adverse event, misleading informed consent, inadequate protocol review by IRB to a culture of possible coercion in the solicitation and recruitment of volunteers. Considering that patientsâ?T safety in clinical trials is a shared responsibility, it is of utmost importance that each party involved in research has thorough knowledge of their responsibilities. The responsibility for patients safety in clinical trials were presented with the objective of identifying roles that are expected of them.

It is hereby recommended that effective channel of communications be established among various groups or entities involved in the conduct of clinical trials to prevent the occurrence of related incidents in the future. Based on the earlier discussions, there seemed to be no single group who can provide a complete protection of patients. A programmatic plan or strategy is required so that appropriate inputs from various entities can be combined together for inclusion in the clinical trial oversight. Each entity should function as indispensable part to contribute towards ensuring patientsâ?T safety. Ideally, better interactions and effective communications among various entities need to be enhanced. Morever, it is about time for various groups to come to an understanding of their complimentary and unique roles in the conduct of clinical trials.
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Ariel E. Quinio, Ph.D.*

 

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