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A clinical trial primer: Historical perspective and modern implementation
Urologic Oncology: Seminars and Original Investigations 30 (2012) S28 –S32
Article
A clinical trial primer: Historical perspective and modern implementation夡 Lawrence I. Karsh, M.D., F.A.C.S., C.P.I.* The Urology Center of Colorado, Denver, CO 80211, USA
Abstract The structure of modern clinical trials is designed to protect patient safety while generating safety and efficacy data. Safety is the primary concern, and United States regulations are shaped by a series of responses to incidents, including notable safety lapses and unethical trials. These regulations focus on 3 essential components, defined by the 1979 Belmont Report: respect for persons, beneficence, and justice. Further, the international community has formally outlined good clinical practice (GCP), which mandates that trials are designed to produce meaningful data, conform to international ethics regulations, and provide assurances that data are reported in a credible and reliable manner. The Food and Drug Administration (FDA) and federal government have outlined the necessary components of clinical trials in the Code of Federal Regulations (CFR). These include institutional review boards (IRBs), standard operating procedures (SOPs), sites, sponsors, investigators, and patients. The investigator is the center of the trial and is required to sign an agreement with the federal government to uphold the CFR. Investigator duties include making sure that investigator and support staff having appropriate qualifications, delegating duties, monitoring the study for compliance and record keeping, providing care, and accepting accountability for the trial, among other duties. Physicians, who already have significant time demands, need a well-trained staff, including clinical coordinators, to adequately meet these duties. Despite these requirements, trials can have significant benefits for investigators, practices, and patients, foremost of which is the ability to provide cutting edge care. However, the clinical trial process requires routine evaluation and continual performance improvement in order to ensure that patients not only receive excellent care, but also do so in the safest possible manner. © 2012 Elsevier Inc. All rights reserved. Keywords: Clinical trials; Compliance; FDA; GCP
How we got here: The evolution of United States regulations The structure of modern clinical trials began after World War II, but was shaped by several notable events prior to this. In 1937, 107 people, many children, died as a result of the Elixir Sulfanilidamide tragedy [1,2]. In order to increase the popularity of sulfanilidamide, a Tennessee company created a liquid formulation in which the sulfanilidamide had been diluted with diethylene glycol—the main compoDisclosure/Conflict of Interest Statement: L.I. Karsh is a consultant for Amgen, Dendreon, Bayer, Allergan, Spectrum, Janssen and Astellas/Medivation. 夡 LIK serves on advisory boards for Amgen, Johnson and Johnson, Pfizer, Sanofi Aventis, and Spectrum, and as a speaker for Allergan, Amgen, Dendreon, Ferring, GlaxoSmithKline, and Pfizer. * Corresponding author. Tel.: ⫹1-303-825-8822; fax: ⫹1-303-8254022. E-mail address: [email protected] (L.I. Karsh). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2011.05.012
nent of antifreeze—that caused vascular nephropathy [2]. The toxicity of the inactive ingredients was not tested, as it was not required by existing regulations. As a direct result of the event, the FDA established the 1938 Federal Food, Drug, and Cosmetic Act, which required drug manufacturers to send new drug application (NDA) reports to the FDA, showing drug safety. It also banned false labeling and dangerous ingredients, requiring manufacturers to disclose all active ingredients [3]. Prescriptions were required for certain medications, although it would take the 1951 DurhamHumphrey Amendment to create the category of prescription drugs. Most importantly, the 1938 act was the first to require scientific tests when manufacturing a drug. This was not the first drug regulatory act on the books. Previously, the 1906 Pure Food and Drug Act was designed to eliminate adulterated and misbranded food and drugs [3]. While the legislation had been under consideration for some time, the 1906 publication of Upton Sinclair’s The Jungle, an exposé of the Chicago meatpacking industry, generated
L.I. Karsh / Urologic Oncology: Seminars and Original Investigations 30 (2012) S28 –S32
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Fig. 1. The foundations of modern clinical trial regulations [21].
public support for the measure [4]. The act was regulated by the Bureau of Chemistry in the Department of Agriculture, which became the FDA in 1930 [3]. The act did not regulate drug safety or advertisement. While the 1938 Federal Food, Drug, and Cosmetic Act significantly affected the way pharmaceuticals were dispensed, it did not require proof of efficacy, nor did it standardize clinical testing. The FDA did not review an NDA until the drug was marketed, and drugs were automatically approved if the FDA had not completed its NDA review within 60 days [3]. It would take another 23 years before significant changes would be made in the drug review process. In the interim, another tragedy shaped human clinical trials. The 1947 Nuremberg Code was drafted in response to experiments conducted by Nazi scientists [5]. The code outlined 10 principles for conducting human clinical trials. These included voluntary consent, ensuring that experiments are useful and necessary, conducting animal experiments before using human subjects, allowing subjects to stop at any time, and the use of qualified scientists to conduct the research [5]. These became the backbone of research ethics and the protection of human subjects. It would take yet another tragedy to move the industry forward. The first “thalidomide baby” was born in Germany in 1957, although it was several years before the connection between thalidomide and birth defects was made. This tragedy was largely confined to Europe, where an estimated 8,000 deformed babies were born as a result of thalidomide [3]. In the United States, thalidomide was denied US approval— based on one FDA reviewer’s objections that its sponsor failed to show the product’s pharmacologic and toxicologic characteristics [1]. Accordingly, there were only 17 cases of thalidomide malformations in the United States, and the reviewer, Dr. Frances Kelsey, received the Presi-
dent’s Award for Distinguished Federal Civilian Service from President Kennedy [6]. The tragedy, though, spurred the 1962 Kefauver-Harris Amendment [7]. The act required “substantial evidence” of safety and efficacy for new drugs before they come to market [1]. It also regulated drug marketing and placed it under control of the FDA, established good manufacturing practices, and allowed the FDA to verify those practices. It introduced informed consent requirements and established the current format of clinical testing [1]. This was soon followed by the 1964 Declaration of Helsinki, which along with the 1947 Nuremberg Code forms the basis of protection of subject rights. The World Medical Association, an organization created in 1947 to ensure ethical behavior and care by physicians, developed the declaration, which clarified and interpreted the Nuremberg Code [8]. In addition to acknowledging the importance of clinical research, it defined the process. This included the formal outline of an experimental protocol, including ethical statements, ethical review by an independent outside body, engaging in human research only when the risks involved have been assessed, conducting trials in which there is a likely or potential benefit, the use of informed volunteers who consent to the study, and safeguards for the integrity of the subjects [8]. The Declaration of Helsinki is periodically updated, with the last version (the eighth revision) released in 2008 [9]. While there were codes to foster the ethical study of human subjects in the United States, these codes were not followed in the case of the Tuskegee Syphilis Experiment, a study conducted among rural African-American men in Alabama between 1932 and 1972. The men, who were infected with syphilis, were given free medical care— but they were not told they had syphilis nor were they treated for it [10]. Public awareness of this study, along with sev-
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Table 1 The fundamentals of clinical development [22] Phase I
Phase II Phase III
Phase IV
Evaluation of safety, determination of a safe dosage range, and identification of side effects in a small group of subjects (20–80). Larger trials (100–300 subjects) to determine whether a treatment is effective and further evaluate safety. Larger studies (1000–3000 subjects) to confirm safety and efficacy and compare the investigational treatment with other options. Post-marketing trials comparing different approved treatments or side effects. Phase IV trials are designed to help optimize already available treatments.
eral other unethical studies, resulted in the creation in 1979 of The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. Of note, it would take almost 2 more decades until the United States Government formally apologized for the Tuskegee study. However, in 1979 the commission published the Belmont Report, defining the essential components of ethical research: respect for persons, beneficence, and justice [11]. These principles were to be applied in the form of informed consent, assessment of risk and benefits, and selection of subjects. It also recommended boundaries between clinical practice and clinical research [11]. The Belmont Report specified the ethical principles that underlie all clinical research conducted in the United States today. These are not the only acts and provisions that pushed clinical research to the model we employ today: unfortunately, there are many other examples of tragedies and unethical practices that necessitated changes in clinical research processes. However, these are the major benchmarks that have left us with a well-defined, methodical system designed—first and foremost—to ensure the safety of our subjects, as well as to show clinical efficacy (Fig. 1). As medical science continues to evolve, regulations have been set in place to cover new realms with ethical implications, including stem-cell research, gene therapy, and in vitro fertilization.
Where we are today: Good clinical practice in research Regulations focus on ensuring patient safety in clinical trials. Clinical trials fall into the span after an investigational new drug application is filed. They include Phase I through post-marketing Phase IV trials. The fundamental phases of clinical development are shown in Table 1. Today, there is a laundry list of regulations involved in the design and implementation of ethically conducted clinical trials. With globalization, a need for global standardization became apparent. In 1990, the United States, members of the future European Union, and Japan formed the International Conference on Harmonization (ICH), which is
designed to facilitate the mutual acceptance of clinical data by regulatory authorities [12]. The ICH, which includes Australia, Canada, other countries, and the World Health Organization, provide guidance on quality, efficacy, safety, and multidisciplinary issues. It has defined good clinical practice (GCP) as: “A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the right, integrity, and confidentiality of trial subjects are protected.” [13]. This definition also pertains to any trials that address other investigational procedures, including surgical procedures, diagnostic assays, and medical devices. The ICH has released the ICH-GCP, which consists of 13 points that are the foundation for GCP [14] (Table 2). The Code of Federal Regulations (CFR) requires that all phases of clinical investigation be conducted in accordance with GCP [15]. The CFR has a number of regulations specifically focused on clinical trials; these outline the components required for protection of human subjects, as well as how the trial participants interface with regulatory bodies. Among these is the requirement for Institutional Review Boards (IRB). The IRB, and independent ethics committee (IECs; an alternative name for IRBs), serve to ensure that trials are designed such that trials meet the requirements outlined by the various regulations. The IRB/ IEC is one primary component of clinical trials, as are the subjects, sites, sponsors/contract research organizations (CROs; companies that are hired to help conduct research trials), regulatory bodies, and the investigators. The clinical investigator is the interface between these components and, as such, has significant responsibilities: ● Ensuring investigator and support staff having appropriate qualifications ● Accountability for investigational product use ● Complying with GCP and applicable regulatory requirements ● Permitting monitoring, auditing, and inspection ● Delegation ● Ensuring sufficient resources ● Providing medical care ● Obtaining IRB/IEC approval ● Complying with protocol ● Obtaining informed consent ● Keeping records and submitting reports ● Safety reporting. For investigators—who already have significant time demands—this may seem overwhelming. According to a 2010 survey conducted by the Association of Clinical Research Organizations (ACRO), the number of physicians participating in clinical trials in the United States has continued to decrease over the past decade. The survey indicated that 70% of over 300 respondents in the United States and Europe believe that the current regulations make it chal-
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Table 2 The principles of the ICH-GCP Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol that has received prior IRB/IEC approval/favorable opinion. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Freely given informed consent should be obtained from every subject prior to clinical trial participation. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
lenging to manage clinical trials [16]. In the United States, investigators sign a Form FDA 1572 at study initiation [17]. This is an agreement by the investigator and the federal government to comply with FDA regulations for clinical trials, providing sponsors with information about the investigator and site qualifications, and to inform the investigator of his or her obligations [17]. It is nearly impossible to comply with regulations and meet responsibilities without adequate support staff. Thus, it is imperative to have the proper components to adequately manage these requirements. First and foremost of these are the study coordinators, who work under the direction of the investigator. As trial managers, an excellent study coordinator is reliable, competent, and trustworthy, supporting the daily activities critical to the trial. These activities involve tasks associated with study start-up, conduct, and closure, often including aiding in the preparation of scientific, budget, and protocol proposals, acquiring and reporting data, ensuring safety, and general administrative tasks. Larger clinical trial sites may have additional staff to oversee some of these aspects, while smaller sites may rely on the study coordinator to handle these tasks. Regardless, when investigators delegate tasks, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated [15]. Therefore, it is critical that the investigator be able to work well with his or her staff to ensure that all regulations are followed. While the investigator is the interface, the patient is the focus of the trial, and all of the components serve to ensure that the patient receives the safest care possible within the clinical trial. The FDA serves to assure safety and the rights of subjects/patients, provide input on design of protocols and overall clinical program, assure quality and integrity of data, and assure quality of clinical trial materials, issue regulations and guidelines [18]. While GCP is the expected standard, errors can and do occur. Accordingly, the FDA has an audit process to ensure
that clinical trials are conducted to standards. The CFR requires “a systematic and independent examination of trialrelated activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsors standard operating procedures (SOPs) [GCP], and the applicable regulatory requirements,” also known as the dreaded audit [19]. An audit may be conducted by the study sponsor (sometimes at the request of an investigator or site as quality control) or by the FDA. It may be initiated for multiple reasons, including high or low enrollment, cause-specific, or it could be entirely random. The auditor looks at all of the components of a site, including investigators, consents, protocols, and safety. Following an FDA inspection, the agency can produce a form FDA 483 report. The 483 report does not specifically cite regulations, but is rather an observation report [20]. The observations are the opinion of the auditor(s) and are subject to further FDA review, which will then produce a follow-up letter for investigators. The FDA letter is not necessarily meant to punish investigators, as it may result in no further action required, but it can require disciplinary actions or sanctions for the investigator and/or site [20]. While an audit may be stressful, ultimately, it is an opportunity to improve the strength of a trial site and ensure that GCP is being conducted. It may result in improved or added standard operating procedures (SOPs) and greater employee scrutiny. As such, it is an important oversight component that improves the clinical trial process [20]. While there are significant challenges to participating as a trial investigator, there are many benefits to get involved in clinical trials. Importantly, working within the clinical trial system allows investigators to offer cutting-edge technology and treatments for patients who may need access to these services. Clinical trial investigators are part of the important process of advancing medicine, clarifying best
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practices, and validating investigational agents. This imparts prestige to a site and helps condense expertise towards the center. Clinical investigations serve to educate both patients and physicians involved in the process. Aside from the more important altruistic reasons for conducting clinical trials, involvement in clinical studies can have a financial incentive. In the 2010 ACRO survey, 68% of US respondents said that generating more revenue was “very important” [16]. Of course, this may be in part because conducting a clinical trial involves significant time and expenses. Research and development is critical to the success of any business or organization, especially in medicine. It allows providers to offer tomorrow’s therapies to their patients today. Further, randomized, controlled clinical trials are the primary means to evaluate these therapies. Those involved in clinical trials should constantly strive to improve the investigational program by improving enrollment, procedures, and patient and investigator education, as well as acquiring the most-qualified and best employees, and attracting sponsors and studies. Most importantly, those involved in conducting clinical trials should continue to push the boundaries of urologic medicine in the attempt to provide the best possible care for their patients. Acknowledgments The author thanks all of the patients who participated in clinical trials at TUCC. A special thanks to the research staff at TUCC, to Robin Dorsey for her support and dedication to clinical trials, and to Michael Linde for medical writing assistance in preparation of this manuscript. References [1] Hamburg MA. Shattuck lecture. Innovation, regulation, and the FDA. N Engl J Med 2010;363:2228 –32. [2] Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug, and Cosmetic Act. Ann Intern Med 1995;122:456 – 61. [3] Borchers AT, Hagie F, Keen CL, et al. The history and contemporary challenges of the US Food and Drug Administration. Clin Ther 2007;29:1–16. [4] Barkan ID. Industry invites regulation: The passage of the Pure Food and Drug Act of 1906. Am J Public Health 1985;75:18 –26. [5] Markman JR, Markman M. Running an ethical trial 60 years after the Nuremberg Code. Lancet Oncol 2007;8:1139 – 46.
[6] Hilts PJ. The FDA at work— cutting-edge science promoting public health. 2006. Available from: http://www.fda.gov/aboutfda/whatwedo/ history/overviews/ucm109801.htm. Accessed March 31, 2011. [7] Howland RH. How are drugs approved? Part 1: The evolution of the Food and Drug Administration. J Psychosoc Nurs Ment Health Serv 2008;46:15–9. [8] World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2000; 284:3043–5. [9] World Medical Association. Declaration of Helsinki. 2011. Available from: http://www.wma.net/en/20activities/10ethics/10helsinki/ index.html. Accessed April 1, 2011. [10] Howland RH. How are drugs approved? Part 2: Ethical foundations of clinical research. J Psychosoc Nurs Ment Health Serv 2008;46:15–20. [11] The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Department of Health, Education, and Welfare, 1979. [12] International Conference on Harmonization. Introduction. 2011. Available from: http://ichgcp.net/introduction. Accessed April 1, 2011. [13] International Conference on Harmonization. ICH GCP. 2011. Available from: http://ichgcp.net/. Accessed March 31, 2011. [14] International Conference on Harmonization. The Principles of ICH GCP. 2011. Available from: http://ichgcp.net/2-the-principles-of-ichgcp-2. Accessed April 1, 2011. [15] International Conference on Harmonization. Clarification of Certain Investigator Responsibilities. 2011. Available from: http://ichgcp.net/ clarification-of-certain-investigator-responsibilities. Accessed April 1, 2011. [16] Eastman P. Association of Clinical Research Organizations Survey: Number of US physicians participating in clinical research continuing to drop. Oncology Times 2010;32:21–3. [17] U.S. Department of Health and Human Services. Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement of Investigator (Form FDA 1572); 2010. [18] U.S. Food and Drug Administration. New Drug, Antibiotic, and Biologic Drug Product Regulations. 1987. Available from: http://www.fda.gov/ ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm120111.htm. Accessed April 1, 2011. [19] U.S. Food and Drug Administration. Available from: www.fdaregulatory. com/ichgcp/glossary.html. Accessed April 1, 2011. [20] Goebel PW, Whalen MD, Khin-Maung-Gyi F. What a Form 483 Really Means. Applied Clinical Trials Online 2001. Available from: http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/ article/articleDetail.jsp?id⫽92055. Accessed April 1, 2011. [21] U.S. Food and Drug Administration. Significant Dates in U.S. Food and Drug Law History. 2010. Available from: http://www.fda.gov/ AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm. Accessed March 31, 2011. [22] National Institutes of Health. Understanding clinical trials. 2007. Available from: http://clinicaltrials.gov/ct2/info/understand#Q19. Accessed May 6, 2011.
Article
A clinical trial primer: Historical perspective and modern implementation夡 Lawrence I. Karsh, M.D., F.A.C.S., C.P.I.* The Urology Center of Colorado, Denver, CO 80211, USA
Abstract The structure of modern clinical trials is designed to protect patient safety while generating safety and efficacy data. Safety is the primary concern, and United States regulations are shaped by a series of responses to incidents, including notable safety lapses and unethical trials. These regulations focus on 3 essential components, defined by the 1979 Belmont Report: respect for persons, beneficence, and justice. Further, the international community has formally outlined good clinical practice (GCP), which mandates that trials are designed to produce meaningful data, conform to international ethics regulations, and provide assurances that data are reported in a credible and reliable manner. The Food and Drug Administration (FDA) and federal government have outlined the necessary components of clinical trials in the Code of Federal Regulations (CFR). These include institutional review boards (IRBs), standard operating procedures (SOPs), sites, sponsors, investigators, and patients. The investigator is the center of the trial and is required to sign an agreement with the federal government to uphold the CFR. Investigator duties include making sure that investigator and support staff having appropriate qualifications, delegating duties, monitoring the study for compliance and record keeping, providing care, and accepting accountability for the trial, among other duties. Physicians, who already have significant time demands, need a well-trained staff, including clinical coordinators, to adequately meet these duties. Despite these requirements, trials can have significant benefits for investigators, practices, and patients, foremost of which is the ability to provide cutting edge care. However, the clinical trial process requires routine evaluation and continual performance improvement in order to ensure that patients not only receive excellent care, but also do so in the safest possible manner. © 2012 Elsevier Inc. All rights reserved. Keywords: Clinical trials; Compliance; FDA; GCP
How we got here: The evolution of United States regulations The structure of modern clinical trials began after World War II, but was shaped by several notable events prior to this. In 1937, 107 people, many children, died as a result of the Elixir Sulfanilidamide tragedy [1,2]. In order to increase the popularity of sulfanilidamide, a Tennessee company created a liquid formulation in which the sulfanilidamide had been diluted with diethylene glycol—the main compoDisclosure/Conflict of Interest Statement: L.I. Karsh is a consultant for Amgen, Dendreon, Bayer, Allergan, Spectrum, Janssen and Astellas/Medivation. 夡 LIK serves on advisory boards for Amgen, Johnson and Johnson, Pfizer, Sanofi Aventis, and Spectrum, and as a speaker for Allergan, Amgen, Dendreon, Ferring, GlaxoSmithKline, and Pfizer. * Corresponding author. Tel.: ⫹1-303-825-8822; fax: ⫹1-303-8254022. E-mail address: [email protected] (L.I. Karsh). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2011.05.012
nent of antifreeze—that caused vascular nephropathy [2]. The toxicity of the inactive ingredients was not tested, as it was not required by existing regulations. As a direct result of the event, the FDA established the 1938 Federal Food, Drug, and Cosmetic Act, which required drug manufacturers to send new drug application (NDA) reports to the FDA, showing drug safety. It also banned false labeling and dangerous ingredients, requiring manufacturers to disclose all active ingredients [3]. Prescriptions were required for certain medications, although it would take the 1951 DurhamHumphrey Amendment to create the category of prescription drugs. Most importantly, the 1938 act was the first to require scientific tests when manufacturing a drug. This was not the first drug regulatory act on the books. Previously, the 1906 Pure Food and Drug Act was designed to eliminate adulterated and misbranded food and drugs [3]. While the legislation had been under consideration for some time, the 1906 publication of Upton Sinclair’s The Jungle, an exposé of the Chicago meatpacking industry, generated
L.I. Karsh / Urologic Oncology: Seminars and Original Investigations 30 (2012) S28 –S32
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Fig. 1. The foundations of modern clinical trial regulations [21].
public support for the measure [4]. The act was regulated by the Bureau of Chemistry in the Department of Agriculture, which became the FDA in 1930 [3]. The act did not regulate drug safety or advertisement. While the 1938 Federal Food, Drug, and Cosmetic Act significantly affected the way pharmaceuticals were dispensed, it did not require proof of efficacy, nor did it standardize clinical testing. The FDA did not review an NDA until the drug was marketed, and drugs were automatically approved if the FDA had not completed its NDA review within 60 days [3]. It would take another 23 years before significant changes would be made in the drug review process. In the interim, another tragedy shaped human clinical trials. The 1947 Nuremberg Code was drafted in response to experiments conducted by Nazi scientists [5]. The code outlined 10 principles for conducting human clinical trials. These included voluntary consent, ensuring that experiments are useful and necessary, conducting animal experiments before using human subjects, allowing subjects to stop at any time, and the use of qualified scientists to conduct the research [5]. These became the backbone of research ethics and the protection of human subjects. It would take yet another tragedy to move the industry forward. The first “thalidomide baby” was born in Germany in 1957, although it was several years before the connection between thalidomide and birth defects was made. This tragedy was largely confined to Europe, where an estimated 8,000 deformed babies were born as a result of thalidomide [3]. In the United States, thalidomide was denied US approval— based on one FDA reviewer’s objections that its sponsor failed to show the product’s pharmacologic and toxicologic characteristics [1]. Accordingly, there were only 17 cases of thalidomide malformations in the United States, and the reviewer, Dr. Frances Kelsey, received the Presi-
dent’s Award for Distinguished Federal Civilian Service from President Kennedy [6]. The tragedy, though, spurred the 1962 Kefauver-Harris Amendment [7]. The act required “substantial evidence” of safety and efficacy for new drugs before they come to market [1]. It also regulated drug marketing and placed it under control of the FDA, established good manufacturing practices, and allowed the FDA to verify those practices. It introduced informed consent requirements and established the current format of clinical testing [1]. This was soon followed by the 1964 Declaration of Helsinki, which along with the 1947 Nuremberg Code forms the basis of protection of subject rights. The World Medical Association, an organization created in 1947 to ensure ethical behavior and care by physicians, developed the declaration, which clarified and interpreted the Nuremberg Code [8]. In addition to acknowledging the importance of clinical research, it defined the process. This included the formal outline of an experimental protocol, including ethical statements, ethical review by an independent outside body, engaging in human research only when the risks involved have been assessed, conducting trials in which there is a likely or potential benefit, the use of informed volunteers who consent to the study, and safeguards for the integrity of the subjects [8]. The Declaration of Helsinki is periodically updated, with the last version (the eighth revision) released in 2008 [9]. While there were codes to foster the ethical study of human subjects in the United States, these codes were not followed in the case of the Tuskegee Syphilis Experiment, a study conducted among rural African-American men in Alabama between 1932 and 1972. The men, who were infected with syphilis, were given free medical care— but they were not told they had syphilis nor were they treated for it [10]. Public awareness of this study, along with sev-
S30
L.I. Karsh / Urologic Oncology: Seminars and Original Investigations 30 (2012) S28 –S32
Table 1 The fundamentals of clinical development [22] Phase I
Phase II Phase III
Phase IV
Evaluation of safety, determination of a safe dosage range, and identification of side effects in a small group of subjects (20–80). Larger trials (100–300 subjects) to determine whether a treatment is effective and further evaluate safety. Larger studies (1000–3000 subjects) to confirm safety and efficacy and compare the investigational treatment with other options. Post-marketing trials comparing different approved treatments or side effects. Phase IV trials are designed to help optimize already available treatments.
eral other unethical studies, resulted in the creation in 1979 of The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. Of note, it would take almost 2 more decades until the United States Government formally apologized for the Tuskegee study. However, in 1979 the commission published the Belmont Report, defining the essential components of ethical research: respect for persons, beneficence, and justice [11]. These principles were to be applied in the form of informed consent, assessment of risk and benefits, and selection of subjects. It also recommended boundaries between clinical practice and clinical research [11]. The Belmont Report specified the ethical principles that underlie all clinical research conducted in the United States today. These are not the only acts and provisions that pushed clinical research to the model we employ today: unfortunately, there are many other examples of tragedies and unethical practices that necessitated changes in clinical research processes. However, these are the major benchmarks that have left us with a well-defined, methodical system designed—first and foremost—to ensure the safety of our subjects, as well as to show clinical efficacy (Fig. 1). As medical science continues to evolve, regulations have been set in place to cover new realms with ethical implications, including stem-cell research, gene therapy, and in vitro fertilization.
Where we are today: Good clinical practice in research Regulations focus on ensuring patient safety in clinical trials. Clinical trials fall into the span after an investigational new drug application is filed. They include Phase I through post-marketing Phase IV trials. The fundamental phases of clinical development are shown in Table 1. Today, there is a laundry list of regulations involved in the design and implementation of ethically conducted clinical trials. With globalization, a need for global standardization became apparent. In 1990, the United States, members of the future European Union, and Japan formed the International Conference on Harmonization (ICH), which is
designed to facilitate the mutual acceptance of clinical data by regulatory authorities [12]. The ICH, which includes Australia, Canada, other countries, and the World Health Organization, provide guidance on quality, efficacy, safety, and multidisciplinary issues. It has defined good clinical practice (GCP) as: “A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the right, integrity, and confidentiality of trial subjects are protected.” [13]. This definition also pertains to any trials that address other investigational procedures, including surgical procedures, diagnostic assays, and medical devices. The ICH has released the ICH-GCP, which consists of 13 points that are the foundation for GCP [14] (Table 2). The Code of Federal Regulations (CFR) requires that all phases of clinical investigation be conducted in accordance with GCP [15]. The CFR has a number of regulations specifically focused on clinical trials; these outline the components required for protection of human subjects, as well as how the trial participants interface with regulatory bodies. Among these is the requirement for Institutional Review Boards (IRB). The IRB, and independent ethics committee (IECs; an alternative name for IRBs), serve to ensure that trials are designed such that trials meet the requirements outlined by the various regulations. The IRB/ IEC is one primary component of clinical trials, as are the subjects, sites, sponsors/contract research organizations (CROs; companies that are hired to help conduct research trials), regulatory bodies, and the investigators. The clinical investigator is the interface between these components and, as such, has significant responsibilities: ● Ensuring investigator and support staff having appropriate qualifications ● Accountability for investigational product use ● Complying with GCP and applicable regulatory requirements ● Permitting monitoring, auditing, and inspection ● Delegation ● Ensuring sufficient resources ● Providing medical care ● Obtaining IRB/IEC approval ● Complying with protocol ● Obtaining informed consent ● Keeping records and submitting reports ● Safety reporting. For investigators—who already have significant time demands—this may seem overwhelming. According to a 2010 survey conducted by the Association of Clinical Research Organizations (ACRO), the number of physicians participating in clinical trials in the United States has continued to decrease over the past decade. The survey indicated that 70% of over 300 respondents in the United States and Europe believe that the current regulations make it chal-
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Table 2 The principles of the ICH-GCP Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol that has received prior IRB/IEC approval/favorable opinion. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Freely given informed consent should be obtained from every subject prior to clinical trial participation. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
lenging to manage clinical trials [16]. In the United States, investigators sign a Form FDA 1572 at study initiation [17]. This is an agreement by the investigator and the federal government to comply with FDA regulations for clinical trials, providing sponsors with information about the investigator and site qualifications, and to inform the investigator of his or her obligations [17]. It is nearly impossible to comply with regulations and meet responsibilities without adequate support staff. Thus, it is imperative to have the proper components to adequately manage these requirements. First and foremost of these are the study coordinators, who work under the direction of the investigator. As trial managers, an excellent study coordinator is reliable, competent, and trustworthy, supporting the daily activities critical to the trial. These activities involve tasks associated with study start-up, conduct, and closure, often including aiding in the preparation of scientific, budget, and protocol proposals, acquiring and reporting data, ensuring safety, and general administrative tasks. Larger clinical trial sites may have additional staff to oversee some of these aspects, while smaller sites may rely on the study coordinator to handle these tasks. Regardless, when investigators delegate tasks, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated [15]. Therefore, it is critical that the investigator be able to work well with his or her staff to ensure that all regulations are followed. While the investigator is the interface, the patient is the focus of the trial, and all of the components serve to ensure that the patient receives the safest care possible within the clinical trial. The FDA serves to assure safety and the rights of subjects/patients, provide input on design of protocols and overall clinical program, assure quality and integrity of data, and assure quality of clinical trial materials, issue regulations and guidelines [18]. While GCP is the expected standard, errors can and do occur. Accordingly, the FDA has an audit process to ensure
that clinical trials are conducted to standards. The CFR requires “a systematic and independent examination of trialrelated activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsors standard operating procedures (SOPs) [GCP], and the applicable regulatory requirements,” also known as the dreaded audit [19]. An audit may be conducted by the study sponsor (sometimes at the request of an investigator or site as quality control) or by the FDA. It may be initiated for multiple reasons, including high or low enrollment, cause-specific, or it could be entirely random. The auditor looks at all of the components of a site, including investigators, consents, protocols, and safety. Following an FDA inspection, the agency can produce a form FDA 483 report. The 483 report does not specifically cite regulations, but is rather an observation report [20]. The observations are the opinion of the auditor(s) and are subject to further FDA review, which will then produce a follow-up letter for investigators. The FDA letter is not necessarily meant to punish investigators, as it may result in no further action required, but it can require disciplinary actions or sanctions for the investigator and/or site [20]. While an audit may be stressful, ultimately, it is an opportunity to improve the strength of a trial site and ensure that GCP is being conducted. It may result in improved or added standard operating procedures (SOPs) and greater employee scrutiny. As such, it is an important oversight component that improves the clinical trial process [20]. While there are significant challenges to participating as a trial investigator, there are many benefits to get involved in clinical trials. Importantly, working within the clinical trial system allows investigators to offer cutting-edge technology and treatments for patients who may need access to these services. Clinical trial investigators are part of the important process of advancing medicine, clarifying best
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practices, and validating investigational agents. This imparts prestige to a site and helps condense expertise towards the center. Clinical investigations serve to educate both patients and physicians involved in the process. Aside from the more important altruistic reasons for conducting clinical trials, involvement in clinical studies can have a financial incentive. In the 2010 ACRO survey, 68% of US respondents said that generating more revenue was “very important” [16]. Of course, this may be in part because conducting a clinical trial involves significant time and expenses. Research and development is critical to the success of any business or organization, especially in medicine. It allows providers to offer tomorrow’s therapies to their patients today. Further, randomized, controlled clinical trials are the primary means to evaluate these therapies. Those involved in clinical trials should constantly strive to improve the investigational program by improving enrollment, procedures, and patient and investigator education, as well as acquiring the most-qualified and best employees, and attracting sponsors and studies. Most importantly, those involved in conducting clinical trials should continue to push the boundaries of urologic medicine in the attempt to provide the best possible care for their patients. Acknowledgments The author thanks all of the patients who participated in clinical trials at TUCC. A special thanks to the research staff at TUCC, to Robin Dorsey for her support and dedication to clinical trials, and to Michael Linde for medical writing assistance in preparation of this manuscript. References [1] Hamburg MA. Shattuck lecture. Innovation, regulation, and the FDA. N Engl J Med 2010;363:2228 –32. [2] Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug, and Cosmetic Act. Ann Intern Med 1995;122:456 – 61. [3] Borchers AT, Hagie F, Keen CL, et al. The history and contemporary challenges of the US Food and Drug Administration. Clin Ther 2007;29:1–16. [4] Barkan ID. Industry invites regulation: The passage of the Pure Food and Drug Act of 1906. Am J Public Health 1985;75:18 –26. [5] Markman JR, Markman M. Running an ethical trial 60 years after the Nuremberg Code. Lancet Oncol 2007;8:1139 – 46.
[6] Hilts PJ. The FDA at work— cutting-edge science promoting public health. 2006. Available from: http://www.fda.gov/aboutfda/whatwedo/ history/overviews/ucm109801.htm. Accessed March 31, 2011. [7] Howland RH. How are drugs approved? Part 1: The evolution of the Food and Drug Administration. J Psychosoc Nurs Ment Health Serv 2008;46:15–9. [8] World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2000; 284:3043–5. [9] World Medical Association. Declaration of Helsinki. 2011. Available from: http://www.wma.net/en/20activities/10ethics/10helsinki/ index.html. Accessed April 1, 2011. [10] Howland RH. How are drugs approved? Part 2: Ethical foundations of clinical research. J Psychosoc Nurs Ment Health Serv 2008;46:15–20. [11] The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Department of Health, Education, and Welfare, 1979. [12] International Conference on Harmonization. Introduction. 2011. Available from: http://ichgcp.net/introduction. Accessed April 1, 2011. [13] International Conference on Harmonization. ICH GCP. 2011. Available from: http://ichgcp.net/. Accessed March 31, 2011. [14] International Conference on Harmonization. The Principles of ICH GCP. 2011. Available from: http://ichgcp.net/2-the-principles-of-ichgcp-2. Accessed April 1, 2011. [15] International Conference on Harmonization. Clarification of Certain Investigator Responsibilities. 2011. Available from: http://ichgcp.net/ clarification-of-certain-investigator-responsibilities. Accessed April 1, 2011. [16] Eastman P. Association of Clinical Research Organizations Survey: Number of US physicians participating in clinical research continuing to drop. Oncology Times 2010;32:21–3. [17] U.S. Department of Health and Human Services. Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement of Investigator (Form FDA 1572); 2010. [18] U.S. Food and Drug Administration. New Drug, Antibiotic, and Biologic Drug Product Regulations. 1987. Available from: http://www.fda.gov/ ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm120111.htm. Accessed April 1, 2011. [19] U.S. Food and Drug Administration. Available from: www.fdaregulatory. com/ichgcp/glossary.html. Accessed April 1, 2011. [20] Goebel PW, Whalen MD, Khin-Maung-Gyi F. What a Form 483 Really Means. Applied Clinical Trials Online 2001. Available from: http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/ article/articleDetail.jsp?id⫽92055. Accessed April 1, 2011. [21] U.S. Food and Drug Administration. Significant Dates in U.S. Food and Drug Law History. 2010. Available from: http://www.fda.gov/ AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm. Accessed March 31, 2011. [22] National Institutes of Health. Understanding clinical trials. 2007. Available from: http://clinicaltrials.gov/ct2/info/understand#Q19. Accessed May 6, 2011.