Clinical Trials
Jeanette A. Linebaugh
WHAT ARE CLINICAL TRIALS AND WHY SHOULD THEY BE DONE?
New medical knowledge can be acquired and disseminated in many ways, including case reports, collected experiences, retrospective studies, clinical trials, and meta-analyses. Of these alternatives, prospective randomized clinical trials, although not perfect, have become the gold standard. Designed properly, they are the best method to avoid many of the disadvantages of other methodologies, including small sample sizes, investigator bias, changes in therapy or supportive care over time, unequal distribution of prognostic factors, and improper use of statistical methods.
A clinical trial is a research approach to developing new drug treatments, devices, or surgical techniques in a clinical setting. Cancer research has not progressed rapidly but has made important incremental steps with constant progress. In the 1990s, research produced the first ever decline in cancer mortality and cancer incidence in the United States. More than 60% of patients now survive an average of 5 years, compared with 49% who survived 20 years ago. Mortality for both men and women has declined from 2001 to 2006 by 2% per year for men and 1.5% per year for women, compared with 0.8% per year from 1994 to 2002. Pain and discomfort from cancer and cancer therapies have also been reduced with more effective analgesics and antiemetics. Furthermore, the incidence of cancer has decreased for all cancer sites by 1.3% per year in men from 2000 to 2006 and 0.5% per year in women.1
Clinical research has also demonstrated that some drugs may reduce the risks of cancer. The use of tamoxifen for women who are determined to be at high risk for breast cancer serves as an example. In addition, the possibilities of targeted cell treatment (drug treatments that find and destroy the genetic abnormality in cancer cells) such as imatinib and erlotinib and cancer vaccines open an exciting new world for cancer therapy. The addition of the targeted agent trastuzumab (Herceptin) to chemotherapy reduces the risk of cancer recurrence compared with chemotherapy alone in women with early, HER2-positive breast cancer. By ongoing clinical trial research, continued progress in the prevention and cure of cancer can be achieved.
Clinical trials are divided into four different phases, with each progressive phase asking a different level of scientific question. A phase I trial is the first level of research carried out on human subjects using available results from animals or cell model research. Clinical oncology phase I trials have two main goals: “the precise definition of an optimal dose and safe treatment of the individual patient at doses that are close to therapeutic.”2 Phase I studies in oncology are usually focused on patients who have no currently effective treatment or in whom conventional therapy has failed. They are the most commonly performed at one or a few treatment centers with a small number of patients in a controlled setting. If the results show side effects to be tolerable and the drug appears promising, the next phase of study is pursued. A phase II trial explores the therapeutic effects of this anticancer treatment regimen. The goal is to determine the extent of response that a specific tumor type may have when treated with the protocol agent. This phase may also help define the drug dose for further use. This type of trial can be performed in a handful of centers, usually focusing on patients with the same disease characteristics, for example, lung cancer or breast cancer. Efficacy in a target population is the main question of phase II trials. Significant positive results from phase II trials lead to phase III trials, which compare the experimental drug or combination with an already established treatment for the same diagnosis. Phase III trials are typically randomized trials and usually include stratifications according to patient characteristics, such as age, extent of disease, performance status, menopausal status, and so forth depending on the disease, in order to achieve balance between arms. A large number of patients with the same disease characteristics are enrolled at a number of different institutions. Cooperative groups and pharmaceutical companies commonly sponsor phase III trials so that the required large number of participants can be enrolled in a shorter period. A phase IV trial is the final phase of new drug or drug combination investigations. These studies are postmarketing trials, not required for licensure. They look to establish the optimal use of this treatment for large populations of patients with the same cancer characteristics. The objectives are to monitor the drug’s safety in larger populations, provide indications for its use, and establish the dosing and patient populations for labeling purposes.
Patients diagnosed with cancer or those at high risk for the development of cancer seek an oncologist, who can help them improve the quality of their life (or expected life), increase their survival, and, most importantly, cure their cancer. Patients deserve the opportunity to reach these goals. More and more, they choose an oncologist, not for travel convenience but for involvement in the “cutting edge” world of research. Clinical studies offer patients the opportunity to receive tomorrow’s cancer treatments today. Patients participate in clinical trials to fight cancer effectively. They also participate to support cancer research with the hope that, even if they are not helped, their participation will help lead to the discovery of a cure. In her book, She Came to Live Out Loud,3 Anna, a patient with stage
IV breast cancer, states that, “I am part of a (National Institutes of Health) study that may turn up a wonderful drug for a bunch of other people down the road.”
IV breast cancer, states that, “I am part of a (National Institutes of Health) study that may turn up a wonderful drug for a bunch of other people down the road.”
Clinical trial investigators have the same goals in mind for their patients when seeking to participate in coordinating trials at their centers. Three main types of clinical trial avenues are available: National Cancer Institute (NCI) sponsored studies, pharmaceutical industry-sponsored studies, and studies developed at an individual institution (in-house trials). The NCI views clinical trials as a “crucial component in the process of developing new treatments, preventive measures, and detection and diagnostic techniques.” The NCI 2000 Bypass Budget shows that $11.1 million will be spent on cooperative group research.4
Professional involvement in national oncology groups allows investigators to participate in NCI-sponsored trials. A center can participate as a main member or parent site or may choose to participate as an affiliate of a parent center. Each national cooperative group has specific membership guidelines to determine the definition of parent and affiliate enrollment. Information on each oncology group can be found on the Web site http://ctep.cancer.gov.
The pharmaceutical industry looks for investigators who can perform quality trials in accordance with the Good Clinical Practice (GCP) guidelines in the shortest time possible. The GCP was prepared under the auspices of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use and is published in the Federal Register.5 An established clinical research center/office is the first choice of pharmaceutical companies when looking for quality sites to perform their trials. A history of successful and ethical conduct with an NCI-sponsored group provides credibility with industry sponsors.
Many oncologists identify research questions within their own practice. Often, there may not be an oncology group or pharmaceutical-sponsored trial that may fit that particular area and/or stage of disease,or thoughts of a commercially available drug used in a different indication than that approved may initiate ideas of better response alone or in combination with another drug or modality of treatment. These ideas can be developed into an in-house trial, in which oncologists, using current background research, write their own protocol, and conduct this study at their site. The manufacturers of these drugs can guide an investigator through the U.S. Food and Drug Administration (FDA) requirements in receiving FDA approval to conduct this study. Often, FDA approval is required before the trial can begin, because the study objective may differ from the clinical indication. FDA guidance is recommended for in-house studies.
WHAT IS INVOLVED IN PERFORMING CLINICAL TRIALS?
Before embarking on the road to conducting clinical trials, novice investigators should determine what is involved in participation in these trials. Several important questions must be considered beginning with
How do I select a trial?
What are the federal regulations for clinical studies?
What are my requirements and responsibilities as a principal investigator (PI)?
What is involved in the patient consent process?
What financial considerations are involved?
How do we handle investigative drugs?
How do I prepare a study budget?
How do I prepare for audits?
Federal Requirements for Clinical Trials
An Institutional Review Board (IRB) has the responsibility of assessing the risk-benefit ratio of each study solely for the protection of the rights and safety of the patients served. The Office for Human Research Protections is the warden’s office for the Department of Health and Human Services. The main responsibility of this office is to ensure that patient safeguards are in place for human studies through IRBs. This responsibility is carried out by monitoring the activities of each IRB through routine audits and required certifications.
The federal requirements for conducting a clinical study are specifically outlined in the Code of Federal Regulations (CFR)6 under sections 21 CFR 50 for informed consent, 21 CFR 312 for investigative new drug (IND) regulations, and 21 CFR 56 for IRB regulations. The CFR is a permanent set of rules published in the Federal Register by executive departments of the federal government and these are legally enforceable requirements. A full set of the CFR is available on the Internet at http://www. gpoaccess.gov/nara/index.html. Any research project, all protocol changes (updates) to that project, and the related written patient consent document must receive IRB approval before any patient can be screened for eligibility, enrolled, and treated on a study. All serious unexpected adverse experiences must also be reported to the controlling IRB and the study sponsor, even those adverse events occurring at other sites involved in the same study. Some hospitals/institutions defer to regional IRB committees rather than develop a local board. Institutional officials should be able to supply information on their IRB preferences.
Exceptions for “compassionate use” studies, studies used to procure an investigational drug in an emergency situation, are also covered in the CFR. All sponsors, including cooperative oncology groups (COGs), require proof of IRB approval of any project before they allow enrollment to that particular study. Many cooperative groups have databases of institutional IRB deadlines and mail reminders of the expiration date of IRBapproved projects. Documentation to support IRB approval is thoroughly inspected during the oncology group audits. Any activity on a study that does not have current IRB approval is reported to the NCI as a major IRB deviation. Pharmaceutical companies require several documents before studies can be initiated. Items most often found in these so-called regulatory packets are listed in Table 5-1
Copies of the regulatory packet are kept on-site in a “regulatory binder.” The regulatory binder and all patient-related documentation are reviewed at each company monitoring visit and must be retained by the investigator for a period of 2 years
postmarketing approval in that particular country. Document retention for 15 years’ postmarketing is required if licensure is obtained in a different country. IRB approvals of all protocol updates, investigator brochure (IB) updates, or safety reports/adverse experiences reported by the company should be filed in the regulatory binder.
postmarketing approval in that particular country. Document retention for 15 years’ postmarketing is required if licensure is obtained in a different country. IRB approvals of all protocol updates, investigator brochure (IB) updates, or safety reports/adverse experiences reported by the company should be filed in the regulatory binder.
The Central Institutional Review Board (CIRB) initiative is sponsored by the NCI in consultation with the Offices of Human Research Protections. The CIRB provides a “facilitated review” process that can streamline local IRB reviews of adult and pediatric cancer treatment trials. The CIRB was designed to help reduce the administrative burden on local IRBs and investigators while continuing to provide a high level of protection for human research participants.
There are several benefits to using a CIRB for both the investigator and the local IRBs. There is little to no preparation for IRB review at the site. Sites can download a complete IRB packet and submit the packet to the local IRB with the model consent on local letterhead. This allows sites to enroll patients faster because they do not have to wait for the next IRB meeting. Benefits to the local IRB include carrying out the review process without having to wait for a full board meeting. Continuing review, amendments, and adverse events are handled by the CIRB as well. The adult CIRB meets monthly and has been reviewing protocols since January 2001. The Adult Board reviews all phase III Cooperative Group trials. The Pediatric CIRB began meeting in November 2004. The board reviews COG phase II, III, and pilot protocols. Both the boards are composed of individuals who represent a broad range of oncology disciplines. These may include oncology physicians, nurses, patient representatives, pharmacists, and attorneys. None of the members or the Chairs are NCI employees.
Requirements of Principal Investigators
The responsibilities of a PI (the “charge person” of the study), should be taken very seriously. Along with the CFR, the ICH GCP5 describes each responsibility in detail. All aspects of the conduct of the clinical trial are the full responsibility of the PI. He or she may have coinvestigators involved, such as physician colleagues, nurses, associates, pharmacists, data managers, or secretaries. However, the PI is wholly responsible for each individual aspect of the study.
By choosing scientifically sound research studies, PIs are on the road to giving quality care and medical attention to their patients. Investigators should be educated and trained and have experience in conducting clinical studies and they should have adequate resources to conduct quality trials. These include a suitable patient population for potential patient accrual, qualified staff to assist in protocol compliance throughout the duration of the trial, and adequate facilities to conduct the trial.
Compliance in following the protocol is mandated in the GCP guidelines. By signing a Form 1572, the PI agrees to be completely compliant in the following all protocol guidelines established by the regulatory authorities, the IRB, and the sponsor. Deviations from the approved protocols cannot be made by the investigator without prior approval from the sponsor and the IRB. Only when there is an imminent danger to the patient can an investigator make changes in protocol treatment. Emergency changes in the written protocol must be documented and explained and then immediately reported to the sponsor, the IRB, and, when appropriate, the regulatory authorities.
Table 5-1 Items Required in Regulatory Packets | ||||||||||||||
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