Dr. Grant Williams, MD (FDA) Today I will briefly provide the regulatory background for discussion of single-patient use of investigational drugs and biologic products. When I speak today of drugs, please understand that I am referring to both drugs and biological products. I am from the Division of Oncology Drug Products for drugs at FDA, but our Division works closely with the Center for Biologics and oncologists there, and today we have Karen Weiss and Pat Keegan at the table with us. As you know, this committee commonly reviews applications from both drugs and biologics. So, what are the objectives for our meeting today? One objective is to educate the public on the many issues surrounding the treatment use of experimental drugs. I think you have been educated already from the patients that have spoken today, and we will be hearing from many others. A second objective is to get the advice and input on when it is appropriate to allow experimental drugs to be used for the treatment of individual cancer patients. To accomplish these goals today, we plan to hear from a number of individuals who may have a variety of perspectives on this issue. First, I will make a few introductory remarks about the law and about FDA experience. Next, we will be hearing from ethicists who will provide us with principles and language that will be useful when having our dialogue. Then, we will be hearing from the perspective of industry, from two individuals representing drug companies involved in studying cancer drugs. Finally, we will hear the perspective of patients as communicated by representatives from three patient advocate groups. After hearing these presentations and the perspectives that they represent, the committee will be asked to discuss the relevant issues. We are looking forward to these discussions and to your advice, and we will consider them very carefully as we evaluate our approach to single-patient use of investigational drugs. First I wast to begin with a few definitions. All use of experimental drugs is regulated by FDA under an IND. An IND is an investigational new drug application. There are several different individuals that may be involved in an IND. First, there is the IND sponsor. The sponsor is the individual, company or institution that assumes responsibility for overseeing the study for assuring that the regulations are followed and for reporting to FDA on the progress of the study. The sponsor may or may not be the manufacturer of the drug. Next, there is the investigator. The investigator is the individual that actually performs the trial or administers the drug. At times the investigator and the sponsor are the same person. The regulations stipulate that a sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug. For most cancer drug applications, we expect the investigator to be a licensed physician and to have training and experience in treating cancer FDA may receive a request for treatment at any stage in the process of drug development. So it is important to understand something about the process. The stage of development tells you how much information there is about a drug. For those of you that are not oncologists, I will briefly outline the drug development process in oncology. The first stage is the preclinical stage before a drug has been studied in humans. We may have data from laboratory studies or from animal studies. These data allow investigators to select a cost for the first studies in humans and to identify toxicities caused by the drug in animals. The sponsor subsequently files an IND. This IND contains, among other things, a clinical protocol for a Phase I study. Phase I studies in oncology are generally small studies, done carefully in just a few patients to determine what is an acceptable dose of drug for future study, and to determine the most obvious toxicities of a drug. The next phase of the cancer drug development is Phase II. Separate Phase II studies are performed in different types of cancers. Generally one or two studies 1usually totaling 30-100 patients are evaluated in each disease. The purpose of a Phase II study is to see if there is preliminary evidence that the drug might work. Such evidence might be tumor shrinkage or often known as tumor response. Finally, the last stage of development before drug approval is Phase III. Phase III trials are larger trials, designed to demonstrate whether the evidence of drug activity noted in Phase II actually translates into clinical benefit. These are usually randomized trials in hundreds or thousands of patients comparing the experimental drug to a standard therapy. So, that is a brief overview of the development of cancer drugs. The stage of development is one important consideration in evaluating the request for treatment use of an experimental drug. The usual purpose of an IND is to allow for clinical investigators to determine whether a drug is safe and effective. If the findings from the studies are favorable, the sponsor will submit all of the data from these investigations to FDA to determine whether the drug can be approved for marketing. In this way, the drug becomes widely available to the American public. The FDA strongly endorses participation in clinical trials because it is in the best interests of the American public to determine whether a drug is safe and effective. Individual patients also benefit by participating in cancer clinical trials. The best treatments available are selected for testing in these trials. However, there are times when it may be appropriate to test make an investigational drug available primarily for treatment rather than for the usual purpose of investigating the drug's safety and effective. Generally, this unusual step of authorizing such use is warranted only for patients with serious diseases and conditions, such as cancer, and for whom there are no remaining satisfactory treatments. The terminology surrounding treatment use of experimental drugs can be confusing because the regulations do not explicitly describe all of the practices. Different terms are frequently used for the same practices. Treatment use of experimental drugs can be divided into two main groups, single-patient treatment use and expanded access treatment use. Expanded access refers to the fact that multiple patients are being treated under a single protocol, whereas for single-patient use individual type treatment plans are drawn up for individual patients. I will briefly describe expanded access. In oncology, historically there are two well-defined procedures for expanded access. Since the 1970's NCI has worked with FDA to provide investigational treatment for use under a mechanism called Group C. In 1987 regulations were adopted that formalized this process and extended it beyond the treatment of cancer to all diseases that are serious and life-threatening. The name of this mechanism of expanded access is the treatment IND or treatment protocol. Both Group C and treatment IND are intended to allow for widespread distribution of a drug that is nearing marketing approval. Over the years expanded access protocols have also11 been approved for promising drugs not yet at this stage of development, that is, near marketing approval stage and treatment IND. The requirements and format for these other expanded access protocols are not really described in the regulations as a separate section, but the considerations for their approval are similar. In a little while you will be hearing from Dr. Linden and Dr. Kennealey about their experiences with such protocols. Now I will describe single-patient use. In single- patient use treatment plans are drawn up individually for each patient. There are two mechanisms for handling single-patient use. In the first mechanism, the single-patient IND, a new sponsor files separate IND. We know that hundreds of patients per year receive drug under single-patient INDs. In general, this process is less desirable and involves more paperwork for everybody. Also, there is not a single sponsor who communicates with all the physicians treating patients. Generally there is one sponsor per IND. In the second mechanism, called single-patient exception, there is already an existing IND, an existing sponsor and an existing investigational protocol. Under the single-patient exception mechanism a patient who is ineligible for an investigational protocol is treated under a plan that is a slight modification of the existing protocol. The same IND and the same sponsor are used. This is a more efficient mechanism for single-patient treatment. In summary, investigational cancer drugs are provided for treatment use by a variety of mechanisms. Over the years many thousands of patients have received investigational cancer drugs through treatment IND or Group C mechanism, by other expanded access mechanisms or by single-patient treatment use. So, what are the legal requirements? Legal requirements for single-patient use are basically the same as those for any IND. There must be a drug manufacturer that will supply the drug. There must be a sponsor who reports to FDA. There must be a medically trained investigator and, again, sometimes the sponsor and the investigator are the same person. There must be informed consent and IRB approval, and there must be concurrence by FDA that there is sufficient evidence supporting the drug's safety and efficacy. Please note, however, that FDA cannot initiate this process even after a request from a patient or a patient's doctor. The FDA does not produce drugs and the FDA is not a sponsor. You should be aware that if there is a problem with a requirement for treatment use, FDA may not always be able to directly communicate the reason for the problem, and I think you have heard that earlier. Legally, much of the information generated under an IND is proprietary and confidential and it cannot be communicated by FDA without permission of the sponsor. But we did find interesting the comments earlier, and we will look into what we are legally able to communicate in the future. When evaluating any requirement for treatment use, these are the items one must consider: whether evidence suggests that the drug is active or toxic; whether patients have other acceptable treatment options; whether the sponsor is conducting clinical trials needed for marketing of the drug; and whether the proposed treatment is likely to interfere with clinical studies needed to prove whether the drug is safe and effective. These latter two issues may be less important for single-patient use, especially if such use is infrequent. In summary, when evaluating a requirement for single-patient use of an investigational drug these seem to be the central issues: First, what evidence do we have regarding the drug's effect in people? One aspect of this question is to consider the stage of drug development. Do we have data from Phase I studies, Phase II studies, Phase III studies? Then we need to consider the results of the studies. Are there data suggesting that the drug has activity or that it is toxic? The other important consideration is whether there is available standard therapy for the patient's cancer. For diseases where there is no standard therapy or where standard therapy is not satisfactory, FDA has usually permitted single-patient therapy if data suggests that experimental treatment is relatively safe. Ann's NOTE: You can find the entire meeting summary at the FDA website below. You must locate 12/14 first http://www.fda.gov/ohrms/dockets/ac/cder00.htm#Oncologic/20Drugs/20Advisory/%2020Committee Oncologic Drugs Advisory Committee Start Day Transcript ID (size in kb) Transcript Text ID (size in kb) Minutes ID (size in kb) Other Docs ID (size in kb) 12/13 12/14 3671t1.asc 3671t2.asc Agenda 3671a1.doc, pdf Roster 3671r1.doc and pdf Briefing Information 3671b1.htm Questions 3671q1.pdf 3671q1_01.doc, pdf 3671q1_02.doc, pdf Slides 3671s1.htm 12/1 4 3671b2.htm     December 14, ODAC by letter   Member of PANCAN and user of Chinese Herbs with chemotherapy   National Patient Advocate Foundation