Briefing Document for the ODAC
Single Patient Use of Investigational Anticancer Agents
Page No.
II. Investigational Use versus Treatment Use of an Investigational Drug 2
III. Single patient use of an investigational drug 3
VI. Issues and Examples 7
Draft Questions for ODAC 9
Appendices
I. Introduction
At the meeting of the Oncologic Drugs Advisory Committee (ODAC) on the afternoon of December 14, 2000 we will discuss single patient use of investigational cancer drugs, also called single patient INDs (Investigational New Drug Application), special exception use and sometimes referred to outside of FDA as compassionate use. Single patient use generally refers to treatment use of an investigational drug for an individual patient that is not part of the overall development. Single patient use may be requested by a commercial sponsor under an existing IND or by a physician-investigator under a new IND. This is distinct from more expanded access protocols that allow access to large numbers of patients, including Treatment INDs, that allow wide use prior to marketing late in development for a drug that has demonstrated promising results in an area without satisfactory available therapies.
The primary objectives of this meeting are to:
The FDA will ask experts in biomedical ethics, representatives from the pharmaceutical industry, and patient advocates to provide their perspective on the issues involved in single patient treatment with investigational therapy.
II. Investigational Use versus Treatment Use of an Investigational Drug
FDA’s responsibilities for oversight for the use of investigational drugs are described in part 312 of the Code of Federal Regulations (21 CFR part 312—Investigational New Drug Application (IND)). Most clinical trials conducted under an IND are designed to evaluate some aspect of the safety or effectiveness of the drug (See Appendix (i) for an overview of the cancer drug development process). The FDA strongly endorses participation in clinical trials because it is in the best interest of the patient and the American public to determine whether a drug is safe and effective for the proposed use. There are situations, however, in which it is appropriate to make an investigational drug available under an IND where the primary purpose is to treat a disease or condition rather than evaluate the drug’s safety and effectiveness. Generally, the unusual step of authorizing use of an investigational drug for what is primarily a treatment purpose is warranted only for patients with serious diseases or conditions who are without satisfactory therapeutic alternatives.
Particularly when a drug is being developed to treat a serious or life-threatening condition, FDA will receive requests for individual patient treatment use throughout the development program. Thus, the amount of information about safety and effectiveness that the agency has available at the time of a treatment use request can vary considerably but is often very limited. Therefore, safeguards are needed to protect patients and to ensure that treatment use does not interfere with development of critical safety and effectiveness information.
III. Single patient treatment use of an investigational drug
Treatment use of experimental drugs can generally be grouped into two broad categories according to the number of people treated: expanded access and single patient treatment. Regardless of the category of treatment use, all applications for investigational treatment require an investigator, informed consent, a sponsor who accepts responsibility for the study and communicates with the FDA, a drug supplier (who may also be the sponsor), and oversight by an Institutional Review Board.
A. Expanded access protocols
Expanded access protocols outline a treatment regimen that will be used for a predefined patient group. Since the early 1970s, FDA has facilitated access to drug under investigation for serious and life-threatening diseases, including cardiovascular, antiviral, and oncology drugs to thousands of patients. Two specific types of expanded access programs are Treatment INDs and Group C.
In 1987, the agency promulgated regulations formalizing the Treatment IND mechanism that permits widespread access to an investigational drug if there is no comparable or satisfactory alternative, if the sponsor is pursuing marketing approval with due diligence, if the drug is nearing the end of its development, and if the data support the conclusion that the drug may be effective for the intended use in the intended population.
In the field of oncology, through an agreement with FDA, NCI has provided provided expanded access to approximately 20 investigation agents through a mechanism called Group C.
B. Single patient treatment use of investigational cancer drugs
Single patient use is a treatment use of experimental drugs for an individual patient rather than a group of patients and this can occur in one of several ways. FDA can grant a single patient exception to receive drug under an existing IND when a patient is ineligible for the specified protocol. Under a single patient exception, the existing commercial IND sponsor provides drug and is responsible for reporting to the FDA.
If the commercial sponsor is unwilling to assume responsibility for a special exception, an investigator may perform the role of sponsor for a single patient treatment use. Under this model, the investigator must obtain the drug from a willing manufacturer and must apply directly to the FDA for an IND. This application should include a completed 1571 form (http://www.fda.gov/cder/cancer/singleind.htm, an outline of the patient’s history, a treatment plan, and a commitment to obtain informed consent and IRB approval.
At times, FDA has granted hundreds of such INDs per year, for instance 435 for aerosolized talc in 1996 and 515 for Thalidomide in 1998. In general, however, we believe that a single protocol covering such uses is preferable and it provides a better opportunity to obtain data useful to the drug’s development.
While evaluating requests for single patient use of investigational drugs, FDA often receives telephone calls from investigators or patients. FDA staff in the Office of Special Health Issues are available to help address patient questions. However, because the information contained in the IND is confidential, proprietary material, the FDA is limited in the information that may be communicated to the investigator or public. It is also important to remember that the process of requesting single patient use of a drug cannot begin with the FDA. The first step is for a qualified investigator to contact a manufacturer or commercial sponsor that is willing to supply the drug for this use.
IV. Legal Authority
Prior to 1997, there were no express regulatory criteria for assessing whether an individual patient should have access to an investigational drug for treatment use. The regulations described only procedures for obtaining an emergency IND for a single patient (21 CFR 312.36 permits authorization by telephone before the agency has received the IND submission) if the situation does not allow time for submission of an IND in accordance with 21 CFR 312.23 or 24.
The Food and Drug Administration Modernization Act (FDAMA) of 1997 sought to address the concern that because there were no guiding criteria there could be inconsistent or arbitrary implementation of individual treatment access. FDAMA identifies specific criteria for determining whether an individual patient should have access to an investigational drug for treatment use that, for the most part, formalize the general criteria FDA had been using to evaluate individual patient treatment use requests. FDAMA makes clear that any individual patient, acting through a licensed physician, is empowered to seek to obtain an investigational drug for treatment use. The expanded access provisions in FDAMA (Section 561) specify that an individual patient may obtain an investigational drug for treatment use when:
Sponsors and investigators must also comply with reporting IND requirements (e.g., safety reports), obtain the informed consent of the patient, and obtain IRB approval.
The stated criteria are necessarily general, and subject to some interpretation. In applying these criteria to individual patient treatment use in the oncology setting, the following questions commonly arise:
Other issues, not unique to oncology, arise as single patient use increases for a particular investigational drug. These issues include:
V. FDA’s Analysis of Safety and Possible Benefit
In patients for whom no curative therapy exists, the usual practice in oncology is to approve requests for single patient treatment use that are reasonably safe with little regard for the evidence for potential benefit. The safety question can be framed as whether the drug would present an unreasonable risk compared to non-treatment in the clinical situation for which use is contemplated. The evidence for potential benefit may be only theoretical.
In patients for whom there is proven curative therapy, the safety analysis must consider the alternative therapy. Patients can be indirectly harmed by an experimental therapy that does not by itself cause injury if the experimental drug is used in lieu of a proven curative therapy. For example, if an unproven therapy is used instead of a proven curative therapy, and the unproven therapy turns out not to work, a patient could be irretrievably harmed if there disease had advanced to a point where the proven curative therapy could no longer help.
There have been two well publicized cases where FDA refused to allow patients access to an unproven cancer therapy prior to receiving the standard of care that was likely to cure the disease. There were, in addition, no clinical data to suggest a benefit from the investigational product requested. The standard of care for these two diseases was considered "CURATIVE THERAPY," a rare opportunity in cancer treatment.
As long as a curative treatment for a disease is available, and particularly where there is evidence that the unproven therapy is likely to be no more effective than a placebo, FDA believes strongly that use the unproven agent would be unethical, is unsafe and can not be permitted.
VI. Issues and examples
The following is a list of issues and examples (grouped by category) often encountered by the FDA when reviewing requests for treatment use of investigational cancer drugs.
Decision making
The fate of drug development
Draft Questions for ODAC
Single Patient Treatment Use of Investigational Drugs
As discussed in the briefing document, the FDA strongly endorses participation in clinical trials because it is in the best interest of the patient and the American public. Individual patients benefit by receiving the best available treatment and the American public benefits by sound development of new therapies. However, sometimes patients are ineligible for clinical trials or are unable or unwilling to participate.
The FDA is seeking advice from the committee to help FDA in its role of assessing the risk to benefit ratio of treatment use with an experimental drug in an individual patient.
When determining the apparent risk to benefit ratio, the following are important considerations:
At any stage of development, evidence from ongoing trials may suggest that the drug is effective or ineffective, or that it is toxic or non-toxic.
The appropriateness of treatment use of experimental therapy also depends upon the patient’s medical history, especially whether the patient has already received standard therapy. The following are scenarios that FDA may encounter. They are listed according to the benefit available from standard therapy in the particular clinical situation.
Questions
The following are draft questions. The final questions may change as we explore other question formats to guide discussion of these multi-dimensional issues.
1. For each of the following clinical scenarios describing standard therapy, please discuss the following question:
FDA receives a request from an investigator to use Drug X under a single patient IND. The commercial sponsor (manufacturer) of drug X has granted permission for the investigator to use the drug and also has provided written permission for FDA to refer to the commercial IND. The patient’s medical history is outlined in each of the scenarios below.
The investigator states that the patient is aware of the benefits of standard therapy but wants to receive investigational treatment with Drug X instead. The patient is ineligible or unable to participate in a clinical trial using Drug X.
When would single patient treatment with Drug X be appropriate?
In your discussion consider:
Standard Therapy Cases
A. There is no standard therapy available.
EXAMPLE:
A patient with metastatic nonsmall cell lung cancer has received all available therapy.
B. Available treatment shows a marginal survival benefit.
EXAMPLE:
A patient has metastatic nonsmall cell lung cancer. Standard chemotherapy produces a 1-2 month median survival benefit and produces moderate toxicity.
C. Standard therapy provides a substantial prolongation of median survival.
EXAMPLE:
A patient has advanced ovarian cancer. Standard chemotherapy produces a 1 to 2 year median survival benefit but is generally not curative.
D. Standard therapy provides a substantial rate of cure.
EXAMPLE:
A 40 year old patient with acute leukemia does not want to receive chemotherapy that is associated with a 40-50% rate of cure with substantial acute toxicity but that produces few lasting toxic effects.
E. Available therapy provides cure in most patients, but treatment involves permanent morbidity.
EXAMPLE:
A 60 year old man has recurrent superficial bladder cancer that has recurred despite treatment with all available intravesical chemotherapy agents. Recently, a muscle-invading bladder tumor (Stage T2) was removed during cystoscopy. Cystectomy (surgical removal of the bladder) is standard therapy and is associated with a high cure rate. The patient does not want to undergo cystectomy despite counseling about various surgical techniques that can be used to provide a substitute for the urinary bladder after it is removed. He also refuses radiation therapy.
2. As noted above, FDA strongly endorses participation in clinical trials. Patients should first consider entering a clinical trial before pursuing treatment under a single patient IND. If a patient is eligible and able to receive drug X as part of a clinical trial but is unwilling to do so, should that patient be allowed to receive drug X under a single patient IND?
3. If FDA has sufficient evidence to conclude that a drug is ineffective for treatment of a particular cancer, discuss under what circumstances, if any, single patient treatment use should be permitted.
__________________ __________________
Grant Williams, MD Richard Pazdur, MD
Medical Team Leader Division Director
Division of Oncology Drug Products
CDER/ODEI/FDA
Draft Briefing Document for the ODAC
Single Patient Use of Investigational Anticancer Agents
Page No.
Single-Patient Use of Experimental Therapy 5
VI. When there is Curative Therapy 9
VII. Issues and Examples 10
Draft Questions for ODAC 12
Appendices
ii. National Cancer Institute publication on NCI Non-Research(Compassionate)Use of Investigational Anticancer Agents
At the meeting of the Oncologic Drugs Advisory Committee (ODAC) on the afternoon of December 14, 2000 we will discuss single-patient use of investigational cancer drugs, also referred to as a single-patient IND, compassionate use, special exception use, or use under an emergency IND (Investigational New Drug Application). This is the treatment use of investigational drugs for an individual patient rather than as part of an investigational protocol, a treatment IND, or an expanded access protocol. Single patient use may be accomplished with a corporate sponsor under an existing IND or with a physician-investigator under a new IND.
The following are the primary objectives of this meeting:
The FDA will ask experts in biomedical ethics, representatives from the pharmaceutical industry, and patient advocates to provide perspectives on the issues involved in single patient treatment with investigational therapy.
The committee will subsequently be asked to discuss this issue and to discuss questions proposed by the Agency.
II. The FDA and the Drug Development Process
The responsibilities of the FDA and of sponsors of investigational drug applications are outlined in the Code of Federal Regulations (CFR) 21 part 312.
Single-patient use of investigational drugs outside of a clinical trial may be requested at any time during drug development. The stage of drug development, that is, the amount of knowledge we have about a drug’s effectiveness or safety, is an important consideration when evaluating such a request for single-patient use of an investigational drug The following is a brief overview of the normal drug-development process.
The formal role of the FDA begins with submission of an IND. Prior to submitting the IND, the sponsor analyzes the drug’s main physical and chemical properties and studies its pharamacologic and toxic effects in pre-clinical studies. Sponsors are encouraged to meet with FDA at pre-IND meetings. These meeting assure that the FDA and sponsor agree upon the proper preclinical tests prior to submission of the IND.
The sponsor subsequently files an IND. This application must contain evidence describing the drug’s identity, assuring that the drug will be manufactured safely, and describing the toxic effects of the drug in preclinical studies. The clinical protocol, a carefully written clinical plan that describes how the drug will be studied in humans, must also be submitted with the IND. In the IND submission, the sponsor must provide data from preclinical tests supporting a safe starting dose and administration schedule.
After the IND is submitted, a team of FDA reviewers has 30 days to establish whether the IND can proceed. The FDA review team includes PhD chemists who evaluate the drug’s chemistry and manufacturing, PhD toxicologists who evaluate the drug’s toxic effects in animals, and oncologists who evaluate the clinical protocol. The research proposal must be approved by an Investigational Review Board. Finally, patients must be informed of the risks and potential benefits of the study.
The IND process, in other words, the time it takes to fully test the drug’s safety and effectiveness, may last several years while the sponsor conducts trials in different diseases. The earliest clinical study is a Phase 1 study, usually a small trial in patients who have exhausted available therapy. In this study the dose is gradually increased until either toxicity is observed or the investigator decides an effective dose has been established. Subsequently, the sponsor may perform Phase 2 studies, preliminary investigations of drug activity. Traditionally in oncology, Phase 2 studies are single-arm trials in a small number of patients. Often, the goal of these studies is to see whether the drug can cause tumor size reduction. For diseases where the drug shows evidence of antitumor activity, the sponsor then designs larger randomized trials (Phase 3 trials) that usually compare the drug’s effect to a standard therapy. The objective of these studies is to demonstrate whether the drug produces clinical benefit, such as improvement in survival or improvement in disease-related symptoms.
Finally, if studies suggest that a drug is efficacious, these studies and the data that support them are submitted to the FDA in a marketing application. Depending upon the priority of the application, FDA has 6 or 10 months to review the marketing application.
Marketing applications are large applications that contain all the information learned about the drug during IND investigations. The application includes chemistry and manufacturing data, animal data, and human clinical trials data. A larger team of FDA reviewers evaluates these applications. In addition, a field team evaluates the investigational sites where the clinical data were generated to assure the validity of the submitted data. The results of the FDA review of the data submitted in the marketing application are often presented to an advisory committee. Based upon the results of FDA review of the data and on advice from the advisory committee, FDA renders a decision: an Approval Letter, an Approvable Letter, or a Non-Approval letter. If the drug is approved, the sponsor may distribute and market the drug for the approved indication.
III. Single-patient use of an investigational drug
The purpose of the above system is to evaluate new drugs and to bring them to market after they have been proven to be safe and effective. Treatment use of experimental drugs has been described by many names, and can be generally grouped into two categories according to the number of people treated: expanded access and single patient treatment. Regardless of the category of treatment use that is anticipated, all applications for investigational treatment require an investigator, informed consent, a sponsor who accepts responsibility for the study and communicates with the FDA, a drug supplier (who may also be the sponsor), and oversight by an Institutional Review Board.
A. Expanded access protocols
Expanded access protocols are designed to outline a treatment regimen that will be used for a predefined patient group. Through an agreement with FDA, NCI provided expanded access through a mechanism called Group C. Since 1976, NCI has provided over 20 Group C protocols. In the late 1980’s, regulations were instituted that generalized these Group C provisions to other serious diseases, and established the Treatment IND. Under both Group C and Treatment IND the drug’s development is nearly complete, and a marketing application is either under review or is near submission. The FDA has also granted other forms of expanded access. The FDA has approved expanded access protocols allowing a drug’s use when a formal Treatment IND is not indicated. Generally, when many single-patient treatment exceptions have been granted, FDA will evaluate the appropriateness of an expanded access protocol. Ethical issues, drug supply issues, and the potential negative impact of the protocol on accrual to studies must be considered in this decision.
B. Single patient compassionate use
Single patient compassionate use is the treatment use of experimental drugs for an individual patient rather than in an investigational protocol, a treatment IND, or an expanded access protocol. As noted above, this may be referred to as single-patient compassionate use, special exception use, or use under an emergency IND.
Either a corporate sponsor under an existing IND or a physician-investigator under a new IND may request single-patient use. In the single-patient exception a patient who is ineligible for an existing investigational protocol is granted permission to receive investigational drug under the sponsor’s existing IND. That patient is treated by an investigator according to the plan outlined in investigational protocol, however, the patient is not included in the analysis of the protocol. Under a single-patient exception, the existing commercial IND sponsor provides drug and is responsible for reporting to the FDA.
If the commercial sponsor is unwilling to assume responsibility for a special exception, an investigator may perform the role of sponsor for a single-patient treatment. Under this model, the investigator must obtain the drug from a willing manufacturer and must apply directly to the FDA for an IND. This application should include a completed 1571 form (http://www.fda.gov/cder/cancer/singleind.htm), an outline of the patient’s history, a treatment plan, and a commitment to obtain informed consent and IRB approval. Written permission from the commercial sponsor for the FDA to examine the commercial sponsor’s IND must be submitted. The commercial sponsor’s IND is confidential, proprietary knowledge, and the FDA could not determine the safety of the approach without this letter of cross-reference. This form of single patient compassionate use is termed a single patient IND. At times, FDA has granted hundreds of such INDs per year, for instance 435 for aerosolized talc in 1996 and 515 for Thalidomide in 1998. Both of these drugs were subsequently approved by the FDA.
While evaluating requests for single-patient use of investigational drugs, FDA often receives telephone calls from investigators or patients. Special FDA staff in the Office of Special Health Issues are available to help address patient questions. However, because the information contained in the IND is confidential, proprietary material, the FDA is limited in the information that may be communicated to the investigator or public. Sometimes a patient’s question can only be answered by the IND Sponsor. And, of course, the process of requesting single-patient use of a drug cannot begin with the FDA. The first step is for a qualified investigator to contact a manufacturer or commercial sponsor that is willing to supply the drug for this use.
IV. Regulations
Regulations describing Treatment Protocols and Treatment INDs do not specifically address single patient use of investigational drugs. The emergency IND regulations (21 CFR 312.36) refer to methods for obtaining a single patient IND for treatment use quickly by telephone in advance of submitting the written IND, but do not identify separate standards for approval of such INDs.
The principles that the FDA considers when evaluating requests for single patient exceptions are embodied in the regulations describing Treatment Protocols or Treatment INDs (21CFR 312.24-.25 and 312.80-.83). The following are principles described in these regulations:
In summary, the regulations direct the FDA to consider the following criteria:
In evaluating requests for single-patient compassionate use, the following questions commonly arise:
Other issues arise as single patient use increases for a particular investigational drug. These issues include
V. Why is FDA involved?
The independent scientific consideration provided by the Agency is critical and is an essential component of patient protection, when one is considering drugs about which relatively little is often known. In the typical single patient IND situation, especially those involving emergency IND requests, the patient’s physician generally has limited information about the investigational therapy being requested. There may be several INDs for the same product with each sponsor working without knowledge of what others are doing and of their results. FDA is often the only party that has access to all of the information.
The FDA’s primary responsibility in deciding whether to allow a single patient treatment with an investigational drug to proceed is to determine whether use of the therapy in the particular patient would be reasonable or safe. In oncology, with respect to patients for whom no curative treatments exist, the general practice has been to approve requests for single-patient use of drugs that are reasonably safe without regard to efficacy or potential efficacy.
VI. When there is Curative Therapy
Indirectly harmful products are those that do not themselves cause injury, but may lead people to delay or reject proven remedies, possibly worsening their condition. For example, if cancer patients reject curative drug therapies in favor of unproven therapies and the unproven therapies turn out not to work, their disease may advance beyond the point where proven curative therapies can help.
There have been two well publicized cases where FDA refused to allow patients access to an unproven cancer therapy prior to receiving the standard of care that was likely to cure the disease. In these cases FDA refused access because there were no clinical data to suggest a benefit from the investigational product requested. More importantly, the standard of care for these two diseases was, and is, considered "CURATIVE THERAPY," a rare opportunity in cancer treatment. Prior to use of the curative therapy in these situations, death was the most certain outcome for patients with these diseases. It is now highly likely that patients can expect long term survival.
As long as a curative treatment for a disease is available, FDA’s position has been that treatment use of an unproven investigational agent should not be allowed because of the unacceptable risk associated with forgoing the use of proven treatments. We invite committee discussion of this position.
VII. Issues and examples
The following is a list of issues and examples (grouped by category)encountered by the FDA when reviewing requests for treatment use of investigational drugs.
Decision making
The fate of drug development
Unbridled treatment use of investigational drugs may interfere with accrual to trials.
Special role of FDA
Draft Questions for ODAC
Single Patient Use of Investigational Drugs
The FDA strongly endorses participation in clinical trials because it is in the best interest of the American public. Individual patients benefit by receiving the best available treatment and the American public benefits by sound development of new therapies. However, sometimes patients are ineligible for clinical trials or are unable or unwilling to participate. The Agency receives requests on their behalf to receive single-patient treatment with an investigational agent.
According to regulations, any request for use of an investigational drug must fulfill the following requirements:
If these requirements have been met and if a manufacturer (or commercial sponsor) agrees to supply the drug, the FDA must decide whether the proposed treatment use of the investigational drug is acceptable. The FDA must ask, "Is the risk to benefit ratio for treatment with this experimental drug acceptable for a patient with this medical history?" The FDA is seeking advice from the committee to help answer this question.
When determining the apparent risk to benefit ratio, the following are important considerations:
For the purpose of our discussion, the degree to which a drug has been studied may be categorized as follows:
3 The drug has been tested in Phase 3 studies and we have some knowledge about whether it affects survival or other endpoints indicating clinical benefit.
At any stage of development, evidence from ongoing trials may suggest that the drug is effective or ineffective, or that it is toxic or non-toxic.
The appropriateness of treatment use of experimental therapy also depends upon the patient’s medical history, especially whether the patient has already received standard therapy. The following are scenarios that FDA may encounter. They are listed according to the benefit available from standard therapy in the particular clinical situation.
Question:
For each of the following clinical scenarios, please discuss the following question:
FDA receives a request from an investigator to use Drug X under a single-patient IND. The commercial sponsor (manufacturer) of drug X has granted permission for the investigator to use the drug and also has provided written permission for FDA to refer to the commercial IND. The patient’s medical history is outlined in each of the scenarios below.
The investigator states that the patient is aware of the benefits of standard therapy but wants to receive investigational treatment with Drug X instead. The patient is ineligible or unable to participate in a clinical trial using Drug X.
When would single-patient treatment with Drug X be appropriate?
In your discussion address:
Clinical Scenarios
1. There is no standard therapy available.
EXAMPLE:
A patient with metastatic nonsmall cell lung cancer has received all available therapy.
2. Available treatment shows a marginal survival benefit.
EXAMPLE:
A patient has metastatic nonsmall cell lung cancer. Standard chemotherapy produces a 1-2 month median survival benefit and produces moderate toxicity.
Standard therapy provides a substantial prolongation of median survival.
EXAMPLE:
A patient has advanced ovarian cancer. Standard chemotherapy produces a 1 to 2 year median survival benefit but is generally not curative.
Standard therapy provides a substantial rate of cure.
EXAMPLE:
A 40 year old patient with acute leukemia does not want to receive chemotherapy that is associated with a 40-50% rate of cure with substantial acute toxicity but that produces few lasting toxic effects.
5.Available therapy provides cure in most patients, but treatment involves permanent morbidity.
EXAMPLE
A 60 year old man has recurrent superficial bladder cancer that has recurred despite treatment with all available intravesical chemotherapy agents. Recently, a muscle-invading bladder tumor (Stage T2) was removed during cystoscopy. Cystectomy (surgical removal of the bladder) is standard therapy and is associated with a high cure rate. The patient does not want to undergo cystectomy despite counseling about various surgical techniques that can be used to provide a substitute for the urinary bladder after it is removed. He also refuses radiation therapy.
6. A patient is unwilling to participate in a clinical trial.
As noted above, FDA strongly endorses participation in clinical trials because it is good for the public and good for individuals that participate in them. Patients should first consider entering a clinical trial before pursuing treatment under a single-patient IND. If a patient is eligible and able to receive drug X as part of a clinical trial but is unwilling to do so, should that patient be allowed to receive drug X under a single-patient IND?
__________________ __________________
Grant Williams, MD Richard Pazdur, MD
Medical Team Leader Division Director
Division of Oncology Drug Products
CDER/ODEI/FDA
Appendix i.
Excerpts from the regulationsOverview of Cancer Drug Development
The responsibilities of the FDA and of sponsors of investigational drug applications are outlined in the Code of Federal Regulations (CFR) 21 part 312.
Any use of an investigational drug that is not marketed must be done under an IND. The CFR defines IND as Notice of Claimed Investigational Exemption for a New Drug. The IND provides permission to use an investigational drug according to a plan (a protocol) filed with the FDA.
Single patient use of investigational cancer drugs outside of a clinical trial may be requested at any time during drug development. The stage of drug development, which is related to the amount of knowledge we have about a drug’s effectiveness or safety, is an important consideration when evaluating such a request for single patient use of an investigational drug. The following is a brief overview of the traditional drug-development process for cancer drugs.
The formal role of the FDA begins with receiving the IND submission. Prior to submitting the IND, the sponsor analyzes the drug’s main physical and chemical properties and studies its pharamacologic and toxic effects in pre-clinical studies. Sponsors are encouraged to meet with FDA at pre-IND meetings. These meeting assure that the FDA and sponsor agree upon the proper preclinical tests prior to submission of the IND.
The sponsor subsequently files an IND. Among other things, this application describes the drug’s identity, the manufacturing process, and the toxic effects of the drug in preclinical studies. The clinical protocol, a carefully written clinical plan that describes how the drug will be studied in humans, must also be submitted with the IND. In the IND submission, the sponsor must provide data from preclinical tests supporting a safe starting dose and administration schedule.
After the IND is submitted, a team of FDA reviewers has 30 days to determine whether the IND can proceed. The FDA review team includes PhD chemists who evaluate the drug’s chemistry and manufacturing, PhD toxicologists who evaluate the drug’s toxic effects in animals, and oncologists who evaluate the clinical protocol. The research proposal must be approved by an Institutional Review Board. Finally, patients must be informed of the risks and potential benefits of the study.
The IND process, i.e., the time it takes to fully test the drug’s safety and effectiveness, generally lasts several years while the sponsor conducts trials in different diseases. The earliest clinical study is a Phase 1 study. In oncology, these are usually small trials to evaluate toxicity at a range of doses. Subsequently, the sponsor may perform Phase 2 studies, preliminary investigations of drug activity at a selected dose. Traditionally, in oncology, Phase 2 studies are single-arm trials to see whether the drug can cause tumor size reduction, but, especially if tumor shrinkage is not anticipated, studies may be concurrently controlled trials. For diseases where the drug shows evidence of antitumor activity, the sponsor then designs larger randomized trials (Phase 3 trials) that usually compare the drug’s effect to a standard therapy, if it exists. The objective of these studies is to demonstrate whether the drug produces clinical benefit, such as improvement in survival or improvement in disease-related symptoms.
Finally, if studies suggest that a drug is efficacious, these studies and the data that support them are submitted to the FDA in a marketing application. Depending upon the priority of the application, FDA has 6 or 10 months to review and act on the marketing application.
Marketing applications are large applications that contain all the information learned about the drug during IND investigations. The application includes chemistry and manufacturing data, animal data, and human clinical trials data. A larger team of FDA reviewers evaluates a sample of these applications. In addition, a field team evaluates the investigational sites where the clinical data were generated to assure the validity of the submitted data. The results of the FDA review of the data submitted in the marketing application are often presented to an advisory committee. Based upon the results of FDA review of the data and on advice from the advisory committee, FDA renders a decision: an Approval Letter, an Approvable Letter, or a Non-Approval letter. If the drug is approved, the sponsor may distribute and market the drug for the approved indication.
Appendix ii
Regulations do not specifically address the practice of single patient exception use of investigational drugs. The compassionate use activitiy is supported by the spirit of the Treatment Protocol Regulations (312.24-.25 and 312.80-.83). These regulations govern large treatment protocols or treatment INDs.
The following are principles that I have selected from these regulations:
The following Attachment Contains excerpts from the relevent regulations in 21 CFR 312.
312.34 Treatment use of an investigational new drug.
(a) General. A drug that is not approved for marketing may
be under clinical investigation for a serious or immediately
life-threatening disease condition in patients for whom no comparable
or satisfactory alternative drug or other therapy is available.
During the clinical investigation of the drug, it may be appropriate
to use the drug in the treatment of patients not in the clinical
trials, in accordance with a treatment protocol or treatment
IND. The purpose of this section is to facilitate the availability
of promising new drugs to desperately ill patients as early
in the drug development process as possible, before general
marketing begins, and to obtain additional data on the drug's
safety and effectiveness. In the case of a serious disease,
a drug ordinarily may be made available for treatment use under
this section during Phase 3 investigations or after all clinical
trials have been completed; however, in appropriate circumstances,
a drug may be made available for treatment use during Phase
2. In the case of an immediately life-threatening disease, a
drug may be made available for treatment use under this section
earlier than Phase 3, but ordinarily not earlier than Phase
2. For purposes of this section, the ``treatment use'' of a
drug includes the use of a drug for diagnostic purposes. If
a protocol for an investigational drug meets the criteria of
this section, the protocol is to be submitted as a treatment
protocol under the provisions of this section.
(b) Criteria. (1) FDA shall permit an investigational drug
to be used for a treatment use under a treatment protocol or
treatment IND if:
(i) The drug is intended to treat a serious or immediately
life-threatening disease;
(ii) There is no comparable or satisfactory alternative drug
or other therapy available to treat that stage of the disease
in the intended patient population;
(iii) The drug is under investigation in a controlled clinical
trial under an IND in effect for the trial, or all clinical
trials have been completed; and
(iv) The sponsor of the controlled clinical trial is actively
pursuing marketing approval of the investigational drug with
due diligence.
(2) Serious disease. For a drug intended to treat a serious
disease, the Commissioner may deny a request for treatment use
under a treatment protocol or treatment IND if there is insufficient
evidence of safety and effectiveness to support such use.
(3) Immediately life-threatening disease. (i) For a drug intended
to treat an immediately life-threatening disease, the Commissioner
may deny a request for treatment use of an investigational drug
under a treatment protocol or treatment IND if the available
scientific evidence, taken as a whole, fails to provide a reasonable
basis for concluding that the drug:
(A) May be effective for its intended use in its intended
patient population; or
(B) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk
of illness or injury.
(ii) For the purpose of this section, an ``immediately life-
threatening'' disease means a stage of a disease in which there
is a reasonable likelihood that death will occur within a matter
of months or in which premature death is likely without early
treatment.
(c) Safeguards. Treatment use of an investigational drug is
conditioned on the sponsor and investigators complying with
the safeguards of the IND process, including the regulations
governing informed consent (21 CFR part 50) and institutional
review boards (21 CFR part 56) and the applicable provisions
of part 312, including distribution of the drug through qualified
experts, maintenance of adequate manufacturing facilities, and
submission of IND safety reports.
(d) Clinical hold. FDA may place on clinical hold a proposed
or ongoing treatment protocol or treatment IND in accordance
with 312.42.
[52 FR 19476, May 22, 1987, as amended at 57 FR 13248, Apr.
15, 1992]
312.35 Submissions for treatment use.
(a) Treatment protocol submitted by IND sponsor. Any sponsor
of a clinical investigation of a drug who intends to sponsor
a treatment use for the drug shall submit to FDA a treatment
protocol under 312.34 if the sponsor believes the criteria
of 312.34 are satisfied. If a protocol is not submitted under
312.34, but FDA believes that the protocol should have been
submitted under this section, FDA may deem the protocol to be
submitted under 312.34. A treatment use under a treatment
protocol may begin 30 days after FDA receives the protocol or
on earlier notification by FDA that the treatment use described
in the protocol may begin.
(1) A treatment protocol is required to contain the following:
(i) The intended use of the drug.
(ii) An explanation of the rationale for use of the drug,
including, as appropriate, either a list of what available regimens
ordinarily should be tried before using the investigational
drug or an explanation of why the use of the investigational
drug is preferable to the use of available marketed treatments.
(iii) A brief description of the criteria for patient selection.
(iv) The method of administration of the drug and the dosages.
(v) A description of clinical procedures, laboratory tests,
or other measures to monitor the effects of the drug and to
minimize risk.
(2) A treatment protocol is to be supported by the following:
(i) Informational brochure for supplying to each treating
physician.
(ii) The technical information that is relevant to safety
and effectiveness of the drug for the intended treatment purpose.
Information contained in the sponsor's IND may be incorporated
by reference.
(iii) A commitment by the sponsor to assure compliance of
all participating investigators with the informed consent requirements
of 21 CFR part 50.
(3) A licensed practioner who receives an investigational
drug for treatment use under a treatment protocol is an ``investigator''
under the protocol and is responsible for meeting all applicable
investigator responsibilities under this part and 21 CFR parts
50 and 56.
(b) Treatment IND submitted by licensed practitioner. (1)
If a licensed medical practitioner wants to obtain an investigational
drug subject to a controlled clinical trial for a treatment
use, the practitioner should first attempt to obtain the drug
from the sponsor of the controlled trial under a treatment protocol.
If the sponsor of the controlled clinical investigation of the
drug will not establish a treatment protocol for the drug under
paragraph (a) of this section, the licensed medical practitioner
may seek to obtain the drug from the sponsor and submit a treatment
IND to FDA requesting authorization to use the investigational
drug for treatment use. A treatment use under a treatment IND
may begin 30 days after FDA receives the IND or on earlier notification
by FDA that the treatment use under the IND may begin. A treatment
IND is required to contain the following:
(i) A cover sheet (Form FDA 1571) meeting 312.23(g)(1).
(ii) Information (when not provided by the sponsor) on the
drug's chemistry, manufacturing, and controls, and prior clinical
and nonclinical experience with the drug submitted in accordance
with 312.23. A sponsor of a clinical investigation subject
to an IND who supplies an investigational drug to a licensed
medical practitioner for purposes of a separate treatment clinical
investigation shall be deemed to authorize the incorporation-
by-reference of the technical information contained in the sponsor's
IND into the medical practitioner's treatment IND.
(iii) A statement of the steps taken by the practitioner to
obtain the drug under a treatment protocol from the drug sponsor.
(iv) A treatment protocol containing the same information
listed in paragraph (a)(1) of this section.
(v) A statement of the practitioner's qualifications to use
the investigational drug for the intended treatment use.
(vi) The practitioner's statement of familiarity with information
on the drug's safety and effectiveness derived from previous
clinical and nonclinical experience with the drug.
(vii) Agreement to report to FDA safety information in accordance
with 312.32.
(2) A licensed practitioner who submits a treatment IND under
this section is the sponsor-investigator for such IND and is
responsible for meeting all applicable sponsor and investigator
responsibilities under this part and 21 CFR parts 50 and 56.
(Collection of information requirements approved by the Office
of Management and Budget under control number 0910-0014)
[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr.
15, 1992]
312.36 Emergency use of an investigational new drug.
Need for an investigational drug may arise in an emergency
situation that does not allow time for submission of an IND
in accordance with 312.23 or 312.34. In such a case, FDA
may authorize shipment of the drug for a specified use in advance
of submission of an IND. A request for such authorization may
be transmitted to FDA by telephone or other rapid communication
means…
ii. National cancer Cancer Institute’s Treatment Referral Center and Non-Research (Compassionate) Use of Investigational Anticancer Agents. Am. J. Health-Syst. Pharm. 55:651-660, 1998.
_____________________________________________________________________________
The National Cancer Institute’s Treatment Referral Center
and Non-Research (Compassionate) Use of Investigational Anticancer Agents
M Montello, J J Greenblatt, A Fallavollita, D Shoemaker*
Affiliations of authors: Michael J Montello M.S., R.Ph. and Alfred Fallavollita M.S., R.Ph. (Pharmaceutical Management Branch), Jay J. Greenblatt Ph.D. and Dale Shoemaker Ph.D. (Regulatory Affairs Branch), Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Correspondence to: Michael Montello, M.S., R.Ph., Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, NCI, Executive Plaza North, Rm. 707, Bethesda, MD 20892, telephone (301) 496-5725, Fax (301) 402-0429, e-mail montellom@ctep.nci.nih.gov
The National Cancer Institute’s Treatment Referral Center
and Non-Research (compassionate) Use of Investigational Anticancer Agents
M Montello, J J Greenblatt, A Fallavollita, D Shoemaker
Abstract: The Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI) allows early access to investigational anticancer agents for patients who are unable to participate in clinical trials. The ultimate purpose of the DCTD non-research (or compassionate) program is to make investigational anticancer agents, that have significant activity against specific malignancies, available to individual cancer patients. The DCTD early access programs, (Special Exception, Group C and Treatment Referral Center Protocols) and the policy and procedures for each program are described. Health care professionals may contact the NCI’s Treatment Referral Center, by telephone (301) 496-5725, or fax (301) 402-4870, for information or questions regarding the DCTD early access program.
Key Words: Early Access, Special Exception, Group C, Compassionate Use, Oncology
The National Cancer Institute’s Treatment Referral Center
and Non-Research (Compassionate) Use of Investigational Anticancer Agents
Michael Montello, Jay Greenblatt, A Fallavollita, Dale Shoemaker*
The Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI) sponsors more than 1,300 active clinical protocols through the Cooperative Groups, Clinical and Comprehensive Cancer Centers and Phase I/II cooperative agreement holders. Approximately 20,000 cancer patients are treated on these protocols annually. The DCTD also allows early access to investigational anticancer agents for patients who are unable to participate in clinical trials.
The DCTD provides early access to investigational anticancer agents through several different mechanisms including; Special Exception, Group C and Treatment Referral Center Protocols. The early access program is sometimes described as non-research (or compassionate) use of investigational agents. The ultimate purpose of the non-research (compassionate) program is to make investigational anticancer agents, that have significant activity against specific malignancies, available to individual cancer patients and their physicians.
When requesting an agent for non-research use physicians must consider the following questions:
A request for non-research use may be considered if the answer to all the above questions is affirmative. Each non-research (compassionate) mechanism differs in purpose and in the reporting and procedural responsibilities of the investigator.
Special Exception:
The Special Exception mechanism is the functional equivalent of a emergency Investigational New Drug Applications (IND) but differs from it in that any registered investigator may obtain an agent directly from the DCTD, instead of having to obtain an IND from the FDA. A Special Exception request may be considered for any investigational agent for which DCTD sponsors an IND. The DCTD currently sponsors over 200 INDs with the FDA for approximately 150 different investigational anticancer agents. Approval depends on meeting the standard criteria for non-research release of investigational agents (see above) and agent availability. Each Special Exception request is reviewed and approved on a patient by patient basis.
Group C/Treatment IND:
Investigational agents for which the DCTD has requested Group C/Treatment IND designation from the FDA have reproducible efficacy in one or more specific tumor types. Such an agent is likely to alter the pattern of treatment of the disease and can be safely administered by properly trained physicians without specialized supportive care facilities. Typically DCTD will only seek Group C classification for those agents whose activity is well enough established that a New Drug Application (NDA) or Biologic License Application (BLA) approval is likely in the relatively near future. If an agent meets these criteria DCTD may initiate a formal application to the FDA to authorize Group C distribution for a specific indication. Such approval is not equivalent to formal FDA approval of effectiveness for this indication. Any registered investigator may receive a Group C agent. The NCI has sponsored over twenty Group C protocols since 1976 (Table #1). The only active Group C protocol is 5-azacitidine in Refractory Acute Myelogenous Leukemia.
Treatment Referral Center (TRC) Protocols:
The DCTD may make investigational treatments available via a TRC protocol for certain high promising agents or high priority diseases. TRC protocols can also be used as a mechanism to ensure equitable distribution of agents with limited availability. TRC protocols are initially offered to the NCI-designated Clinical and Comprehensive Cancer Centers. All patients enrolled on a TRC protocol must receive their investigational therapy at an NCI-designated Cancer Center. The NCI has completed three TRC protocols utilizing paclitaxel in the treatment of refractory ovarian cancer (TRC 9103) and refractory breast cancer (TRC-9202 and TRC-9301).
Treatment Referral Center:
All requests for early access to DCTD-sponsored investigational chemotherapeutic agents are conducted through the NCI’s Treatment Referral Center. The Treatment Referral Center is managed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), DCTD, NCI. The Treatment Referral Center (TRC) is a means for the NCI to provide information to community oncologists and other health care professionals about therapeutic options for cancer patients. The TRC uses several resources, such as the Physicians Data Query (PDQ) and CTEP-Information System (CTEP-IS), to maintain a referral list of the most current active research protocols. First priority is given to referring patients to Cooperative Group or Cancer Center trials. If a patient is unable to participate on a clinical trial, then a non-research mechanism might be considered. Health care professionals may contact the Treatment Referral Center regarding potential therapeutic options, either clinical trials or non-research programs, by telephone (301) 496-5725, fax (301) 402-4870.
Procedures for Obtaining Investigational Anticancer Agents for Non-Research Use:
The NCI has attempted to simplify the process for obtaining and managing investigational anticancer agents for each non-research program described above. Extraneous paperwork has been eliminated and when possible standardized reporting methods are used. PMB pharmacists can assist investigators in addressing the medical, regulatory and administrative requirements associated with non-research protocols. All investigational agents are provided by DCTD at no cost to the physician or patient (shipping costs are borne by the receiver).
While Group C and TRC protocols have established criteria to determine patient eligibility, each Special Exception request is based on its own merit. The following information is required for the NCI to properly evaluate each Special Exception request: patient identifier (initials or ID #), age, sex, diagnosis, previous cancer therapy, current clinical status, intended dose and schedule of the requested agent (based on the current literature), potential concomitant therapy, and pertinent laboratory data.
Every attempt is made to provide investigators with a response as quickly as possible. Typically investigators are notified of a decision within the same day and if approved, investigators can often obtain an investigational agent via a non-research program within 3 to 5 days. In the event of a medical emergency investigational agents may be shipped for next day, or even same day, delivery. All established NCI policies regarding drug accountability and storage of the agent must be adhered to. A separate drug accountability record should be maintained for each compassionate protocol.
Investigators are provided with treatment guidelines for Group C and Treatment Referral Center protocols. Occasionally treatment guidelines are also provided for Special Exception protocols. Investigators are required to complete a Special Exception protocol document if treatment guidelines are not available. The Special Exception protocol document includes a brief patient history, a description of the treatment plan, dose modifications, and monitoring parameters. Patient treatment should be based on published reports. The completed Special Exception protocol document should be signed and returned to the PMB within 10 working days. A copy of the Special exception protocol is submitted to the appropriate IND.
FDA and NCI policy requires all investigators who participate in a DCTD-sponsored trial, including non-research studies, to have a FDA form 1572 (Statement of Investigator) and a current curriculum vitae on file with the Pharmaceutical Management Branch, CTEP. Investigators are asked to provide their office, shipping and Institutional Review Board (IRB) addresses on the FDA 1572. CTEP has attempted to expedite and simplify the investigator registration process as much as possible. When necessary activation of new investigators can be accomplished within 24 to 48 hours.
The FDA and NCI require that IRB approval and informed consent be obtained prior to treating a patient with an investigational agent. The NCI provides model informed consent forms for Group C, TRC and some Special Exception protocols. The IRB requirements differ slightly for each compassionate mechanism. IRB approval is required prior to activation of a Treatment Referral Center protocol at a participating institution. A waiver of the requirement for IRB approval may be obtained from the FDA for Group C protocols. Group C protocols have been reviewed and approved by the NCI’s IRB. Although local IRB’s are not required to review Group C protocols they retain the right to do so. Investigators are encouraged to contact their local IRB to determine the institutional policy regarding IRB review of Group C protocols.
IRB approval is also required for Special Exception protocols. The NCI makes no distinction as to how or in what form IRB approval is obtained (e.g. full IRB, IRB chair, etc.). The local IRB may set whatever policy it determines is appropriate for approval of Special Exception protocols. NCI policy however, requires that written documentation of IRB approval and a signed informed consent must be retained in the patient’s medical record for future reference.
The NCI requires a final report for all patients treated on non-research protocols. The information required for a final report is usually minimal. Standardized data collection forms have been developed for Group C and TRC protocols and several Special Exception agents. The Report of the Independent Investigator is a "generic" data collection form used for most Special Exception protocols.
The principal purpose of the DCTD’s non-research program is to increase patient access to promising investigational anticancer agents rather than to obtain clinical data. The NCI has, however, published the results of several Group C and TRC protocols (references). Since the eligibility criteria for Group C and TRC protocols are often much less stringent than a clinical trial the results are often described as being more representative of typical practice settings. Each Special Exception has been reviewed on its own merit and is considered a separate protocol. Therefore publication of Special Exception data should be limited to case reports and anecdotal data. It should be clearly stated that patients were treated on separate Special Exception protocols when the data from a group of Special Exception patients are presented.
Investigators are required to submit Adverse Event Reports (AER) reports to CTEP for all agents obtained via a non-research mechanism. Investigators should use the phase II and III ADR reporting guidelines. The NCI Common Toxicity Criteria table should be used for AER reports.
The scope and purpose of the non-research program is to allow early access to promising investigational agents. In addition, limited efficacy and safety data can be obtained through the non-research programs. The NCI has designed policy and procedures to expedite the review, registration, approval and distribution of non-research protocols and agents. The CTEP home page (http://ctep.info.nih.gov) contains current information, policies and procedures related to DCTD non-research activities and other programs.
References:
Cancer Therapies Provided Through the
Group C Treatment Protocol Mechanism
Treatment IND Approval Group C Approval NDA Approval
Carmustine Jun-63 Apr-76 May-77
Lomustine Feb-68 Apr-76 Oct-76
5-Azacytidine Jan-71 Aug-76 Active Group C
Daunorubicin Dec-65 Aug-76 May-80
Semustine Jan-71 Aug-76 IND withdrawn
Streptozotocin Mar-67 Aug-76 Jun-82
Asparaginase (E.coli) Jan-68 Oct-76 Apr-78
Cisplatin Jul-71 Jul-77 Dec-78
Hexamethylamine Jun-63 Jul-77 Feb-91
Aspariginase (Erwinia) Mar-71 Feb-78 IND withdrawn
Etoposide Sep-72 May-78 Oct-83
Tetrahydrocannabinol Sep-78 Oct-80 May-86
Amsacrine Aug-77 Dec-81 IND Withdrawn
Interleukin-2/LAK cells Feb-84 May-87 May-92
Ifosfamide/Mesna Jan-87 Dec-87 Dec-88
Deoxycoformycin Jun-79 Jul-88 Feb-92
Teniposide Sep-72 Oct-88 Oct-92
Levamisole Feb-77 May-89 Jun-90
Fludarabine Nov-82 Oct-89 Dec-91
2-Chlorodeoxyadenosine Dec-91 Mar-92 Mar-93
Paclitaxel Apr-84 Jul-92 Dec-92
Appendix iii Excerpt from IND Regulations
TITLE 21—CFR Part 312
Sec. 312.22 General principles of the IND submission.
(a) FDA's primary objectives in reviewing an IND are, in all phases
of the investigation, to assure the safety and rights of subjects, and,
in Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the drug's
effectiveness and safety. Therefore, although FDA's review of Phase 1
submissions will focus on assessing the safety of Phase 1
investigations, FDA's review of Phases 2 and 3 submissions will also
include an assessment of the scientific quality of the clinical
investigations and the likelihood that the investigations will yield
data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be
submitted in an IND to assure the accomplishment of the objectives
described in paragraph (a) of this section depends upon such factors as
the novelty of the drug, the extent to which it has been studied
previously, the known or suspected risks, and the developmental phase of
the drug.
(c) The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human
studies. Subsequent amendments to the IND that contain new or revised
protocols should build logically on previous submissions and should be
supported by additional information, including the results of animal
toxicology studies or other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general
investigational plan for the coming year.
(d) The IND format set forth in Sec. 312.23 should be followed
routinely by sponsors in the interest of fostering an efficient review
of applications. Sponsors are expected to exercise considerable
discretion, however, regarding the content of information submitted in
each section, depending upon the kind of drug being studied and the
nature of the available information. Section 312.23 outlines the
information needed for a commercially sponsored IND for a new molecular
entity. A sponsor-investigator who uses, as a research tool, an
investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but
ordinarily may, if authorized by the manufacturer, refer to the
manufacturer's IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A sponsor-
investigator who uses an investigational drug not subject to a
manufacturer's IND or marketing application is ordinarily required to
submit all technical information supporting the IND, unless such
information may be referenced from the scientific literature.