### Briefing Document for the ODAC

#### Single Patient Use of Investigational Anticancer Agents

[Page No.]{.underline}

## Introduction 2

II\. Investigational Use versus Treatment Use of an Investigational Drug
2

III\. Single patient use of an investigational drug 3

A.  Expanded Access

B.  Single Patient Access

## Legal Authority 5

## FDA's Analysis of Safety and Possible Benefit 7

##### VI. Issues and Examples 7

##  {#section .unnumbered}

## Draft Questions for ODAC 9 {#draft-questions-for-odac-9 .unnumbered}

Appendices

i.  Overview of Cancer Drug Development

ii. National Cancer Institute publication on NCI
    Non-Research(Compassionate)Use of Investigational Anticancer Agents

iii. Excerpt from IND regulations

# 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[^1], 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:

-   solicit advice from ODAC on the evaluation of requests for single
    patient treatment with investigational cancer drugs;

-   educate the public, physicians, and ODAC on the issues surrounding
    access to investigational cancer drugs for single patient treatment
    use.

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:

(1) The patient's physician determines that the patient has no
    comparable or satisfactory alternative therapy;

(2) FDA determines that there is sufficient evidence of safety and
    effectiveness to support use of the investigational drug;

(3) FDA determines that provision of the investigational drug will not
    interfere with the initiation, conduct, or completion of clinical
    investigations to support marketing approval; and

(4) The sponsor or clinical investigator submits information sufficient
    to satisfy the IND requirements.

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:

-   How much evidence of anti-tumor activity or efficacy is required to
    support single patient use of an investigational drug? Does this
    depend upon the degree of observed or expected toxicity?

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-   How strongly should the effectiveness of standard therapy be weighed
    in deciding whether single patient use of an investigational drug is
    appropriate? What if standard therapy is moderately effective
    (giving an advantage in median survival) or very effective (with
    cure in some patients)?

Other issues, not unique to oncology, arise as single patient use
increases for a particular investigational drug. These issues include:

-   whether an expanded access protocol should be developed,

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-   whether treatment use is adversely affecting the development of the
    drug, and

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-   whether lack of evidence of efficacy in ongoing studies should lead
    to discontinuation of treatment use of the drug.

**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**

-   Local or individual autonomy: patients, physicians and IRBs may feel
    that the decision about patient treatment should be theirs alone.
    Further, may not understand that our statue and regulations do not
    permit FDA to permit use of an investigational agent if we believe
    that the potential risks outweigh the potential benefits.

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-   Access to information: a patient may wish to forego or delay
    effective or even curative therapy to receive treatment use of a
    investigational drug. Statements in the news media and on websites
    may present overoptimistic accounts of efficacy that the FDA knows
    not to be supported by existing data or to be otherwise misleading.

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-   When to stop when the therapy is unlikely to help: A patient with
    metastatic cancer has failed all standard therapy and has very poor
    performance status, and the physician wishes to treat the patient
    with experimental therapy. Even proven therapy seldom has any
    benefit in such circumstances. Should FDA accede to the wishes of
    the physician?

> **The fate of drug development**

-   Unbridled treatment use of investigational drugs may interfere with
    enrollment in clinical trials to evaluate the safety and
    effectiveness of new drugs. Sponsors and FDA may be concerned that
    patients may refuse to enroll in a randomized trial designed to
    compare standard treatment to experimental treatment if the
    experimental treatment is available outside of trials.

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-   Sponsors may not have sufficient drug supply to support widespread
    treatment use.

-   Meaningful data collection is difficult in the context of single
    patient use of investigational therapy.

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-   Sponsors may worry that adverse events from treatment use reported
    in patients who have a poor performance will have an adverse impact
    on 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:

-   How thoroughly has the drug been studied in humans?[^2]

-   What do the preliminary results from these studies suggest about the
    safety and efficacy (or activity) of the drug?

-   What are the other therapeutic options available to the patient?

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:

-   The drug's **stage of development** (0-3 above), and

-   The **level of efficacy and toxicity** of Drug X that would be
    acceptable in the following standard therapy cases.

## **Standard Therapy Cases** {#standard-therapy-cases .unnumbered}

**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.** {#d.-standard-therapy-provides-a-substantial-rate-of-cure. .unnumbered}

> 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

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**Appendix i.**

# Overview 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.

-   The *sponsor* of an IND initiates and assumes responsibility for the
    clinical investigation. The sponsor may be a pharmaceutical company,
    but individuals or academic institutions may also serve as IND
    sponsors.

-   The *investigator* is the individual that actually performs the
    trial. The regulations stipulate that a sponsor shall "select only
    investigators qualified by training and experience as appropriate
    experts to investigate the drug." In most cases we expect the
    investigator to be a licensed physician and have training and
    experience in treating cancer.

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[^3]. 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

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**National** **Cancer** **Institute's Treatment Referral Center and
Non-Research (Compassionate) Use of Investigational Anticancer Agents.
Am. J. Health-Syst. Pharm. 55:651-660, 1998.**

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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.

[^1]: ^1^In this document *cancer drugs* refers to drug or biologic
    products for treating cancer.

[^2]: For the purpose of our discussion, the degree to which a drug has
    been studied may be categorized as follows:

    0: The drug has not yet been tested in humans.

    1: The drug has been tested in Phase 1 studies to evaluate toxicity.

    2: The drug has been tested in Phase 2 studies to evaluate whether
    it can reduce tumor size in some patients.

    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.

[^3]: A marketing application for a drug is a New Drug Application (NDA)
    and for a Biologic product is a Biologics License Applications
    (BLA).