Docstoc

Outline

Document Sample
Outline Powered By Docstoc
					                Briefing Document for the ODAC
      Single Patient Use of Investigational Anticancer Agents

                                                       Page No.
I.   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
IV. Legal Authority..................................... 5
V.   FDA’s Analysis of Safety and Possible Benefit....... 7
VI. Issues and Examples................................. 7

Draft Questions for ODAC................................. 9

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 drugs1, 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
1
 In this document cancer drugs refers to drug or biologic products for
treating cancer.

                                                                         2
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.                 Formatted
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.

                                                                   3
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

                                                                   4
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;



                                                                   5
(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?

         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,

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

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




                                                                     6
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.




                                                                   7
    Decision making

   Local or individual autonomy: patients, physicians and IRBs         Formatted: Bullets and Numbering
    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.

   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.

   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.

   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.

   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.



                                                                    8
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


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.

                                                                              9
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.




                                                                  10
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.

                                                                  11
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.
I.Introduction........................................... 2            Formatted
II.FDA Role in Drug Development.......................... 2            Formatted: Bullets and Numbering
III.Single-Patient Use of Experimental Therapy........... 5
     A.Expanded Access
     B.Single Patient Access
IV.Regulations Addressing Treatment Use.................. 7
V.Why is FDA Involved?................................... 8
VI. When there is Curative Therapy...................... 9
VII. Issues and Examples................................. 10

Draft Questions for ODAC................................. 12

Appendices


                                                                  12
i.Excerpts from the regulations addressing treatment use of        Formatted: Bullets and Numbering
       investigational drugs
ii.    National Cancer Institute publication on NCI Non-
       Research(Compassionate)Use of Investigational
       Anticancer Agents




                                                              13
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 drugs3, 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:

To provide advice to FDA on the evaluation of requests for                   Formatted: Bullets and Numbering
   single patient treatment with investigational drugs.

To educate the public, physicians, and ODAC on the issues                    Formatted: Bullets and Numbering
   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 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.

Any use of an investigational drug must be done under an IND.                Formatted: Bullets and Numbering
   The CFR defines IND as Notice of Claimed Investigational
   Exemption for a New Drug. The IND provides permission to use
1
 In this document cancer drugs refers to drug or biologic products for
treating cancer.

                                                                         14
  an investigational drug according to a plan (a protocol) filed
  with the FDA. FDA collects, reviews, and files information
  submitted by the sponsor under an IND.

The sponsor of an IND initiates and assumes responsibility for        Formatted: Bullets and Numbering
   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         Formatted: Bullets and Numbering
   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 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

                                                                  15
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 application4. 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

4
 A marketing application for a drug is a New Drug Application (NDA) and for a
Biologic product is a Biologics License Applications (BLA).

                                                                            16
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

                                                                  17
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       Formatted
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                Formatted
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

                                                                 18
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:

The purpose of the regulations are to provide drugs to patients       Formatted: Bullets and Numbering
   with life-threatening disease for whom no comparable or
   satisfactory alternative drug or other therapy is available.
   Ordinarily such treatment should not occur before Phase 2.

FDA shall permit investigational use under a treatment protocol       Formatted: Bullets and Numbering
   for serious or life threatening disease if
     A)There is no comparable or satisfactory alternative drug
        to treat the intended population.
     B)The drug is under investigation in a controlled clinical
        trial under an IND or all trials have been completed.
     C)The sponsor is actively pursuing marketing approval with
        due diligence.

The FDA may deny a request for a treatment protocol for an            Formatted: Bullets and Numbering
   investigational drug 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
     B)Would not expose patients to an unreasonable and
          significant additional risk of illness or injury.

Sponsors must comply with IND regulations including requirements      Formatted: Bullets and Numbering
   for providing informed consent, IRB approval, and submission
   of IND safety

                                                                  19
In summary, the regulations direct the FDA to consider the
following criteria:

     Do comparable or satisfactory alternative drugs exist?           Formatted: Bullets and Numbering


     Is the drug under investigation, and is sponsor pursuing         Formatted: Bullets and Numbering
        marketing?

     What is the evidence for safety and efficacy of the              Formatted: Bullets and Numbering
        investigational agent?

     Will treatment expose patients to an unreasonable                Formatted: Bullets and Numbering
        additional risk?

In evaluating requests for single-patient compassionate use, the
following questions commonly arise:

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

     How strongly should the effectiveness of standard therapy        Formatted: Bullets and Numbering
        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 arise as single patient use increases for a
particular investigational drug. These issues include
     whether an expanded access protocol should be developed,         Formatted: Bullets and Numbering

     whether treatment use is adversely affecting the
        development of the drug, and
     whether lack of evidence of efficacy in ongoing should
        studies should lead to discontinuation of treatment use
        of the drug.

V.   Why is FDA involved?

The independent scientific consideration provided by the Agency
is critical and is an essential component of patient protection,


                                                                  20
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


                                                                21
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 issue of local or individual autonomy: patients, physicians     Formatted: Bullets and Numbering
   and IRBs may feel that the decision about patient treatment
   should be theirs to make.

Based on media reports, patients may wish to be treated with an     Formatted: Bullets and Numbering
   experimental agent before the drug has shown any signs of
   activity in human studies.

A patient may wish to forego or delay effective or even curative    Formatted: Bullets and Numbering
   therapy to receive treatment use of a investigational drug.
   Statements in the news media and on websites present hopeful
   and highly inaccurate accounts of efficacy that the FDA knows
   to be misleading.

A patient with metastatic cancer has failed all standard therapy    Formatted: Bullets and Numbering
   and is currently obtunded, 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?

A patient may even refuse to be treated on a single-arm open        Formatted: Bullets and Numbering
   study, but may want to be treated off study.

  The fate of drug development

  Unbridled treatment use of investigational drugs may interfere     Formatted: Bullets and Numbering
with accrual to trials.

Sponsors and FDA may be concerned that patients may refuse to       Formatted: Bullets and Numbering
   enroll in a randomized trial designed to compare standard
   treatment to experimental treatment if experimental treatment
   is available by special exception use.


                                                                22
Sponsors may not have sufficient drug supply to support               Formatted: Bullets and Numbering
   widespread treatment use.

Sponsors may worry that adverse events from treatment use             Formatted: Bullets and Numbering
   reported in patients who have a poor performance will have an
   adverse impact on drug development.

Meaningful data collection is difficult in the context of single      Formatted: Bullets and Numbering
   patient use of investigational therapy.

  Special role of FDA

There may be information about the investigational drug or            Formatted: Bullets and Numbering
   similar products that is available only to FDA but which may
   be important when considering treatment use.

A sponsor might seek to reap large profits from auxiliary             Formatted: Bullets and Numbering
   services provided during use of investigational treatment.
   Treatment use may greatly exceed accrual to trials designed to
   investigate the drug’s safety and efficacy.

There is limited evidence that a drug appears to have efficacy        Formatted: Bullets and Numbering
   in a rare disease. The sponsor will supply drug, but will not
   agree to provide an expanded use protocol. Hundreds of single
   patient INDs are submitted to FDA.




                                                                  23
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:
A sponsor must take responsibility for filing the IND                 Formatted: Bullets and Numbering
   application.
A qualified investigator must agree to treat the patient.
The investigator must provide informed consent.
The investigator must provide a written protocol or treatment
   plan.
An institutional review board (IRB) must approve the plan.

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:
How thoroughly has the drug been studied in humans?                   Formatted: Bullets and Numbering

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?




                                                                  24
For the purpose of our discussion, the degree to which a drug has been studied may be categorized as follows:

0The drug has not yet been tested in humans.                                                                         Formatted: Bullets and Numbering


1The drug has been tested in Phase 1 studies to evaluate                                                             Formatted: Bullets and Numbering
     toxicity.

2The drug has been tested in Phase 2 studies to evaluate whether                                                     Formatted: Bullets and Numbering
     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.

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.




                                                                                                                25
Question:                                                              Formatted


For each of the following clinical scenarios, please discuss the       Formatted
      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:
     The stage of drug development of Drug X (0-3 above), and         Formatted: Bullets and Numbering

     The level of efficacy and toxicity of Drug X that would be
        acceptable in treating the specific examples.

Clinical Scenarios

1. There is no standard therapy available.                             Formatted


   EXAMPLE:
   A patient with metastatic nonsmall cell lung cancer has
   received all available therapy.

     2.     Available treatment shows a marginal survival benefit.     Formatted


   EXAMPLE:
   A patient has metastatic nonsmall cell lung cancer. Standard
   chemotherapy produces a 1-2 month median survival benefit and
   produces moderate toxicity.
                                                                       Formatted
                 3.Standard therapy provides a substantial             Formatted: Bullets and Numbering
                 prolongation of median survival.

                                                                  26
     EXAMPLE:
     A patient has advanced ovarian cancer. Standard chemotherapy
     produces a 1 to 2 year median survival benefit but is
     generally not curative.
                                                                          Formatted
       4.Standard therapy provides a substantial rate of cure.            Formatted: Bullets and Numbering


     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            Formatted
            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.         Formatted


       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?


                                                                          Formatted




                                                                     27
__________________                   __________________
Grant Williams, MD                   Richard Pazdur, MD
Medical Team Leader                  Division Director


Division of Oncology Drug Products
CDER/ODEI/FDA




                                                          28
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.

   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 application5. 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

5
 A marketing application for a drug is a New Drug Application (NDA) and for a
Biologic product is a Biologics License Applications (BLA).

                                                                            ii
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.




                                                               iii
Appendix ii

Regulations do not specifically address the practice of single          Formatted
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:

     Ordinarily such treatment should not occur before Phase II.       Formatted: Bullets and Numbering


     There should be no comparable alternative drug treatment.         Formatted: Bullets and Numbering


     The sponsor should be pursuing approval with diligence; the       Formatted: Bullets and Numbering
      treatment use should not be a threat to or slow the drug
      evaluation process.

     The risk benefit ratio: probability of efficacy versus            Formatted: Bullets and Numbering
      evidence of toxicity, should be acceptable.

     A protocol should exist and contain details such as               Formatted: Bullets and Numbering
      rationale, entry criteria including a list of agents which
      should have been tried prior toentry, details of
      administration, and details of followup.


The following Attachment Contains excerpts from the relevent
regulations in 21 CFR 312.




                                                                   iv
  (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

                                                                        v
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


[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
                           the sponsor believes the criteria


submitted under this section, FDA may deem the protocol to be
                             reatment 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.

                                                                      vi
  (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:

  (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
w
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

  (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]


                                                                           vii
  Need for an investigational drug may arise in an emergency
situation that does not allow time for submission of an IND

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…




                                                                    viii
ii. National cancer Cancer Institute’s Treatment Referral                        Formatted
Center and Non-Research (Compassionate) Use of Investigational
Anticancer Agents. Am. J. Health-Syst. Pharm. 55:651-660, 1998.
_____________________________________________________________________________




                                                                            ix
          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




                                                                               x
          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




                                                                                     xi
          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.




                                                                                xii
When requesting an agent for non-research use physicians must consider the

following questions:

         Is the patient ineligible or unable to participate in a research           Formatted: Bullets and Numbering

          protocol?   Patients should be ineligible or unable to participate on

          a clinical trial for non-safety reasons.

         Have standard therapies been exhausted?

         Is there objective evidence that the investigational agent is active

          in the disease for which the request is being made?   Published phase

          II data is usually required as objective evidence of activity.

         Is the drug likely to benefit the patient with acceptable risk?



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




                                                                              xiii
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


                                                                                    xiv
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


                                                                               xv
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


                                                                               xvi
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.




                                                                                 xvii
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.


                                                                               xviii
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.




                                                                               xix
References:

1. Trimble, EL, Adams, JD, Vena, et al: Paclitaxel for Platinum Refractory                              Formatted: Bullets and Numbering

    Ovarian Cancer: Results from the First 1000 Patients Registered to

    National Cancer Institute Treatment Referral Center (TRC) 9103.                     J. Clin.

    Oncol., 1993:11:2405-2410.

2. Abrams, JS, Vena, D, Baltz, J, et al:                 Paclitaxel Activity in Heavily

    Pretreated Breast Cancer: A National Cancer Institute Treatment Referral

    Center Trial.       J. Clin Oncol. 1995:13:2056-2065.

3. Sorensen JM, Vena DA, Montello MJ, et al: Treatment of Hairy Cell
    Leukemia (HCL) with 2-Chlorodeoxyadenosine (CDA) Under the Group C

    Protocol Mechanism. Proc           Am Soc Clin Oncol 1993:12:302 (abstract 988).

4. Light SE, Stevenson HC, Parkinson DR, et al: Phase II Trial of All Trans
    Retinoic Acid in Acute Promyelocytic Leukemia. Proc Am Soc Clin Oncol.

    1992:11:263 (abstract 861).

    Sorensen JM, Chun HG,       Vena D, et al: Pentostatin (DCF) Therapy forCancer

                                      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



                                                                                                   xx
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


                                                                                     xxi
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.




                                                                              xxii

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:9
posted:8/27/2012
language:English
pages:50