EXPANDED ACCESS

PROTOCOL

DR.SIDDHARTH
KAMERKAR
 The first step of performing a
clinical trial is to prepare a protocol.
It is the written action plan for
the clinical trial.

2
As defines by ICH GCP guideline,
Protocol is a document that
describes the objectives,
design , methodology,
statistical considerations
and organization of a trial.

3
◆ Most human use of investigational new
drugs takes place in controlled clinical
trials conducted to assess safety and
efficacy of new drugs. Sometimes, patients
do not qualify for these carefully-controlled
trials because of other health problems, age,
or other factors. For patients who may
benefit from the drug use but don't qualify
for the trials, FDA regulations enable
manufacturers of investigational new drugs
Definition

The US National Cancer Institute (NCI) describes an

expanded access trial as a way to provide an
investigational therapy to a patient who is not eligible
to receive that therapy in a clinical trial, but who has a
serious or life-threatening illness for which other
treatments are not available.
◆ The primary intent of a treatment
IND/protocol is to provide for access to the
new drug for people with a life-threatening
or serious disease for which there is no
good alternative treatment. A secondary
purpose for a treatment IND/protocol is to
generate additional information about the
drug, especially its safety.
◆ Expanded access protocols can be
undertaken only if clinical investigators are
actively studying the new treatment in well-
controlled studies, or all studies have been
completed. There must be evidence that the
drug may be an effective treatment in
patients like those to be treated under the
protocol. The drug cannot expose patients
to unreasonable risks given the severity of
the disease to be treated.
◆ Expanded access protocols are generally
managed by the manufacturer, with the
investigational treatment administered by
researchers or doctors in office-based
practice.
◆ Concerned health professionals and
consumers alike have long maintained that
even though possibly important new drugs
or biologicals haven't yet completed the
complex and often lengthy path to FDA
approval, physicians should nonetheless be
able to use them in willing patients who
can't benefit from established therapy.
Listening to concerns
◆ Perception that FDA was inconsistent in
application of the procedures
– inequitable access, decisions arbitrary
◆ Perception that broader access will
confer health benefits
◆ Perception that available mechanisms
favored certain diseases
◆ In 1987, FDA changed its regulations on
investigational new drugs (INDs) to
specifically authorize treatment use of such
agents
◆ FDA developed and issued in May 1987
regulations codifying the circumstances
under which Treatment INDs can be
granted. While the purpose is to make
promising investigational drugs available as
early as possible to patients with serious or
 Patients/physicians may have access to investigational
devices under one of four main mechanisms by which
FDA may make an unapproved device available:
◆ Emergency Use
◆ Compassionate Use (or Single Patient/Small Group
Access)
◆ Treatment Use
◆ Continued Access
Emergency Use

◆ Emergency situations may arise in which

there will be a need to use an
investigational device in a manner
inconsistent with the approved
investigational plan or by a physician who
is not part of the clinical study. Emergency
use of an unapproved device may occur
before an IDE is approved.
Criteria:

1.Life-threatening or serious disease or

condition
2.No alternative
3.No time to obtain FDA approval

Time-frame: Before or after initiation of the

clinical trial
1.There are special cases under emergency
research in which the human subject is in a life-
threatening situation and it is not feasible to
obtain informed consent.
2. In order to allow such research to proceed,
special provisions for exception from informed
consent requirements must be met.
3. In addition, the IRB and a physician not
participating in the investigation must review
and approve the investigation. The sponsor
must also submit a separate IDE application to
FDA.
◆ FDA has permitted the emergency use of
unapproved, investigational products for
many years. Under the general rubric
"compassionate use," the agency has
permitted sponsors of investigational agents
to provide them to doctors not involved in
controlled clinical trials for use in
individual patients who might be helped by
the treatment.
Compassionate Use (or Single Patient/Small
Group Access

The compassionate use provision allows access for

patients who do not meet the requirements for inclusion
in the clinical investigation but for whom the treating
physician believes the device may provide a benefit in
treating and/or diagnosing their disease or condition.
This provision is typically approved for individual
patients but may be approved to treat a small group
Criteria:

Serious disease or condition

No alternative

Time-frame: During clinical trial

Prior FDA approval is needed before
compassionate use occurs.
In order to obtain Agency approval, the sponsor
should submit an IDE supplement requesting
approval for a protocol deviation under section
§812.35(a) in order to treat the patient.
•The physician should not treat the patient identified in
the supplement until FDA approves use of the device
under the proposed circumstances.
• In reviewing this type of request, FDA will consider
the above information as well as whether the
preliminary evidence of safety and effectiveness
justifies such use and whether such use would interfere
with the conduct of a clinical trial to support marketing
approval.
If the request is approved, the attending physician should
devise an appropriate schedule for monitoring the patient,
taking into consideration the investigational nature of the
device and the specific needs of the patient. The patient
should be monitored to detect any possible problems
arising from the use of the device. Following the
compassionate use of the device, a follow-up report should
be submitted to FDA as an IDE supplement in which
summary information regarding patient outcome is
presented. If any problems occurred as a result of device
use, these should be discussed in the supplement and
reported to the reviewing IRB as soon as possible.
The above compassionate use criteria and
procedures can also be applied when a physician
wishes to treat a few patients rather than an
individual patient suffering.
In this case, the physician should request access to
the investigational device through the IDE sponsor.
The sponsor should submit an IDE supplement that
includes the information identified above and
indicates the number of patients to be treated. Such
a supplement should include the protocol to be
followed or identify deviations from the approved
clinical protocol. As with single patient
compassionate use, a monitoring schedule should
be designed to meet the needs of the patients while
recognizing the investigational nature of the device.
Follow-up information on the use of the device
should be submitted in an IDE supplement after all
 Treatment Use

An approved IDE specifies the maximum number of

clinical sites and the maximum number of human
subjects that may be enrolled in the study. During the
course of the clinical trial, if the data suggests that the
device is effective, then the trial may be expanded to
include additional patients with life-threatening or
serious diseases.
A device that is not approved for marketing may be
under clinical investigation for a serious or
immediately life- threatening disease or condition in
patients for whom no comparable or satisfactory
alternative device or other therapy is available.
During the clinical trial or prior to final action on the
marketing application, it may be appropriate to use
the device in the treatment of patients not in the trial
under the provisions of the treatment investigational
device exemptions (IDE) regulation. (§812.36)
What are purpose of treatment IND?
◆ The primary intent of a treatment IND/protocol is to
provide for access to the new drug for people with a
life-threatening or serious disease for which there is
no good alternative treatment.
◆ A secondary purpose for a treatment IND/protocol is
to generate additional information about the drug,
especially its safety
FDA would consider the use of an investigational
device under a treatment IDE if:
•The device is intended to treat or diagnose a serious
or immediately life-threatening disease or condition;
•There is no comparable or satisfactory alternative
device or other therapy available to treat or diagnose
that stage of the disease or condition in the intended
patient population;
•The device is under investigation in a controlled
clinical trial for the same use under an approved IDE,
or such clinical trials have been completed;
•The sponsor of the investigation is actively pursuing
marketing approval/clearance of the investigational
device with due diligence.
Criteria:

•Life-threatening or serious disease

•No alternative
•Controlled clinical trial
•Sponsor pursuing marketing approval

Time-frame: During clinical trial

There are four requirements that must be met before a
treatment IND can be issued:

◆ the drug is intended to treat a serious or immediately life-threatening

disease;
◆ there is no satisfactory alternative treatment available;
◆ the drug is already under investigation, or trials have been completed;
and
◆ the trial sponsor is actively pursuing marketing approval.
◆ These trials are particularly important in therapeutic areas such as
HIV/AIDS and Cancer.
FDA action on treatment IDE applications
Approval of treatment IDE's
Treatment use may begin 30 days after FDA receives the
treatment IDE submission. FDA may notify the sponsor in writing
earlier than the 30 days that the treatment use may or may not
begin. FDA may approve the treatment use as proposed or
approve it with modifications
Notice of disapproval or withdrawal
If FDA disapproves or proposes to withdraw approval of a
treatment IDE, FDA will follow the procedures set forth in the IDE
regulations [§812.30(c)]
◆ The first class of drugs beta-blocking
agents
◆ During the mid-1970s, many thousands of
patients were treated with beta blockers for
advanced, life-threatening heart and lung
conditions for which no effective
alternative treatment existed. In one
instance, more than 600 cardiologists
treated some 20,000 patients with the anti-
arrhythmic drug amiodarone before it was
◆ zidovudine, Phase 2 trials to assess the
drug's safety and effectiveness began in
February 1986
◆ These studies were abruptly halted in
September 1986 when it was discovered
that 19 patients receiving placebo had died,
while only one death had occurred among
those receiving AZT. Within a week of
receiving this information, FDA authorized
a treatment protocol for AZT. As a result,
◆ The regulations reiterate the requirement
that, as with all clinical use of
investigational drugs, informed patient
consent must be obtained, and the product
cannot be promoted or otherwise
commercialized. FDA also requires that a
product administered under a Treatment
IND must be under (or have completed)
active clinical investigation, and its sponsor
must be pursuing marketing approval with
◆ A treatment IDE application must include,
in the following order:
◆ The name, address, and telephone number
of the sponsor of the treatment IDE;
◆ The intended use of the device, the criteria
for patient selection, and a written protocol
describing the treatment use;
◆ An explanation of the rationale for use of
the device, including, as appropriate, either
a list of the available regimens that
ordinarily should be tried before using the
investigational device or an explanation of
why the use of the investigational device is
preferable to the use of available marketed
treatments;
◆ A description of clinical procedures,
laboratory tests, or other measures that will
be used to evaluate the effects of the device
and to minimize risk;
◆ Written procedures for monitoring the
treatment use and the name and address of
the monitor;
◆ Instructions for use for the device and all
other labeling as required under section
§812.5(a) and (b);
◆ Information that is relevant to the safety
and effectiveness of the device for the
intended treatment use. Information from
other IDE's may be incorporated by
reference to support the treatment use;
◆ A statement of the sponsor's commitment to
meet all applicable responsibilities under
the IDE regulations (21 CFR 812) and
Institutional Review Boards regulations (21
CFR 56) and to ensure compliance of all
◆ An example of the agreement to be signed
by all investigators participating in the
treatment IDE and certification that no
investigator will be added to the treatment
IDE before the agreement is signed; and
◆ If the device is to be sold, the price to be
charged and a statement indicating that the
price is based on manufacturing and
handling costs only
◆ Safeguards
◆ Treatment use of an investigational device
is conditioned upon the sponsor and
investigators complying with the safeguards
of the IDE process and the regulations
governing informed consent (21 CFR 50)
and institutional review boards (21 CFR
56).
 FDA may disapprove or withdraw approval of a treatment IDE if:

2. The required criteria [§812.36(b)] are not met or

the treatment IDE application does not contain the
required information [§812.36(c)];
3. FDA determines that any of the grounds for
disapproval or withdrawal of approval apply
[§812.30(b)(1) through (b)(5)]. See
Approval Process, FDA Actions, for additional
information;
4. The device is intended for a serious disease or
condition and there is insufficient evidence of
safety and effectiveness to support such use;
5. The device is intended for an immediately life-
threatening disease or condition and the available
5. There is reasonable evidence that the treatment use
is impeding enrollment in, or otherwise interfering
with the conduct or completion of, a controlled
investigation of the same or another investigational
device;
6. The device has received marketing
approval/clearance or a comparable device or
therapy becomes available to treat or diagnose the
same indication in the same patient population for
which the investigational device is being used;
7. The sponsor of the controlled clinical trial is not
pursuing marketing approval/clearance with due
diligence;
8. Approval of the IDE for the controlled clinical
investigation of the device has been withdrawn; or
9. The clinical investigator(s) named in the treatment
IDE are not qualified by reason of their scientific
◆ Ethical concerns make it difficult for
physicians to withhold a promising
investigational drug that might forestall
severe disability or death. But if the study
that showed promise was not well-
designed--if, for example, there was no
control group--what looked like favorable
results may prove to be an illusion. in the
case of ganciclovir, an anti-viral drug used
to treat an eye infection in AIDS patients
◆ Early suggestions of ganciclovir's
effectiveness led to wide use before
controlled clinical trials ever started.
◆ approval of ganciclovir was almost
certainly delayed for years by the lack of
appropriate, controlled clinical
investigation
◆ FDA has indicated, for purposes of
Treatment INDs, what constitutes serious or
immediately life-threatening illness, what
scientific information about the drug's
safety and potential usefulness must be in
hand, and how physicians can obtain
investigational drugs for treatment use.
The sponsor of a treatment IDE must submit
progress reports on a semi-annual basis to all
reviewing IRB's and FDA until the filing of a
marketing application. The date of these
reports are based on the period of time since
initial approval of the treatment IDE. After
filing of a marketing application, progress
reports must be submitted annually in
accordance with the IDE regulation.
The progress report must also include

•the number of patients treated with the device under

the treatment IDE

•, the names of the investigators participating in the

treatment IDE,

• and a brief description of the sponsor's efforts to

pursue marketing approval/ clearance of the device.
The sponsor of a treatment IDE is responsible for
submitting all other reports required under §812.150
(Reports), such as unanticipated adverse device
effects and final reports. The reports are submitted as
supplements to the original IDE application.
◆ As of August 1994, 29 agents had been
granted Treatment IND status. The
conditions for which they have been used
include AIDS and its complications, control
of infection in kidney transplant patients,
severe obsessive-compulsive disorder,
Alzheimer's disease, severe Parkinson's
disease, various advanced cancers, and
respiratory distress syndrome in premature
infants. At press time, 24 of these drugs had
Continued Access

◆ FDA may allow continued enrollment of

subjects after the controlled clinical trial
under an IDE has been completed in order
to allow access to the investigational
medical device while the marketing
application is being prepared by the
sponsor or reviewed by FDA.
Criteria:

•Public health need or

•Preliminary evidence that the
devcie will be effective and
•there are no significant safety
concerns

Time-frame: After completion of

the clinical trial
 The sponsor of a clinical investigation is permitted to
continue to enroll subjects while a marketing
application is being prepared by the sponsor and/or
reviewed by the Agency if there is:

3. A public health need for the device; or

4. Preliminary evidence that the device is likely to be
effective and no significant safety concerns have
been identified for the proposed indication.
The continued enrollment of subjects in an investigation while a
marketing application is being prepared by the sponsor and/or
reviewed by ODE is known as an "extended investigation."
Extended investigations permit patients and/or physicians
continued access to the devices while also allowing the collection
of additional safety and effectiveness data to support the
marketing application or to address new questions regarding the
investigational device. The Continued Access Policy may be
applied to any clinical investigation that meets the criteria
identified above; however, it is intended to be applied late in the
device development process, i.e., after the controlled clinical trial
has been completed.
A sponsor's request for an extended investigation should be submitted as
an IDE supplement and include the following information:

◆ A justification for the extension;

◆ A summary of the preliminary safety and effectiveness data
generated under the IDE;
◆ A brief discussion of the risks posed by the device;
◆ The proposed rate of continued enrollment (the number of sites
and subjects);
◆ The clinical protocol, if different from that used for the
controlled clinical trial, as well as the proposed objectives for
the extended study; and
◆ A brief discussion of the sponsor's progress in obtaining
marketing approval/clearance for the device.
Expanded Access Protocol
FDA requires the following:
◆ approval by an investigational review
board,
◆ informed consent by the patient
◆ adherence to the study protocol
◆ submission of case report forms
◆ a record of drug disposition.
Current Mechanisms/regulations
◆ Treatment Use of an IND
§ 312.34
◆ Emergency Use of an IND
§ 312.36
◆ Promotion and Charging for INDs
§ 312.37
◆ Others:
– parallel track, open protocols, extension
protocols, single patient IND
Caveats
◆ Expanded access should not interfere
with drug development
◆ Data from access studies:
– should be collected
– not be overly burdensome
◆ Need for protection of human subjects
 FDAMA Sec. 402 Basic Principles
◆ Formalized procedures
◆ Clear, simple
◆ Equitable, non-arbitrary application
◆ Opportunity should be available to anyone
with life threatening or seriously
debilitating illness for which no, effective,
approved therapy available
– includes knowledge of availability
402 - dissemination
◆ Secretary may inform medical
profession, health associations about
the availability of investigational
products under expanded access
protocols
◆ A licensed practitioner who receives an
investigational device for treatment use
under a treatment IDE is an "investigator"
under the IDE and is responsible for
meeting all applicable investigator
responsibilities under 21 CFR 812, 21 CFR
50, and 21 CFR 56.
Objectives
◆ Identify federal regulations related to
investigational drugs, devices and biologics
◆ Discuss criteria for when an IND is required
◆ Discuss criteria for when an IDE is required
◆ Discuss the regulations related to humanitarian
use devices
◆ Discuss expanded access of investigational drugs
and devices (“compassionate uses”)
Applicable FDA Regulations
21 CFR
◆ Part 50: Protection of Human Subjects
◆ Part 56: Institutional Review Boards
◆ Part 312: Investigational New Drug (IND)
◆ Part 314: Application for FDA Approval to Market New
Drug
◆ Part 361: Radioactive Drugs
◆ Part 601: Biologics Licensing
◆ Part 803: Medical Device Reporting
◆ Part 812: Investigational Device Exemption (IDE)
◆ Part 814: Premarket Approval of Medical Devices & the
Humanitarian Use Device
Waiver of Informed Consent
◆ FDA regulations do not provide for waiver
of informed consent like Common Rule
◆ Two exceptions:
– Emergency use
– Emergency research
When IRB Review is Required
21 CFR §56.103
◆ Any clinical investigation as defined in
Parts 312 and 812 may not begin without
prior IRB approval and must be subject to
continuing review
◆ FDA may decide not to consider data
collected in support of a research or
marketing application when no IRB
approval
Exemptions from IRB Review
21 CFR §56.104
◆ Following clinical investigations are
exempt from Part 56
– Any investigation commenced prior to July 27,
1981, and subject to IRB requirements in effect
at that time
– Emergency use of a test article
– Taste and food quality evaluations and
consumer acceptance studies
Investigational New Drugs
21 CFR Part 312
◆ Subpart A – General Provisions
◆ Subpart B – Investigational New Drug
Application
◆ Subpart C – Administrative Actions
◆ Subpart D – Responsibilities of Sponsors and
Investigators
◆ Subpart E – Drugs Intended to Treat Life-
Threatening and Severely-Debilitating Illnesses
◆ Subpart F - Miscellaneous
FDA Device Advice:
Device Classes
◆ Class I or II: exempt or 510(K) “clearance”
– Most Class I are exempt by the FDA
– Some Class II are exempt; most require 510(k)
clearance
» 510(k) means the device is “substantially similar” to a
predicate device (one in commerce prior to May 28, 1976)
» 510(k) clearance is not FDA approval, but clears a device for
marketing
» Obtain 510(k) clearance by submitting Premarket Notification
to FDA
» In some cases, clinical investigations will be used to support a
510(k) application (IDE needed)
FDA Device Advice:
Device Classes
◆ Class III: used in supporting or sustaining
human life or preventing impairment of
human health, or that present a potential
unreasonable risk of illness or injury
– Cannot market without Premarket Approval
(PMA) by the FDA
– PMA requires establishment of device’s safety
and efficacy through clinical trials
– Investigational Device Exemption (IDE)
permits shipment for purpose of investigation
IDE Requirements
21 CFR §812.2
◆ Generally, need an IDE whenever conducting a
clinical investigation of a device that is not
“exempt” from IDE requirements
– Conducting a clinical investigation of an unapproved
Class III device
– Unapproved Class II device found not substantially
equivalent to a predicate device and cannot be
reclassified to Class I
– Clinical investigation of approved or cleared device
when use is not consistent with labeling
Exempted Investigations
21 CFR §812.2(c)
◆ The following are exempt from the IDE
requirement:
– A device that was in commercial distribution
prior to May 28, 1976 when used consistent
with labeling (“predicate device”)
– A device in commercial distribution on or after
May 28, 1976 that FDA has determined to be
substantially equivalent to predicate device
when used consistent with labeling (“510(k)
clearance”)
Exempted Investigations
21 CFR §812.2(c)
◆ A diagnostic device if the testing:
– Is noninvasive
– Does not require an invasive sampling
procedure that presents significant risk
– Does not by design or intention introduce
energy into a subject, and
– Is not used as a diagnostic procedure without
confirmation of the diagnosis by another
medically established diagnostic product or
procedure
FDA 2006 Guidance on Informed Consent for
In Vitro Diagnostic Device Studies
◆ Studies that are exempt from IDE requirements still need
IRB review and informed consent of subject
◆ FDA has decided to exercise enforcement discretion with
respect to informed consent requirements for in vitro
diagnostic device
◆ No informed consent required if:
– Study uses leftover specimens not collected for this research
– Specimens are not identifiable to investigator or sponsor
– Individuals caring for patients are not part of research
– IRB reviewed
“Compassionate Use” or
Expanded Access
◆ Treatment IND or IDE
◆ Open label protocol
◆ Group C treatment IND
◆ Parallel track
◆ Emergency use

http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency
http://www.fda.gov/oc/ohrt/irbs/irbreview.pdf
Treatment IND or IDE
21 CFR §312.34, §812.36

◆ Facilitates availability of promising new

drugs/devices to desperately ill as early as
possible in development
◆ Obtain additional data on safety/efficacy
◆ Permits use of drug/device currently under
investigation in treatment of patients not in
clinical trials
◆ Must have IRB approval and informed consent
Treatment IND or IDE
◆ Criteria for Treatment IND or IDE:
– Serious or immediately life-threatening disease or
condition
– No comparable or satisfactory alternative
– Drug/device under investigation in controlled trial
– Sponsor is actively pursuing marketing approval
◆ Sponsor and investigators must comply with all
applicable Parts of FDA regs (IC, IRB review)
FDA 1998 Information Sheet:
Drugs and Biologics
“Life-threatening” means diseases or conditions
where the likelihood of death is high unless the
course of the disease is interrupted, and diseases
or condition with potentially fatal outcomes. The
criteria for life-threatening do not require the
condition to be immediately life-threatening or to
immediately result in death. Includes “severely
debilitating” which relates to diseases or
conditions that cause major irreversible morbitity.

www.fda.gov/oc/ohrt/irbs/drugsbiologics.html
FDA 1998 Information Sheet:
Drugs and Biologics
◆ Open label protocol
– Usually uncontrolled Phase III
– Carried out to obtain additional safety data
– Controlled trial has ended and treatment
continued so that subjects can receive drug
until marketing is approved
– Require prospective IRB review and consent
FDA 1998 Information Sheet:
Drugs and Biologics
◆ Group C treatment IND:
– Established by agreement between FDA and NCI
– Distribution of investigational agents to oncologists for
treatment of cancer
– Protocol is outside of controlled trial
– Distributed only by NIH under NCI protocol
– Primary objective is treatment, but safety and efficacy
data collected
– But not research intent, so FDA has generally waived
IRB review requirement
FDA 1998 Information Sheet:
Drugs and Biologics
◆ Parallel track
– Permits wider access to new drugs for
AIDS/HIV
– Separate “expanded access” protocol that
“parallels” controlled trials
– Requires IRB review and informed consent
Humanitarian Use Device (HUD)
21 CFR §814.100
◆ Medical device that is intended to benefit patients in
treatment or diagnosis of disease or condition that affects
or is manifested in fewer than 4,000 patients per year
◆ No marketed comparable device
◆ Exempt from effectiveness requirements of the PMA
◆ Device is approved and may be marketed once it has HUD
designation and Humanitarian Device Exemption (HDE)
is submitted
◆ If sponsor wants PMA, must obtain IDE and undergo
clinical investigation
Humanitarian Use Device
◆ Use of HUD does not constitute research
◆ Thus, FDA does not require research consent
◆ Under FDA regs, IRBs must approve use of HUD
◆ FDA strongly encourages IRBs to require and
review HUD consent forms
◆ Because use of HUD is clinical, may be required
to use hospital standard surgical consent form in
addition to more specific IC form
Emergency Uses

◆ 21 CFR §50.23 – Exception to informed consent

◆ 21 CFR §56.104 – Exception to IRB review
◆ 21 CFR §312.36 – Exception to IND requirement
◆ 21 CFR §812.35 – Exception to IDE requirement
◆ 21 CFR §814.124 – Emergency Use of HUD
Exception to Informed Consent
21 CFR §50.23
◆ Investigator and unaffiliated physician certify in
writing:
– Life threatening situation requiring use of test article
– Subject cannot communicate or cannot provide legally
effective IC
– No time to obtain IC from LAR
– No available alternative that provides equal or greater
likelihood of saving subject’s life
◆ If no time to consult unaffiliated physician, get
physician review within 5 days of use
Exception to IRB Review
21 CFR §56.104
◆ Life-threatening disease or condition
◆ No standard acceptable treatment available
◆ No sufficient time to obtain IRB approval
◆ Notify IRB chair or Director if possible, but
this is not IRB review
◆ Notify IRB within 5 working days
Exception to IND or IDE Requirement
21 CFR §312.36, §812.35
◆ Life threatening disease or condition
◆ Need for investigational drug/device prior to
submission of IND or IDE, or patient does not
qualify for current protocol
◆ Generally limited to few patients
◆ Notify sponsor who submits report to FDA
◆ Must follow patient protection measures if
possible:
– Independent assessment by uninvolved physician; IRB
chair concurrence; institutional clearance; informed
consent
Emergency Use of HUD
FDA 2001 HDE Guidance
◆ HUD may be used off-label in an emergency
◆ Physician and HDE holder should follow same
patient protection measures set out for emergency
use of an investigational device
◆ Authorization from HDE holder needed prior to
use
◆ Physician should submit follow up report to HDE
holder and IRB if no prior IRB approval (within 5
working days)
Emergency Research
21 CFR §50.24
◆ Research that is aimed at class of subjects in an
emergency (i.e. cardiac arrest, stroke, head
trauma)
◆ IRB (which must include one physician) may
approve study without requiring informed consent
if:
– Life-threatening situation, no alternatives, collection of
evidence is necessary to determine safety/efficacy of
intervention
– Obtaining informed consent not feasible
– Prospect of direct benefit
Emergency Research
21 CFR §50.24
– Investigation could not practicably be carried out if
consent required
– Protocol defines potential therapeutic window (sponsor
responsibility) and investigator attempts to contact
LAR or family member in that window for consent
– IRB has approved a consent form to be used when
feasible
– Additional protections for rights and welfare of
subjects:
» Consultation with community members, notice to community
of research, and disclosure of results to community
» Establishment of independent DMC
Emergency Research
21 CFR §50.24
◆ Protocols performed under this section
require separate IND or IDE
◆ True even if IND or IDE already exists for
same drug/device
◆ IND or IDE must state that some subjects
will be unable to provide consent
Issues for consideration
◆ Defining categories
– indications not being developed
◆ Evidentiary standards to support
each type of access
◆ Procedures
◆ Safeguards
– IRB, informed consent
◆ It is clearly too soon to know whether
efforts to make drugs and biologics more
rapidly and widely available to the
desperately ill are contributing to genuine
advances in health care. But many
thousands of patients who might otherwise
be beyond hope are now able to seek help
from investigational agents, and all of us
stand to gain from a more efficient, more
responsive system by which to bring
THE END

THANK YOU
 SOME ISSUES IN
DEVELOPING COUNTRIES
BETWEEN WHICH PHASE should drug be given
RATIONALE FOR INCLUSION IF patient EXCLUDED
ON LEGITIMATE GROUNDS
IN INDIA is MONITORING OF SUBJECTS STRICT AND REGULAR
Are indian PHYSICIANS READY TO TRY NEW DRUGS
WHAT IS definition of SERIOUS ILLNESS IN INDIA
Is same dose to be given or can it be changed
Are same rules applicable to industry and university researc
IN PAEDIATRIC,PREGNANT,LACTATING,GERIATRIC,DEPENDEN
POPULATION
Another mechanism to permit
wider availability of experimental
agents is the "parallel track" policy
developed by the U.S. Public
Health Service in response to the
AIDS epidemic. Under this policy,
patients with AIDS whose
condition prevents them from
participating in controlled clinical
trials can receive investigational
drugs shown in preliminary studies
to be potentially useful. At press
time, one drug (D4T) had been
made available under the parallel
track mechanism. D4T was
approved for marketing in mid-
1994
Less dramatic, perhaps, than
rushing investigational drugs to the
desperately ill, but almost certainly
of more long-range benefit to
society, are measures to streamline
FDA's review and approval process
and expand the agency's resources
for this task
One change FDA has adopted in
recent years to speed drug review is
categorizing new drugs as either
standard or priority. Standard drugs
are those that offer only minor
improvement (or none) over drugs
already on the market. Priority
drugs, on the other hand--which
may in fact be a new dosage form
of, or new use for, an existing
drug--are believed to represent
potential major advances in health
care. Distinguishing the two
categories of drugs permits
speedier review even before a new
drug application is submitted.
FDA and sponsors of priority drugs
may meet at the earliest stages of
clinical testing to plan studies that
will help develop the information
necessary for a final decision on a
product's approvability. Then,
when a marketing application is
submitted, FDA can mobilize
available personnel and other
resources needed to review the
often large amounts of technical
information contained in a priority
new drug application
In another effort to speed the
review of marketing applications,
the review process is becoming
increasingly computerized. New
drug applications that commonly
run to thousands of pages are now
arriving from sponsors in a form
suitable for computer processing.
This makes review and
communication with the sponsor
more efficient, saving time for both
FDA and the firm
A highly specialized mechanism
for speeding the approval of drugs
or biologics that promise
significant benefit over existing
therapy for serious or life-
threatening illnesses-is the
accelerated approval. Accelerated
review, established by 1991
regulations, can be used in two
very special circumstances: when
approval is based on evidence of
the product's effect on a "surrogate
laboratory finding or physical sign
that may not, in itself, be a direct
measurement of how a patient
feels, functions or survives, but
nevertheless is considered likely to
predict therapeutic benefit. For
example, high blood pressure and
elevated serum cholesterol are risk
factors for heart and blood vessel
disease. Drugs that control blood
pressure or cholesterol can
reasonably be expected to help
control or prevent direct signs of
disease, such as angina, congestive
heart failure after a heart attack,
paralysis following a stroke, and
sudden death. Once a drug has been
shown effective as measured
against such a surrogate endpoint,
sponsor to carry out post-marketing
studies to confirm that the drug
does in fact produce a clinical
benefit, such as increased survival
time. And if further research or
experience shows that a product
that received accelerated approval
cannot safely remain on the market,
FDA can order its prompt
withdrawal.
As a further safeguard, distribution
of accelerated-approval drugs can
be limited to institutions that have
the capability to use them safely
and to physicians with specialized
training or experience. The agency
can also require that specific
medical procedures, such as blood
tests, be carried out if they are
Report of an international expanded
access program of imatinib in adults
with Philadelphia chromosome
positive leukemias – A CASE STUDY
Compassionate use of bevacizumab
(Avastin®) in children and young adults
with refractory or recurrent solid tumors-A
CASE STUDY
issues regarding post-trial treatment for individuals who participate
in these trials must be addressed. Discontinuation of antiretroviral
treatment when a trial ends could have negative health effects,
which include the increased risk of mortality. To help prevent the
possibility of such adverse effects, the NIH developed this
Guidance.
6. Why does the Guidance apply only to trials being conducted in
developing countries?
The Guidance addresses inequities in resources available to
participants in developed versus developing countries. For trials
conducted domestically, there are existing programs (e.g.,
pharmaceutical company patient assistance/compassionate use
programs, Ryan White CARE Act, Medicaid, private insurance
coverage) that can help trial participants continue to receive
antiretroviral treatment following their completion of an
antiretroviral treatment trial. Participants in developing countries
may not have the same types of programs available to them
7. What definition does the NIH use for “Developing” Countries?
For purposes of this Guidance, “developing countries” are defined
as the low- and middle-income economies, using World Bank
classifications. The World Bank's main criterion for classifying
economies is gross national income (GNI) per capita, calculated
using the World Bank Atlas method. Classification by income does
not necessarily reflect development status. The developing
countries include: low income , $735 or less; lower middle income ,
$736 - $2,935; and upper middle income , $2,936 - $9,075.
See http://www.worldbank.org/data/countryclass/classgroups.htm
for a list of the countries included in each group
11. Does the antiretroviral treatment identified for post-trial
provision have to be the same regimen that the participant
received during the trial?
No. The purpose of this Guidance is to assert the importance of
trial participants being able to continue to receive effective
antiretroviral treatment after the trial ends but not to specify a
particular type of treatment. Treatment regimens should be
determined based on individual medical needs, what is available
in the host country, and progress in the field
Bevacizumab was administered on a compassionate basis out of a
specific protocol assuming that the potential benefits and toxicity
would compare favorably with other conventional cytotoxic drugs
in these heavily pretreated patients. In the majority of patients,
bevacizumab was given as third- or fourth-line therapy following
failure to previous relapse therapies. The drug dose and intervals of
administration were on the basis of the currently available clinical
studies in adult patients [12, 14–17]. Bevacizumab was
administered at 5–10 mg/kg body weight (BW) intravenously every
2–3 weeks. Patients and/or their legal guardians were informed
about the potential benefits and side-effects of this experimental
approach and gave their informed consent before the initiation of
bevacizumab administration. During administration of
bevacizumab, patients were monitored according to center
guidelines for side-effects with special emphasis on hypertension,
proteinuria, bleeding, thromboembolic complications, and delays in
wound healing. Assessment of response was done using clinical and
radiographic evaluations at regular intervals. The total duration of
bevacizumab treatment was on the basis of the decision of the
In the present retrospective study bevacizumab was used on a
compassionate basis in 13 heavily pretreated patients with
progressing malignant diseases and in two patients with
nonmalignant angiomatous tumors. Although assessment of the
efficacy of bevacizumab was not the primary goal of the present
report, we did observe objective radiographic responses in patients
who received bevacizumab in combination with other cytotoxic
drugs.
The ‘off-label’ use of a new drug such as bevacizumab in children
and young adults out of a specifically designed protocol might raise
some ethical concerns. It is, however, well known that carrying out
clinical studies in children is nowadays hampered by many factors.
First the pharmaceutical industry is generally very reluctant to
carry out studies on new drugs in children, because the commercial
profit can be expected to be conceivably small compared with the
adult population. The imminent high legal risks further prevent
many pharmaceutical companies from carrying out clinical studies
in children. Secondly, the new EU Clinical Trials Directive to be
 Describe Treatment Access or
Expanded Access Protocol, why
are they important. Are there
regulations in developing
countries that mandate these
types of studies?

DR.SIDDHARTH
KAMERKAR
Expanded Access Protocol

“Expanded access refers to the inclusion of

patients in a clinical trial for a new treatment,
where those patients would not satisfy the
inclusion criteria for the scientific study in
progress. ”
“The guidelines for additional inclusion
determined by the agency running the clinical
trial is called an Expanded access protocol. ”
 Patient suffering from
life- threatening diseases (HIV, Cancer)
Patient not eligible
to receive investigati
No availability of alternate
new drug
Drug

Administration of
New Investigational Drug
• Investigational new drug
•
under control clinical trial
•
•
 History
• Access to unapproved therapies - unrecognized need.
• Before 1987 investigational drugs made available
informally for treatment .
• Informal policies : “Compassionate use protocol” ,
“Single-patient protocol exceptions” and “Large open
protocols”.
• Formal policies-USFDA Regulation1987,FDAMA
regulations 1997,EMEA Guidelines 2007,CDSCO
Guidelines 2008
• EA programs made promising investigational drugs to
large population.
(E.g.- More than 10,000 patients obtained access to
“cardioselective beta-blockers”)
EAP- Purpose
◆ Primary purpose is to provide access to the
new drug for the people with life
threatening or serious disease for which
there is no good alternative treatment.
◆ Secondary purpose is to generate additional
information about the drug especially its
safety.
 Expanded Access Mechanism

*IND (Investigational New Drug): Is one that is under study but does
not have permission from the U.S. Food and Drug Administration
(FDA) to be legally marketed and sold in the United States.
 Expanded Access Mechanism
Treatment IND
• Final regulation issued in May 1987.
• Made available to person with serious and life threatening illness, no
comparative or satisfactory treatment/ therapy.
• Generally granted when the product is well into clinical trial/ trial is
completed, and the sponsor is pursuing marketing approval with due
diligence (according to 21 CFR 312.34 b)

Parallel Track
◆ Published in the Federal Register on April 15, 1992.
◆ Applies only to the person with AIDS and HIV related diseases.
◆ IND made available early in developmental process.
◆ Eg.stavudine
Group C treatment IND
◆ Established by agreement between FDA and NCI
◆ Phase 3 study drugs for the treatment of cancer
Investigational Device Exemption-
IDE
Expanded Access Criteria for use When can it FDA approval Patient protection Measures
Mechanism be used needed?

Emergency Use 1. Life threatening Before or No; submit report 1. Independent assessment by
condition after initiation to FDA following uninvolved doctor
2. No alternative and of clinical trial device use 2. IRB Chairperson Concurrence;
3. No time to obtain FDA 3. Institutional clearance and
approval 4. Informed consent

Compassionate 1. Serious disease or During Clinical Yes 1. Independent assessment by

Use condition and trial uninvolved doctor
2. No alternative 2. IRB Chairperson Concurrence;
3. Institutional clearance and
4. Informed consent
Expanded Access Criteria for use When can it be FDA approval Patient protection
Mechanism used needed? Measures

Treatment 1. Life threatening or During Clinical trial Yes 1. IRB approval and
use serious disease, 2. Informed consent
2. No alternative
3. Controlled clinical trial;
and
4. Sponsor pursuing
marketing approval with
due diligence

Continued access 1. Public health need; or After completion Yes 1. IRB approval and
2. Preliminary evidence of clinical trial 2. Informed consent.
that device will be
effective and no
significant safety
concerns.
Procedure to receive Treatment
IND
 Regulations for EAP in
developed countries (USFDA)
21 CFR:

• Part 312: Investigational New Drug (IND)

• Part 312.34: Treatment Use of an IND

• Part 312.37 : Promotion and Charging for INDs

• Part 812: Investigational Device Exemption (IDE)

• Part 814: Premarket Approval of Medical Devices & the Humanitarian

Use Device
Investigational New Drugs
21 CFR Part 312

◆ Subpart A – General Provisions

◆ Subpart B – Investigational New Drug Application
◆ Subpart C – Administrative Actions
◆ Subpart D – Responsibilities of Sponsors and
Investigators
◆ Subpart E – Drugs Intended to Treat Life-Threatening
and Severely-Debilitating Illnesses
◆ Subpart F - Miscellaneous
 Section 402-
Expanded Access to
Investigational Devices (US FDAMA, Effective:
February 19, 1998):
• Emergency Use:
– FDA can permit the shipment of an investigational device for the purpose of
diagnosing, monitoring or treating a serious disease or condition in an
emergency situation.

• Criteria to be met:
1. Licensed physician determines there is no comparable or satisfactory
alternative treatment .
2. Evidence of safety and effectiveness to support the use of the device.
3. Device will not interfere with clinical investigations to support marketing
approval.
4. Sponsor or investigator submits a protocol to FDA describing the use of the
device in a single patient or in small groups of patients.
 Regulations for EAP in developing
countries
CDSCO GCP Guidelines-
A “compassionate use” of the experimental
evaluation is ethically justified if disease cannot
otherwise be treated

In India, approval for DCGI is required for

conducting Expanded access
• (Ref-Dr. Arun Bhatt , Pharmabiz)
 Case Study
• Imatinib- Selective inhibitor of BCR/ABL tyrosine
kinase.
• Remarkable results of Phase- I trial published in 1999
prompted initiation of Phase- II trial.
• Interest from patients, clinician.
• Demand for access to imatinib before market approval.
• A worldwide EAP for imatinib implemented in May
2000.
 7380 patients with chronic myeloid leukemia
(CML) and acute lymphoblastic leukemia
Enrolled in 106 centers in 34
countries
Results obtained were similar to
those obtained in phase-II trial

Result: Imatinib EAP successfully provided

therapy to patients before marketing
approval
Conclusion:
The program provides efficient framework for development of
global EAPs for innovative investigational anticancer agents in
patients without satisfactory therapeutic alternative.
Ref: Annals of Oncology,2008 19 (7):1320-26
 Advantage/Disadvantage of
EAP
• Advantage:
• To make the drug available to people who normally would have to
wait till the drug reaches the market.
• For large industries, learning about Side effects and Efficacy of their
drug.
• Strong way to influence market.
• Disadvantage:
• Sponsor angle-Economic disincentives is concern for small companies
• Investigator Dynamics
• Hard to get.
• Time-consuming and frustrating.
• List of all the drugs for use not available
• Reimbursement
• Regulations
 Conclusion
It is clearly too soon to know whether efforts to make
drugs more rapidly available to the seriously ill are
contributing to genuine advances in health care. But
many thousands of patients who might otherwise be
beyond hope are now able to seek help from
investigational drugs, and all of us stand to gain from a
more efficient system by which to bring important new
agents to market.
Thank You