Expanded Access Programs
for Drugs and Biologics
_________________________________________________________
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
February 27, 2014
What is Expanded Access?
also called Treatment Use, Compassionate Use
• Use of an investigational drug or biologic to treat a
patient with a serious disease or condition who does
not have comparable or satisfactory alternative
therapies to treat the disease or condition.
– Intent is clearly treatment
- not primarily intended to obtain information about the safety
or effectiveness of a drug
• Contrast with investigational drug in a clinical trial
where the primary intent is research
– systematic collection of data with the intent to analyze it to
learn about the drug
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What is Expanded Access?
• Patient is not considered part of clinical trial
• Minimal data collecting:
– Serious/unexpected adverse event
– Outcome summary
• Not part of study data from trials
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Expanded Access Programs (EAP) Should
Be Option of Last Resort
• Approved Drugs:
–
–
–
–
Studied and characterized
labeled
broadest availability
3rd party reimbursement
• Clinical Trials:
– Provide necessary data to determine safety & effectiveness
• EAP:
– Represent opportunity when other options exhausted
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FDA Published Regulations in 2009
• Subpart I consolidates treatment use into a separate
subpart of the IND regulations containing all necessary
information
• Describes three distinct categories of access
– Individual
– Intermediate-Size
– Treatment IND/protocol
• Describes the general criteria applicable to all
categories of access, and additional criteria that must
be met for each access category
• Describes requirements for submission
• Describes the safeguards applicable to EAPs (e.g.,
informed consent, IRB review, reporting requirements)
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Requirements for all EAPs
21 CFR 312.305
• Serious or immediately life threatening illness or
condition
• No comparable or satisfactory alternative therapy
• Potential benefit justifies the potential risks of the
treatment, and those risks are not unreasonable in
the context of the disease or condition being treated
• Providing drug will not interfere with or compromise
development for the expanded access use
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Human Subject Protections Apply to All EAPs
Drugs in EAPs are investigational drugs, and they are subject
to the following requirements from 21 CFR:
– Part 50- Protection of Human Subjects
(informed consent)
– Part 56- Institutional Review Board
– Part 312 - including Clinical Holds based on safety and
reporting requirements (adverse event reports, annual
reports)
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Requirements for Individual Patient EAPs
21 CFR 312.310
• Physician must determine probable risk from drug does
not exceed that from disease
• FDA must determine that the patient cannot obtain
access under another type of IND
• Procedures for emergency use (where there is not time
to make a written IND submission) – FDA may
authorize starting access without submission, with very
quick turn-around (F/U written submission required
within 15 working days of authorization)
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Requirements for Individual Patient EAPs
– Treatment generally limited to one course (though
FDA may ok ongoing therapy)
– FDA requires written summary report, and may
require special monitoring
Physician often takes role of sponsor/investigator
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Intermediate Size Population
21 CFR 312.315
• Intended for situations where multiple patients with
the same condition might benefit from a particular
investigational product
• No set numerical requirements – meant to be
practical and flexible
– more than a few, and less than a lot
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Requirements for Intermediate Size Population
21 CFR 312.315
• Can be used when a drug is
– Being developed (e.g., patients not eligible for
trial)
– Not being developed (e.g., rare disease, cannot
recruit for a trial)
– Approved (e.g., drug withdrawn, drug shortage
situation- e.g., foreign version of a U.S. approved
drug)
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Requirements for Intermediate Size Population
• Intended for patient populations smaller than intended for
Treatment IND (generally up to 100 patients)
• FDA can request consolidation when a number of individual
requests are received for the same use
• Sufficient evidence drug is safe at proposed dose and duration
to justify size of exposed population
• Preliminary evidence (clinical or plausible pharmacological) of
effect
• Annual review to determine whether treatment use should be
continued and whether a T-IND would be a more appropriate
mechanism
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Requirements for Treatment IND
or Protocol
21 CFR 321.320
• Drug is being investigated in clinical trial designed to
support marketing, or trials are complete
• Company is actively pursuing marketing approval
• Sufficient evidence of safety and effectiveness
– Serious disease: evidence from phase 3 or
compelling data from phase 2 clinical trials
– Immediately life-threatening disease: evidence from
phase 3 or phase 2 studies, but could be based on
more preliminary clinical evidence
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FDA Recognizes a Need for Balance
• Treatment access must be balanced against the systematic
collection of clinical data to characterize safety and
effectiveness
• Patient autonomy must be balanced against exposure to
unreasonable risks and the potential for health fraud,
potential exploitation of desperate patients
• Individual needs must be balanced against societal needs
– Clinical trials are the best mechanism to provide
evidence of safety and effectiveness for potential new
treatments
– FDA approval for marketing is the most efficient means
to make safe and effective treatments available to the
greatest number of patients.
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Concern about Trial Enrollment
• Early access to investigational therapies could make
clinical trials more difficult to perform
– E.g., AZT for HIV, High Dose Chemotherapy +
bone marrow transplant for stage IV breast cancer
• Clinical trial enrollment and conduct is a factor in
consideration of treatment access to experimental
drugs
• Manufacturing capacity is often limitation in early
phases – supply of drug for expanded access could
limit supply for trials
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EAP-Implementing the process
• A community responsibility
– the patient
– the doctor
– the sponsor
– FDA
– IRB
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EAP-Implementing the process
• The patient
– Facing difficult medical circumstances and confusing decisions
– Need to discover options when others are exhausted
– Need to understand and accepts potential risks
– Patients may face costs that are not reimbursed by health insurers
– Navigating uncharted waters that differ significantly from standard
health care, e.g., IRB involvement, informed consent
– Patients (and their advising physicians) may have limited information
about a drug
• confidential commercial information that FDA has access to
• may not have access to developing efficacy and/or safety information
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EAP-Implementing the process
• The doctor
– Helps initiate the process for the patient
– requires commitment to contacting company and
filing paperwork
• may represent unfamiliar processes for many
treating physicians
– responsible for ongoing support and monitoring of
patient
– responsible for adverse event and outcome reporting
– Physicians costs of providing access may not be fully
compensated
– liability issues?
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EAP-Implementing the process
• The sponsor
– must be able and willing to provide the product
– work with doctor to provide product and monitor product
– develop mid-size and large scale program protocols and
support program infrastructure
• administration
• monitoring and reporting responsibilities
• IRB review and continuing review
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EAP-Implementing the process
• FDA
• IND paperwork
• medical records review
• quick turn-around time
• requires resources
– assessment of existing data for safety and
evidence of effectiveness
– assurance of patient protections (IRB
review, informed consent)
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EAP-Implementing the process
• Institutional Review Board (IRB)
– outside physician looking for review for their patient
– not all IRBs are familiar with expanded access protocols
slant of review (intent is treatment, not clinical research)
– may miscalculate risk patient is willing to accept
– workload and scheduling issues for IRB can delay review
– requires entire committee to review (no expedited review
procedures)
– cost concerns and reimbursement for services
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How do patients find access
programs?
– Through their healthcare provider
– Internet
• ClinicalTrials.gov
• Patient organizations
• Patient forums
– Other patients
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Take-Away Messages
• Patient, physician and sponsor all play integral parts
• FDA provides the pathway/mechanism
• Sponsor must be able/willing to provide product
• Investigational product with more unknowns
• Investigator status, IRB, and informed consent
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Web Resources
Access to Investigational Drugs
• http://www.patientnetwork.fda.gov/expanded-access
• http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/A
ccesstoInvestigationalDrugs/default.htm
Physician Request for an Individual Patient IND under Expanded
Access for Non-emergency or Emergency Use
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsar
eDevelopedandApproved/ApprovalApplications/InvestigationalNewDru
gINDApplication/ucm107434.htm
www.fda.gov, search “expanded access”
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For Further Information
Richard Klein
Office of Health and Constituent Affairs
(301) 796.8460
Richard.Klein@fda.hhs.gov
www.fda.gov, search “expanded access”
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