Regulatory issues in HIV cure Research

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Transcript Regulatory issues in HIV cure Research

HIV Cure Research Training Curriculum
Regulatory Issues Module by:
Damon Deming, Ph.D.
FDA Division of Antiviral Products
Nov 2014
The HIV CURE training curriculum is a collaborative project aimed at making HIV
cure research science accessible to the community and the HIV research field.
The opinions expressed in this module are those of the author and may not
represent official FDA policy.
1 Overview of the Regulatory Process
2 Regulatory Decision Making
3 Regulatory Issues in HIV Cure Research
4 Patient Role in the Regulatory Process
Overview of the Regulatory Process
Study Sponsor
Pre-IND Phase
Pre-Clinical Studies
(not in humans)
Drug Discovery/Selection
IND Phase
Clinical Trials
(in humans)
Investigational New Drug (IND)
Phase 1
Phase 2
Phase 3
New Drug Application (NDA)/
Biologics License Application (BLA)
Conduct additional studies
Monitor safety post-approval
Pre-IND Consultation
IND Review
Review clinical data
Advise development
NDA/BLA Review
Review data
Update label
Pre-IND Development
The regulatory approval process usually begins with the submission of
an Investigational New Drug (IND) application, which contains
information that the FDA needs to decide if a drug is safe to study in
The information included in the IND application must be generated
before clinical studies can occur, sometimes called the Pre-IND or Preclinical phase of development.
Although the FDA is not required to be involved during the Pre-IND
phase, the FDA can guide sponsors in putting together an IND package
through the Pre-IND Consultation Program.
Critical Question:
>> Is the drug safe?
IND Application
The IND application supports initial clinical trials and typically includes information
• the composition of the drug and the manufacturing process used to make
the drug
• the drug’s toxicity in multiple species of animals
• any supporting “proof-of-concept” studies; for example, studies that
demonstrate that a drug can reduce HIV reservoirs in cell culture or animal
models of infection
• non-clinical safety and activity data to support the starting dose that will be
tested in humans
• the proposed design of the first trial to test the drug in a specific population
of people
Critical Question:
>> Is the drug safe?
Critical Question:
To what extent is it
IND Clinical Development
A series of progressively larger clinical trials are conducted as more information is
learned about the safety and potential efficacy of the drug. The trials are typically
separated into three phases of development:
Phase I:
Phase II:
Phase III:
THESE TRIALS include several small trials designed to learn how the
drug is broken down by the body and to begin studying the drug’s
safety in humans.
These larger trials look for evidence that the drug is acting as
expected and compare different ways of giving the drug in order to
find a safe and potentially effective dosing strategy.
These MUCH largeR trials are intended to verify that the drug is safe
and prove that the drug is effective.
Phase 1
Phase 2
Critical Question:
To what extent is it >>
Phase 3
New Drug Application (NDA)/
Biologics License Application (BLA)
If the results of the Phase 3 trials show that the drug is safe and effective, then
the Sponsor may submit a New Drug Application (NDA) or Biologics License
Application (BLA). If the NDA/BLA is approved, then the drug may be sold and
used by the public.
The FDA and Sponsor agree upon the drug’s label, which provides information
to help physicians and their patients decide
Phase if1 they wish to use the drug and
provides instructions for how it should be used.
Phase 2
Critical Question:
To what extent is it >>
Phase 3
The FDA may require that additional non-clinical studies or clinical trials be
completed after the NDA/BLA is approved. For example, an additional clinical
study might be conducted to provide information for a group of people who
might benefit from the drug but who were not included in previous trials.
The FDA continues to receive and review long-term safety information for
approved drugs. Identification of new safety issues could require changes to
the drug’s label or, in extreme cases, withdrawal of the drug from the market.
Phase 1
Phase 3
>> Manufactured
More Trials
>> Manufactured
Continual oversight
Phase 2
Phase 1
Phase 3
Continual oversight
Critical Question:
>> Is the drug safe?
Phase 2
Critical Question:
>> Manufactured
>> Application
>> To what extent is it >>
More Trials
>> Manufactured
Benefit-to-Risk Analysis of Clinical Trials
When making regulatory decisions regarding clinical trials, the FDA
considers the potential benefits and harms. For example:
Is there reason to expect a benefit
based on what we know from nonclinical studies or from previous
clinical trials?
Is it possible that participants in a
trial will directly benefit from using
the drug?
Even if there is no direct benefit to
study participants, can the
information learned from the study
benefit people in future trials or
after the drug is approved?
What risks can be expected from
available clinical information (if
available for the drug or from
similar drugs) or from the nonclinical studies?
Are there ways to monitor for
POTENTIAL problems as they arise
and ways to treat them if they
Are drug-related problems expected
to go away when the drug is no
longer being used, or does the drug
potentially cause long-term
Benefit-to-Risk Analysis of Clinical Trials
If the FDA decides that the potential benefits of a drug
outweigh its potential risks, then the trial is allowed to
proceed. If not, then the FDA may require more
information or changes to the trial protocol to
minimize risks. For example:
Additional non-clinical studies might be REQUIRED
in order to provide additional information about
potential concerns.
The protocol might be changed to use lower doses
of the drug or to give fewer doses to people in the
The population of people who are enrolled into the
trial might be restricted in order to exclude those
who are less likely to benefit or at higher risk of
Regulatory Issues in HIV Cure Trials
Like all clinical trials, HIV cure-related trials are evaluated by considering potential
benefits and risks. Potential benefits:
Initial trials are necessary proof-of-concept studies intended to evaluate
particular aspects of biological activity that might be a useful step towards
developing a cure. For example, a drug might be studied for its ability to
activate latently-infected cells in the body.
Although there is little prospect of a direct benefit to the people who
participate in early phase trials, the results from these trials might be useful for
designing later studies and advancing the development of a safe and effective
Regulatory Issues in HIV Cure Trials
The FDA also considers potential risks of early HIV cure-related trials:
These studies are not expected to result in a cure, and the lack of direct benefit
to trial participants requires that those people are not exposed to
unreasonable risk.
The potential of the drug or trial procedures to compromise the effectiveness
of antiretroviral drug treatment IS CONSIDERED.
Safety in new populations: Acceptable risk levels may be different in
populations for which a drug has been PROVEN TO BE SAFE AND EFFECTIVE
(e.g., cancer) versus an investigational population (e.g., HIV-infected) for which
the drug has no proven benefit AND MAY BE HARMFUL.
Other HIV Cure-Related Issues
Regulatory issues are often related to scientific issues
‒ WE need for biomarkers that can be used to determine treatment effects;
for example, changes in the number of latently-infected cells.
‒ We need for new assays that may be sensitive enough to detect clinically
significant changes in those biomarkers.
‒ We need NEW assays may also need to be approved as a companion
diagnostic for HIV cure drugs; that is, physicians may need access to those
assays in order to properly administer an HIV cure therapy.
Antiretroviral treatment interruption (ATI)
‒ Cure trials will ultimately require an interruption of antiretroviral drugs in
order to determine if study subjects have been cured.
‒ Ideally, there will be a useful biomarker that can be used to predict success
before A TREATMENT interruption in order to limit the risks associated with
treatment interruptions, including periods of uncontrolled virus replication
and minimize the risks associated with that replication; (e.g., selecting
resistant virus AND increased risk of transmission).
Other HIV Cure-Related Issues
Development for special populations (e.g., pediatrics)
‒ THE FDA will first require the generation of substantial safety and efficacy
data in adults.
Trial durations may be very long
‒ It is not known how long virus will need to remain undetected once off of
antiretroviral treatment before a person can be considered cured because
virus may take several months to rebound.
‒ It is also unclear how long people should be followed for safety in order to
detect slowly developing adverse events that might be related to the HIV
cure treatment; e.g., cancer risks.
Combination products
‒ An HIV cure may involve a combination OF products; (e.g., drug/biologic.)
‒ THE Contribution of each component to efficacy must be demonstrated.
‒ THE Components may have distinct regulatory requirements.
‒ Review by different FDA Centers MAY BE REQUIRED.
Other HIV Cure-Related Issues
It is not currently known what an “HIV cure” will look like
‒ Ideally, a cure will result in removal of all virus from the body.
‒ However, it is possible that a permanent or temporary reduction in viral load
without antiretroviral drugs might be useful even if a complete cure is not
Approval of such therapies would likely depend on several factors, such
‒ the safety of the therapy
‒ the target population of HIV-infected people that the therapy is
intended to TREAT
‒ the magnitude and duration of viral suppression, and
‒ the potential for re-treatment.
Patient Role in the Regulatory Process
Volunteers should understand the potential benefits and risks of participating
in a trial.
Patients and trial volunteers can help regulators, sponsors, and clinical trial
investigators define the acceptable levels of risk for clinical trials.
The FDA greatly values the perspective and input of patients and potential
clinical trial participants. The community is strongly encouraged to provide
feedback to regulators:
‒ Through COMMUNITY ADVISORY BOARDS and trial sponsors
‒ During public meetings
‒ During NDA/BLA advisory committee meetings
The development of an HIV cure NEEDS TO work within the framework of the
regulatory process.
Regulatory decisions are based on benefit-to-risk analyses.
Regulatory uncertainty regarding HIV cure research is largely related to
scientific uncertainty.
The regulatory path to approval is expected to evolve with advances in the
science DISCOVERED THROUGH potential HIV cure strategies.
There is an important role for patients in the HIV cure development process.