Testimony
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Statement by
Robert J. Meyer, M.D.
Director, Office of Drug Evaluation II,
Center for Drug Evaluation,
and Research Food Drug Administration, HHS
on
FDA's Drug Approval Process
before the
Subcommitte on Criminal Justice, Drug Policy and Human Resources, Committee on Government Reform
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April 1, 2004
Introduction
Good afternoon, Mr. Chairman and Members of the
Subcommittee. I am Dr. Robert Meyer, Director of the
Office of Drug Evaluation II at the Food and Drug
Administration’s (FDA or the Agency), Center for Drug
Evaluation and Research (CDER). I am pleased to be here
today with my colleague, Dr. Nora Volkow, Director of the National
Institute on Drug Abuse (NIDA). FDA appreciates the
opportunity to discuss the need for a science-based approach to
evaluating the merits of marijuana for medicinal purposes.
In my testimony today, I will first describe the FDA drug approval
process. Second, I will clarify FDA’s role in
facilitating the objective evaluation of the potential merits of
cannabinoids for medical uses as well as FDA’s role with
respect to enforcement efforts relating to Schedule I Controlled
Substances such as marijuana.
FDA APPROVAL PROCESS
FDA’s primary mission for over 90 years has been to promote
and protect the public health, under the authority of the Federal
Food, Drug, and Cosmetic (FD&C) Act and the Public Health
Service Act. These statutes were enacted and amended,
in part, in response to public health tragedies resulting from the
sale to, and use by, an unsuspecting public of unsafe and
ineffective products sold as medicines and medical
devices. The FD&C Act requires that new drugs be
shown to be safe and effective before being marketed in this
country.
The single most important public health provision in these statutes
is the requirement that a person wishing to sell to the public a
product to prevent, cure or mitigate illness or injury must first
prove that such product is safe, and actually does what the vendor
claims it does. This statutory provision affords patients the
most effective protection against untested and unproven
products.
A new drug or biologic (referred to in this statement as a drug)
may not be distributed in interstate commerce (except for clinical
studies under an investigational new drug application) until a
sponsor, usually the drug manufacturer, has submitted and FDA has
approved a new drug application (NDA) or a biologics license
application (BLA) for the product. For approval, an NDA
or BLA must contain sufficient scientific evidence demonstrating
the safety and effectiveness of the drug for its intended uses.
The evidence of safety and effectiveness usually is obtained
through controlled clinical trials. The disciplined,
systematic, scientific conduct of such trials is the most effective
and certain means of obtaining the data that document safety and
efficacy of a drug and how to use the new product so that it will
have the most beneficial effect.
A. INVESTIGATIONAL NEW
DRUG APPLICATION PROCESS
The first step a sponsor usually must take to obtain approval for a
new drug is to test the drug in animals for toxicity.
The sponsor then takes that animal testing data, along with
additional information about the drug’s composition and
manufacturing, and develops a plan for testing the drug in
humans. The sponsor submits these data, along with
proposed studies, the qualifications of the investigators who will
conduct the clinical studies, and assurances of informed consent
and protection of the rights and safety of the human subjects, to
FDA in the form of an investigational new drug application (IND).
FDA reviews the IND for assurance that the proposed studies,
generally referred to as clinical trials, do not place human
subjects at unreasonable risk of harm. FDA also
verifies that there are adequate assurances of informed consent and
human subject protection. At that point the first of
three phases of study in humans can begin. Phase I
studies primarily focus on the safety of the drug in
humans. Phase I studies carefully assess how to safely
administer and dose the drug with an emphasis on evaluation of the
toxic manifestations of the therapy, how the body distributes and
degrades the drug, and how side effects relate to dose.
Phase I studies typically include fewer than 100 healthy volunteers
or subjects.
Phase II studies are clinical studies to explore the effectiveness
of the drug for a particular indication over a range of doses and
to determine common short-term side effects. Phase II
studies typically involve a few hundred subjects. Once
Phase II studies are successfully completed, the drug’s
sponsor has learned much about the drug’s appropriate dosing
and its apparent safety and effectiveness. The next
step is to conduct Phase III studies involving up to several
thousand subjects. These studies establish efficacy for
a particular indication, examine additional uses, may provide
further safety data including long-term experience, and consider
additional population subsets, dose response, etc. FDA
strongly encourages sponsors to work closely with the Agency in
planning definitive Phase III clinical trials to help assure that
the trials are designed to have the greatest likelihood of
producing results sufficient to provide adequate data and permit
the Agency to make appropriate decisions about the safety and
efficacy of the product.
Once Phase III trials are completed, the sponsor submits the
results of all the relevant testing to FDA in the form of an
NDA. FDA’s medical officers, chemists,
statisticians, and pharmacologists review the application to
determine if the sponsor’s data in fact show that the drug is
both safe and effective. The drug’s manufacturing
process is evaluated to confirm that the product can be produced
consistently with high quality. It is common to allow
subjects in Phase II and III studies to continue on a therapy if it
seems to be providing benefit. This practice provides
long-term safety information at an early stage in this
process. At present, there are literally thousands of
clinical trials ongoing, involving hundreds of thousands of
subjects. There are over 15,000 active INDs for drugs,
therapeutic biologics, and biologics filed with the Agency.
Results of controlled clinical trials are the basis of
evidence-based medicine. These allow physicians and
patients to use therapies with a clear understanding of their
benefits and risks and, in some cases, a basis for strong public
health recommendations for treatments.
Clinical trials also have saved us from unwanted public health
consequences. For example, when azidothymidine (AZT)
was the only approved AIDS treatment, dideoxycytidine (ddC) was
made available under treatment‑IND for the several years
while clinical trials were underway. These trials were
to assess whether ddC was superior to AZT or if it was effective
for patients intolerant of AZT. Although the product,
ddC, could cause permanent, sometimes severe nerve damage, there
was great demand for early access to the product. It
was even manufactured by sources other than the company (probably
by amateur chemists) and this “bathtub” ddC was made
available through buyers clubs when the demand exceeded the
sponsor’s supply. FDA acted with the sponsor, the
buyers clubs, patient advocates, and investigators to make more of
the drug available and get the illicit, poorly manufactured product
off the market.
What did the ddC clinical trials show? In a
head‑to‑head comparison versus AZT as initial therapy,
an independent data safety monitoring board stopped the trial early
because the death rate in the ddC group was at least twice higher
than in the AZT group. For patients intolerant to AZT,
a clinical trial compared switching to ddC versus dideoxyinosine
(ddI). In this study the trend was that ddC had
superior survival to ddI. Later studies showed that ddC
in combination with AZT had superior survival to AZT
alone. Each of these studies involved hundreds of
patients and was essential to determining where ddC improved
survival and where it did not. Although some of the
early access uses were later found to be poor choices, physicians
considered it reasonable at the time to provide the drug while the
question was still being answered. The important point
is that patients are only well served by early access when the
controlled clinical trials proceed in parallel with early access.
A second example that illustrates the importance of conducting
clinical trials is the recently announced results of the
Women’s Health Initiative (WHI) study of estrogen and
progesterone in treating post-menopausal women conducted by the
National Institutes of Health. This large (more than
16,000 women), scientifically rigorous clinical trial was done to
confirm the widely held belief that estrogen/progesterone therapy
in post-menopausal women would significantly reduce the risk of
cardiovascular events, such as heart attacks and
strokes. There was also some hope that this
post-menopausal therapy might lessen the onset of Alzheimer’s
disease. These widely held beliefs were based on
scientific evidence that was not from clinical trials, such as
epidemiology. On the strengths of these beliefs,
post-menopausal hormone therapy was very widely used and growing in
popularity.
The WHI trial or post-menopausal estrogen/progesterone preceded but
was stopped early due to an excess of harm in women taking these
drugs compared to placebo. Surprisingly and
importantly, women given the active drugs were more likely to
suffer heart attacks and strokes and appeared to be more likely to
develop dementia. This study not only failed to prove
the widely held notion that this therapy was good for preventing
these types of occurrences, but actually confirmed harm.
These important results have led to significant changes in the use
of post-menopausal hormones.
FDA sometimes uncovers individuals who do not comply with statutory
and regulatory drug approval requirements. This puts
patients at risk of using unproven products and also denies to all
patients the knowledge of whether the untested therapies may
actually work. Distribution of unproven products and
subsequent widespread use combined with little accountability or
liability reduces the incentive for manufacturers and health care
practitioners to conduct studies of safety and
effectiveness. We constantly work to find ways to make
safe and effective products available to patients as quickly and
efficiently as possible, consistent with the protections
established in the law. It is essential to preserve the
system of controlled clinical trials that provides the information
necessary to make the final determination on the safety and
effectiveness of unapproved products. The two concepts,
the protection of public health and making available treatments for
individuals, can and must co-exist.
B. HUMAN SUBJECT PROTECTION
The FD&C Act and its implementing regulations are one part of a
complex system of safeguards designed to protect human
subjects. Each participant in a research effort
‑‑ the company that sponsors the research, the clinical
investigator who conducts the research, and the Institutional
Review Board (IRB) is obliged to protect the interests of the
people who are taking part in the experiments.
FDA’s responsibility is to see that the safeguards are
met. FDA monitors the activities of research sponsors,
researchers, IRBs and others involved in the trial. We
take very seriously our role to protect people enrolled in clinical
trials.
The sponsors of research ‑‑ usually, manufacturers or
academic bodies, but sometimes individual physicians ‑‑
must select well‑qualified clinical investigators, design
scientifically‑ sound protocols, make sure that the research
is properly conducted, and make certain that the clinical
investigators conduct the research in compliance with all pertinent
regulations, including requirements for obtaining informed consent
and review by an IRB. The primary regulatory
obligations of the clinical investigator are to: 1) conduct
or supervise the study; 2) conduct the study according to the
approved protocol or research plan; 3) ensure that the study is
reviewed and approved by an IRB that is constituted and functioning
according to FDA and other Federal requirements; 4) obtain informed
consent; 5) maintain adequate and accurate records of study
observations (including adverse reactions); 6) administer the drug
only to subjects under the investigator’s personal
supervision or under the supervision of a sub-investigator
responsible to the investigator; 7) report to the sponsor adverse
experiences that occur in the course of the investigation; and 8)
promptly report to the IRB all unanticipated problems involving
risks to humans or others.
The core of FDA’s informed consent regulations, Title 21,
Code of Federal Regulations (CFR) Part 50, is that the clinical
investigator must generally obtain the informed consent of a human
subject or his/her legally authorized representative before any
FDA‑regulated research can be conducted. The
researcher has to make sure that, whenever possible, the study
participants fully understand the potential risks and benefits of
the experiment before the experiment begins. The
information provided must be in a language understandable to the
subject, and must not require the subject to waive any legal
rights, or release those conducting the study from liability for
negligence. The clinical investigator must tell the
human subjects important information about the study and its
potential consequences so that the person can decide whether to be
in the experiment. The entire informed consent process
involves giving the subject all the information concerning the
study that he or she would reasonably want to know, ensuring that
the subject has comprehended this information, and obtaining the
subject’s written consent to participate.
An IRB is a group (consisting of experts and lay persons) formally
designated to review, approve the initiation of, and periodically
review the progress of, research involving human
subjects. The primary function of IRBs is to protect
the rights and welfare of the people who are in trials.
FDA’s regulations, 21 CFR Part 56, contain the general
standards for the composition, operation, and responsibility of an
IRB that reviews clinical investigations submitted to FDA under
sections 505(i), and 520(g) of the FD&C Act. IRBs
must scrutinize and approve each of the clinical trials that are
conducted on FDA‑regulated products in this country each
year. IRBs must develop and follow procedures for their
initial and continuing review of the trials. Among
other requirements, IRBs must make sure that the risks to subjects
are minimized and do not outweigh the anticipated study benefits,
that the selection of participants is equitable, that there are
adequate plans to monitor data gathered in the trial and provisions
to protect the privacy of subjects and the confidentiality of
data. The IRB has the authority to approve, modify, or
disapprove a clinical trial. The IRB must approve the
informed consent form that will be used. If the
researchers fail to adhere to IRB requirements, the IRB has the
authority and the responsibility to take appropriate steps, which
may include termination of the trial. The IRB is
required to conduct continuing review of ongoing research at
intervals appropriate to the degree of risk, but not less than once
per year. It also has the authority to observe or have a
third party observe the consent process and the research.
IRBs are currently not required to register with FDA nor inform FDA
when they begin reviewing studies. However, FDA
performs on‑site inspections of IRBs that review research
involving products that FDA regulates, including IRBs in academic
institutions and hospitals as well as those independent from where
the research will be conducted. The primary focus of
FDA’s IRB Program is the protection of the rights and welfare
of research subjects, rather than validating the data obtained from
research.
Marijuana
FDA has not approved marijuana for medical use in the United
States. Despite its status as an unapproved new drug,
there has been considerable interest in its use for the treatment
of a number of conditions, including glaucoma, AIDS wasting,
neuropathic pain, treatment of spasticity associated with multiple
sclerosis, and chemotherapy-induced nausea. Under the
Controlled Substances Act (CSA) Congress listed marijuana in
Schedule I. Schedule I substances have a very high
potential for abuse, no accepted medical use in the United States,
and lack accepted safety data for use under medical
supervision. Schedule I substances can still be the
subject of an IND; however, the conditions for its use are more
restrictive.
Pursuant to the FD&C Act, FDA is responsible for the approval
and marketing of drugs for medical use, including controlled
substances. DEA is the lead Federal agency responsible
for regulating controlled substances and enforcing the
CSA. The CSA separates controlled substances into five
schedules, depending upon their approved medical use and abuse
potential. Unlike Schedule I controlled substances,
Schedule II substances are approved for medical use, although they
also have a very high potential for abuse. Schedules
III, IV, and V include those controlled substances that have been
approved for medical use, but whose potential for abuse is
diminished.
FDA’s Office of Criminal Investigations (OCI) is responsible
for managing and conducting the Agency’s criminal
investigations. As a part of its duties, OCI has worked
closely with DEA on a number of criminal investigations involving
the illegal sale, use, and diversion of controlled substances
including controlled substances sold over the Internet.
OCI’s close working relationship with DEA and local law
enforcement agencies has led to many successful criminal cases
involving controlled substances. FDA cooperates with
DEA and other state and Federal agencies. OCI is often
requested by these entities to provide assistance. Both
OCI and DEA have worked together in the past to utilize the full
range of regulatory and administrative tools available to them to
pursue cases involving controlled substances. However,
the primary responsibility for enforcing the CSA resides with DEA,
and, FDA generally defers to DEA on criminal enforcement efforts
related to Schedule I controlled substances. The
criminal penalties related to Schedule I controlled substances are
far greater under the CSA than those available under the FD&C
Act for the distribution of an unapproved new drug.
The Department of Health and Human Services (HHS) and FDA support
the medical research community who intend to study marijuana in
scientifically valid investigations and well-controlled clinical
trials, in-line with the FDA’s drug approval
process. HHS and FDA recognize the need for
objective evaluations of the potential merits of cannabinoids for
medical uses. If the scientific community discovers a
positive benefit, HHS also recognizes the need to stimulate
development of alternative, safer dosage forms. In
February 1997, an NIH-sponsored workshop analyzed available
scientific information and concluded that “in order to
evaluate various hypotheses concerning the potential utility of
marijuana in various therapeutic areas, more and better studies
would be needed.”
In March 1999, the Institute of Medicine (IOM) issued a
detailed report that supports the absolute need for evidence-based
research into the effects of marijuana and cannabinoid components
of marijuana, for patients with specific disease
conditions. The IOM report also emphasized that smoked
marijuana is a crude drug delivery system that exposes patients to
a significant number of harmful substances and that “if there
is any future of marijuana as a medicine, it lies in its isolated
components, the cannabinoids and their synthetic
derivatives.” As such, the IOM recommended that
clinical trials should be conducted with the goal of developing
safe delivery systems.
In May 1999, HHS released “Guidance on Procedures for the
Provision of Marijuana for Medical Research,” a document
intended to provide the medical research community who intend to
study marijuana in scientifically valid investigations and
well-controlled clinical trials on HHS procedures for providing
research-grade marijuana to sponsors. The HHS
guidance is intended to facilitate the research needed to evaluate
pending public health questions regarding marijuana by making
research-grade marijuana available for well-designed studies on a
cost-reimbursable basis. The focus of this HHS program
is the support of quality research for the development of
clinically meaningful data regarding marijuana. An
appropriate scientific study of a drug requires, among other
things, that the drug used in the research must have a consistent
and predictable potency, must be free of contamination, and must be
available in sufficient amounts to support the needs of the
study. NIDA allocates resources to cultivate a grade of
marijuana that is suitable for research purposes. The
HHS Guidance outlines the procedures for obtaining research-grade
marijuana including: 1) the researcher must make an inquiry
to NIDA to determine the availability and costs of marijuana, and
NIDA has to determine that marijuana is available to support the
study; 2) researchers who propose to conduct investigations in
humans must proceed through the FDA process for filing an IND
application: and 3) all researchers must obtain from DEA
registration to conduct research using a Schedule I controlled
substance.
FDA regulates smoked marijuana, a botanical product, when it is
being investigated for use in the diagnosis, cure, mitigation,
treatment or prevention of disease in man or other animals, as a
drug, under the FD&C Act. Botanicals include herbal
products made from leaves, as well as products made from roots,
stems, seeds, pollen or any other part of a plant.
Botanical products pose some issues that are unique to this class
of product, including the problem of lot-to-lot
consistency. These unpurified products, which may be
either from a single plant source or from a combination of
different plant substances, often exert their reported effects
through mechanisms that are either unknown or
undefined. For these reasons, the exact chemical nature
of these products may not be known. In addition, issues
of strength, potency, shelf life, dosing and toxicity monitoring
need to be addressed. If a product varies greatly, as
can occur with botanicals, it is critical to obtain lot-to-lot
product consistency. Without this it is difficult to
determine if the product is causing the change in a patient's
condition, or the change is related to some other
factor. Because of the problems associated with
obtaining lot-to-lot consistency with botanical marijuana, it is
not surprising that IOM recommended that clinical trials should be
conducted with the goal of developing safe delivery systems.
HHS performed a scientific and medical evaluation of marijuana in
2001 and concluded with a recommendation to DEA that marijuana
should remain in Schedule I pursuant to section 201(b) of the
CSA. HHS’s scientific and medical evaluation and
scheduling recommendation can be found at Volume 66, Federal
Register page 20038 (April 18, 2001). After
receiving an HHS evaluation and recommendation, DEA is responsible
for scheduling substances and as noted previously, has primary
responsibility for the regulation and distribution of Schedule I
substances.
FDA Approval of Safer Dosage Forms of
Cannabinoids
FDA has approved two drugs, Marinol and Cesamet, for therapeutic
uses in the U.S., which contain active ingredients that are present
in botanical marijuana. On May 31, 1985, FDA approved
Marinol Capsules, manufactured by Unimed, for nausea and vomiting
associated with cancer chemotherapy inpatients that had failed to
respond adequately to conventional antiemetic
treatments. Marinol Capsules include the active
ingredient dronabinol, a synthetic delta-9- tetrahydrocannabinol or
THC, which is considered the psychoactive component of
marijuana. On December 22, 1992, FDA approved Marinol
Capsules for the treatment of anorexia associated with weight loss
in patients with AIDS. Although FDA approved Cesamet
Capsules for the treatment of nausea and vomiting associated with
chemotherapy on December 26, 1985, this product was never marketed
in the U.S. Cesamet Capsules contain nabilone as the
active ingredient, a synthetic cannabinoid. Nabilone is
not naturally occurring and not derived from marijuana, as is
THC.
These products have been through FDA’s rigorous approval
process and have been determined to be safe and effective for their
respective indications. It is only through the FDA drug
approval process that solid clinical data can be obtained and a
scientifically based assessment of the risks and benefits of an
investigational drug is made. Upon FDA approval for
marketing, consumers who need the medication can have confidence
that the approved medication will be safe and
effective.
CONCLUSION
Having access to a drug or medical treatment, without knowing how
to use it or even if it is effective, does not benefit
anyone. Simply having access, without having safety,
efficacy, and adequate use information does not help
patients. FDA has and will continue to use its IND and
other expanded access programs to provide patients freedom to
choose investigational medical treatments while reasonably
ensuring safety, informed choice, and systematic data collection
that allows us to review drug applications.
FDA will continue to be receptive to sound, scientifically based
research into the medicinal uses of botanical marijuana and other
cannabinoids. FDA will continue to facilitate the work
of manufacturers interested in bringing to the market safe and
effective products.
I would like to thank the Subcommittee again for the opportunity to
testify today on this important issue. I would be
happy, at this time, to answer any questions Members of the
Subcommittee may have.
Last Revised: April 1, 2004
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