FDA Testimony: Potential Merits of Cannabinoids for Medical Uses April 1, 2004

http://www.fda.gov/newsevents/testimony/ucm114741.htm


Statement of:
Robert J. Meyer, M.D.

Director

Office of Drug Evaluation II

Center for Drug Evaluation and Research

Food and Drug Administration

U.S. Department of Health and Human Services before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources
House Committee on Government Reform
http://www.fda.gov/newsevents/testimony/ucm114741....


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.


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.


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.