Cannabidiol: Barriers to Research and Potential Medical Benefits-June 24, 2015

http://www.fda.gov/newsevents/testimony/ucm453989.htm
Statement of Douglas C. Throckmorton, M.D.
Deputy Director for Regulatory Programs
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
Before the
Caucus on International Narcotics Control
United States Senate
June 24, 2015
INTRODUCTION
Chairman
Grassley, Co-Chairman Feinstein, and Members of the Caucus, I am Dr.
Douglas Throckmorton, Deputy Director for Regulatory Programs at the
Center for Drug Evaluation and Research (CDER), Food and Drug
Administration (FDA or the Agency), which is part of the Department of
Health and Human Services (HHS). Thank you for the opportunity to be
here today to discuss the important role that FDA plays in the
regulation of researching marijuana, including its constituent
compounds, such as cannabidiol, for potential medical uses. This is an
important part of FDA's mission to protect and promote the public health
by helping to ensure the safety, efficacy, and quality of medical
products, including drugs. In addition, I will briefly discuss the
regulatory oversight function of the Agency with respect to other
products that may contain cannabidiol.
FDA plays a critical role
in regulating the development and potential use of cannabidiol and other
constituents of marijuana as prescription drugs in the United States.
FDA also, on its own and in partnership with other Federal agencies,
supports the efficient and scientific assessment of cannabidiol and
other constituents of marijuana in drug development. These activities
are critical, if safe and effective drugs are to be developed from
marijuana, including from its constituent components such as
cannabidiol. FDA continues to believe that the drug approval process
represents the best way to help ensure that safe and effective new
medicines, including any such medicines derived from cannabidiol or
other constituents of marijuana, are appropriately reviewed for safety
and effectiveness, consistent with FDA's statutory requirements. It is
important and appropriate to use the same scientific standards in the
development and assessment of potential therapeutic uses of cannabidiol
as with any unapproved drug that the Agency reviews.
FDA's Role in Reviewing Cannabidiol as a Potential Prescription Drug
The
role of FDA in the regulation of cannabidiol as a potential
prescription drug relates to our larger responsibility for the
regulation of all drugs intended for human use. The Agency reviews drug
product applications to determine whether drugs are safe and effective
for their intended uses. Any product intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease is classified by
FDA as a drug. This applies regardless of the product's form, the
product's active or inactive ingredients, or the way in which the
manufacturer chooses to market and label the product.
In approving a drug for marketing, FDA reviews important information about the drug, including:
The indication for which the drug has been studied, including specific uses in children or the elderly, if any
Which patients may benefit from its use, including information about whether the drug has been tested in children
What adverse effects have been reported for individuals taking the drug
How the drug should be taken (e.g., orally, intravenously)
The dose of the drug recommended in the intended patient populations
How the drug is made (e.g., as a pill, liquid) and what is in the drug, including both active and inactive ingredients
Getting
a drug approved requires the collection and submission to FDA of
clinical and non-clinical data about the proposed use of the drug for
review as part of a New Drug Application (NDA) or Biologics License
Application (BLA). Usually, the first step that a sponsor takes to
obtain approval for a new drug is to test the drug in animals to
determine drug toxicity. The sponsor uses those animal data, along with
additional information about the drug's composition and manufacturing,
to develop a plan for testing the drug in humans. The sponsor submits
the animal data to FDA in the form of an Investigational New Drug (IND)
application that includes protocols describing proposed human studies,
the qualifications of the investigators who will conduct the clinical
studies, and assurances of informed consent and protection of the
rights, safety, and welfare of the human participants. FDA reviews the
IND to confirm that the proposed studies, generally referred to as
clinical trials, do not place human participants at unreasonable risk of
harm. FDA also verifies that there are adequate assurances of informed
consent and human subject protection. At that point, drug testing in
humans can begin.1
Typically, the initial clinical
trials (Phase 1) assess how to safely administer and dose the drug when
used in small numbers of healthy volunteers. If Phase 1 trials are
successful, Phase 2 studies explore the effectiveness of the drug for a
particular indication, over a range of doses, and determine short-term
side effects. If Phase 2 studies are successful, pivotal Phase 3 studies
are designed based on the information learned in the earlier studies to
further study safety and assess the efficacy of the investigational
drug for a particular indication in a defined patient population. Phase 3
studies also can provide additional safety data, including long-term
experience effects of the drug in certain patient groups, and efficacy
of different doses of the drug. These later trials sometimes enroll
several hundreds to thousands of participants-depending on the
indication studied-to provide essential information about the
investigational drug's safety and efficacy. Following the completion of
these studies, the data might be submitted to FDA in an NDA or BLA for
the Agency to review. Throughout the development process, FDA strongly
encourages sponsors to work closely with the Agency to support efficient
drug development.
In addition to establishing the safety and
efficacy of the investigational drug, manufacturers also must
demonstrate that they are able to consistently manufacture a
high-quality drug product. This is an essential part of drug development
and presents special challenges when the drug is derived from a
botanical source, such as marijuana. Botanicals include herbal products
made from leaves, roots, stems, seeds, pollen, or any other part of a
plant. Botanical products pose challenges that are unique to this class
of product, including lot-to-lot consistency. These unpurified products,
which may be either from a single plant source or from a combination of
different plant substances, can have effects through unknown or
undefined mechanisms, making it difficult to determine if the product is
causing the change in a patient's condition, or the change is related
to some other factor. For these reasons, a focus of drug development for
botanicals is identification of a source that will provide the
necessary assurance of consistent quality, lot to lot. To support
development of drugs derived from botanical sources, FDA has released
guidance providing information on the development and approval of such
drugs that addresses these issues, as well as providing more general
recommendations on studying botanicals.2
Another
important consideration is the need to identify a method to consistently
provide a given dose of a drug. When the Institute of Medicine (IOM)
reviewed the potential clinical use of marijuana, it identified the
problems associated with obtaining consistent dosing using smoked
products and recommended that clinical trials involving marijuana should
be conducted with the goal of developing safe, alternative delivery
systems:3
If there is any future for marijuana
as a medicine, it lies in its isolated components, the cannabinoids and
their synthetic derivatives. Isolated cannabinoids will provide more
reliable effects than crude plant mixtures. Therefore, the purpose of
clinical trials of smoked marijuana would not be to develop marijuana as
a licensed drug but rather to serve as a first step toward the
development of nonsmoked rapid-onset cannabinoid delivery systems.Another
consideration related to the regulation of cannabidiol as a potential
medicine is its status as a constituent of a controlled substance, in
this case marijuana. Under section 202 of the Controlled Substances Act
(CSA), marijuana is currently listed as a Schedule I controlled
substance.4 Schedule I includes those substances that have a
high potential for abuse, have no currently accepted medical use in
treatment in the United States, and lack accepted safety for use under
medical supervision.5 Nevertheless, Schedule I substances,
including drugs such as marijuana, can be and are the subject of
clinical trials under the Federal Food, Drug and Cosmetic Act (FD&C
Act), provided, among other factors, that FDA authorizes an IND
application submitted by a sponsor. In addition, the CSA requires
researchers to register with the Drug Enforcement Administration (DEA)
before handling Schedule I controlled substances, including conducting
clinical trials.6
Through the drug development
processes described above, FDA has approved two drugs for human use
which contain synthetic cannabinoids: Marinol (Schedule III) and Cesamet
(Schedule II). FDA approved Marinol capsules in 1985 for the treatment
of nausea and vomiting associated with cancer chemotherapy in patients
who had failed to respond adequately to existing antiemetic treatments.
Marinol capsules include the active ingredient dronabinol, a synthetic
delta-9-tetrahydrocannabinol, or THC, which is a psychoactive component
of marijuana. Marinol capsules were also approved in 1992 for the
treatment of anorexia associated with weight loss in patients with AIDS.
FDA approved Cesamet capsules for the treatment of nausea and vomiting
associated with chemotherapy in 1985. Cesamet capsules contain the
synthetic cannabinoid nabilone as the active ingredient.
These
products have undergone FDA's rigorous approval process and have been
determined to be safe and effective for their respective indications and
dosing, and demonstrate the views of the IOM that the future of
marijuana as a potential medicine lies in classical pharmacological drug
development.7 As a result, patients who need medication can
have confidence that any approved drug will be safe and effective for
its indicated uses.
FDA's Role in Supporting Development of New Therapies
FDA
also plays a role in supporting the development of new drugs. This role
broadly affects all of drug development. Because of FDA's role as both a
regulator and as a public health agency, FDA has a unique perspective
on drug development, a perspective we use to identify and facilitate the
development of new, innovative products to meet the needs of patients
and the American public. We recognize that many scientific discoveries
still need to be translated into treatments, even as patients are
urgently waiting for new lifesaving therapies, and FDA is committed to
helping bridge this gap.
As a part of this activity to streamline
drug development, FDA has been actively scrutinizing, strengthening, and
streamlining our regulatory processes at various steps along the path
from drug discovery to delivery-including the clinical development
phase, the longest and most expensive period of drug development. We
have developed and successfully used a number of flexible and innovative
approaches to expedite the development and review of drugs-to the
benefit of millions of American patients. For instance, in 2014 almost
two-thirds (26 of 41, 63 percent) of new molecular entities approved by
CDER were approved in the United States before any other country.8
This is comparable to the previous year, 2013, in which almost three-
quarters of CDER-approved new molecular entities (74 percent of 27) were
approved first in the United States.9
FDA has several
programs that directly facilitate and expedite development and review of
new drugs that address unmet medical needs in the treatment of serious
or life-threatening conditions: Fast Track10, Accelerated Approval11, Priority Review12, and Breakthrough Designation13.
A look at recent drug approvals in CDER suggests that these programs
have played an important role in bringing innovative drugs to market.
Nearly half of the 27 novel drugs approved by CDER in 2013 took
advantage of at least one of these expedited drug development and review
approaches. Utilization of these accelerated programs was even more
pronounced in 2014, with two-thirds (27 of 41) of novel drugs approved
by CDER using at least one of these programs.
Development programs
for drugs derived from marijuana and its constituents, including
cannabidiol, may be eligible for these expedited review and development
programs under appropriate circumstances and, in fact, some of these
programs are currently being used in the development of such drugs. For
example, in April 2014, GW Pharmaceuticals announced14 that
FDA granted Fast-track designation to its investigational drug product
Sativex®, composed primarily of two cannabinoids: cannabidiol and THC,
administered as a metered-dose oromucosal spray, for the treatment of
pain in patients with advanced cancer, who experience inadequate
analgesia during optimized chronic opioid therapy. GW Pharmaceuticals
has announced15 that Sativex is currently in Phase 3 clinical
trials for this indication. In addition, on June 6, 2014, GW
Pharmaceuticals announced16 that FDA granted Fast-track
designation to its investigational cannabidiol product, Epidiolex®, in
the treatment of Dravet syndrome, a rare and catastrophic
treatment-resistant form of childhood epilepsy. In February 2015, Insys
Therapeutics announced17 that FDA granted Fast-track designation to the cannabidiol formulation they are studying for the same condition.
As
it does in other new drug development processes, FDA is working with
researchers who are conducting studies on the development of new drugs
derived from marijuana, including from its constituents such as
cannabidiol, meeting with them regularly as they plan and carry out the
trials as a part of their INDs. Although marijuana is a Schedule I
substance, it can be, and is being, used in clinical trials conducted
under INDs. A number of government-funded research projects involving
marijuana or its component compounds, including cannabidiol, have been
completed or are currently in progress, many of which are listed on the www.ClinicalTrials.gov website.
FDA
also understands the interest in making investigational products
available to patients while being studied for approval, and there are
expanded access provisions in both FDA's statute and its regulations to
make this possible, where appropriate and where the manufacturer chooses
to participate. FDA's expanded access mechanisms are designed to
facilitate the availability of investigational products to patients with
serious diseases or conditions when there is no comparable or
satisfactory alternative therapy available, either because the patients
have exhausted treatment with, or are intolerant of, approved therapies,
or because the patients are not eligible for an ongoing clinical trial.18
FDA cannot mandate or require a drug company to provide an unapproved
drug to patients, and the availability of an investigational product
through expanded access depends on the agreement of the drug company to
make the drug available for the expanded access use, either through the
company's own expanded access program, or to a treating physician for
administration to a patient or patients.
As noted, Epidiolex, containing cannabidiol, is being developed for the treatment of certain seizure disorders in children.19
GW Pharmaceuticals reports that 20 Epidiolex intermediate-size expanded
access INDs have been authorized to treat approximately 420 children
and that approximately 95 percent of Epidiolex expanded access INDs are
for patients between 1 and 17 years of age.20
FDA also
has worked with investigators to provide clear information on how to
conduct research in this area. To help address common basic questions
about research with marijuana, FDA, the National Institute on Drug Abuse
(NIDA), and DEA have posted materials online to help researchers.21
We also know that a number of states are interested in allowing access
to cannabidiol-containing oils to treat childhood epilepsy. FDA
encourages and supports medical research into the safety and
effectiveness of products containing cannabidiol and other marijuana
constituents through adequate and well-controlled clinical trials
conducted under an IND and consistent with DEA requirements for research
on Schedule I substances. FDA has talked with representatives from
several states considering support for medical research of marijuana and
its derivatives, including cannabidiol, to provide scientific advice
and to help ensure that their research is rigorous and appropriate.
FDA's Role in Investigations and Enforcement Actions With Regard to Products Containing Cannabidiol
FDA
recognizes that DEA is the lead Federal Government agency for
enforcement matters related to the diversion of controlled substances,
including marijuana. Historically, FDA has deferred to DEA regarding the
illegal sale and use of illicit drugs of abuse, such as Schedule 1
drugs, which have no currently accepted medical use.
However, in
addition to regulating medical products, FDA maintains regulatory
oversight over foods, including dietary supplements. For any product
found to be in violation of the FD&C Act, FDA considers many factors
in deciding whether or not to initiate an enforcement action. Those
factors include, among others, Agency resources and the threat to the
public health. FDA also may consult with its Federal and state partners
in making decisions about whether to initiate a Federal enforcement
action.
In late February 2015, FDA issued several Warning Letters
to firms that were marketing unapproved drugs for the diagnosis, cure,
mitigation, treatment, or prevention of diseases. Some of these firms
claimed that their products, which the firms made available nationwide
via the Internet, contained cannabidiol which the firms claimed could
help to address cancer, diabetes, multiple sclerosis, and other
ailments. FDA tested those products and, in some, did not detect any
cannabidiol.22 It is important to note that these products
are not approved by FDA for the diagnosis, cure, mitigation, treatment,
or prevention of any disease. Often they do not even contain the
ingredients found on the label. Although FDA advised these firms that
their products were in violation of the FD&C Act, and FDA is
committed to keeping violative products off the market, consumers should
be extremely cautious in purchasing and using such products. Marketing
of products that are not what they claim to be, such as those purporting
to contain cannabidiol but don't, does more than simply defraud
consumers who anticipate that the products purchased will contain the
ingredients expected. These products and marketing can create false hope
in a population especially vulnerable: those seeking relief from
serious medical conditions for themselves or their loved ones, including
their children. Moreover, it might divert patients from products with
demonstrated safety and effectiveness.
The recent examples of the
products being marketed to individuals seeking relief from serious
medical conditions-products that FDA has not evaluated for safety and
efficacy and that often do not even contain the ingredients they claim
to contain-serves as another reminder of the important role FDA and the
drug approval process play in this area.
CONCLUSION
FDA
appreciates this opportunity to discuss the Agency's work in the
regulation of cannabidiol for potential medical uses in the United
States, which is a part of FDA's core mission to protect and promote the
public health by helping to ensure the safety, efficacy, and quality of
medical products, including drugs. There is considerable public
interest in developing new therapies from marijuana and its
constituents, especially cannabidiol. FDA will continue to play its role
in ensuring that any such new therapies are safe, effective, and
manufactured to a high quality, applying the drug development paradigm
that continues to provide new medicines that meet these standards for
patients. This paradigm, grounded in rigorous scientific research, is
essential to determining any appropriate uses of marijuana and its
constituents in the treatment of human disease. As a part of this
important work, we are committed to collaborating with Federal and state
agencies, researchers, and manufacturers also working on issues related
to the use of cannabidiol and other constituents of marijuana in the
United States. The drug approval process remains the best way to
identify new treatments that are safe and effective for patients and to
protect patients from products that are not what they purport to be.
Thank you for your interest in this important topic, and I am happy to answer any questions.
1 In
the case of Schedule I controlled substances, such as marijuana from
which cannabidiol is derived, the Controlled Substances Act requires
researchers to register with the Drug Enforcement Administration (DEA)
before handling the controlled substances, including proceeding with
clinical trials using controlled substances. Registration requirements
applicable to research involving Schedule I controlled substances differ
from those for drugs controlled in Schedules II-V (21 U.S.C. 823(f)).
2 FDA guidance document on the development of botanical drug products is posted at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf.
3 IOM Report, p. 11 (1999), Marijuana and Medicine: Assessing the Science Base.
4 21 U.S.C. 812
5 21 U.S.C. 812(b)(l)(A)-(C)
6 21
U.S.C. 823(f) (stating that registration applications by practitioners
wishing to conduct Schedule I research shall be referred to the
Secretary of HHS, who shall determine the qualifications and competency
of each practitioner, as well as the merits of the research protocol);
see also 21 CFR 1301.18 (outlining specific application procedures and
information to be provided by Schedule I researcher applicants).
7 Institute of Medicine, Marijuana and Medicine: Assessing the Science Base (IOM Report), p.193 (2003).
8 CDER Report, “Novel new Drugs, 2014 Summary,” (1/14/15) is posted at http://www.fda.gov/downloads/Drugs/DevelopmentAppr...
9 “President's
Fiscal Year 2015 Budget Request for the FDA” Testimony of Commissioner
Margaret Hamburg before the Senate Committee on Appropriations (April 3,
2014) at http://www.fda.gov/newsevents/testimony/ucm392262.htm.
10 Fast-track
designation: Provides opportunities for frequent interactions with FDA
to discuss the drug's development plan and ensure collection of
appropriate data needed to support drug approval, including such things
as the design of the proposed clinical trials and use of biomarkers.
11 Accelerated
Approval: Basing approval on an agreed-upon surrogate marker that is a
measure, such as a blood test or urine marker, that is believed to be
indicative of a disease state and treatment effect but not demonstrative
of a direct health gain to the patient, or on an intermediate clinical
endpoint likely to predict clinical benefit. Since its inception in
1992, 89 original new drug or biologic applications have been approved
in CDER under the Accelerated Approval pathway. It has long been
successful in driving innovation in cancer and HIV therapies, but we are
encouraging its broader application in other areas, helped by the 2012
Food and Drug Administration Safety and Innovation Act (FDASIA), which
clarified that FDA has the authority to consider epidemiologic,
pharmacologic, or other evidence developed using biomarkers or other
scientific methods or tools in determining whether an endpoint can
support accelerated approval.
12 Priority Review: Acting on drug applications within six months instead of 10 months for standard review
13 Breakthrough
Therapy designation: Providing all of the benefits of Fast-track
designation plus intensive guidance on an efficient drug development
program, beginning as early as Phase 1, and the commitment from FDA's
review staff, including senior managers, to work closely together
throughout the drug development and review process. FDA's new
Breakthrough Therapy Designation was created as part of FDASIA. As of
May 29, 2015, CDER received 258 requests for designation, and granted
78. As of May 29, 2015, 24 drug development programs designated
breakthrough have been approved by CDER. Of these 24, 14 were for
original applications and 10 were for supplements (to expand or add a
new indication to an already approved drug).
14 http://www.gwpharm.com/GW Pharmaceuticals Anno...
15 http://www.gwpharm.com/Third phase III Sativ...
16 http://www.gwpharm.com/GW Pharmaceuticals Anno...
17 http://www.insysrx.com/investors/recent-news/ (Link at February 26, 2015)
18 http://www.fda.gov/ForPatients/Other/default.htm
19 Epidiolex
received orphan product designation for treatment of Dravet syndrome.
http://www.accessdata.fda.gov/scripts/opdlisting/o...
and more recently for the treatment of Lennox-Gastaut syndrome: http://www.accessdata.fda.gov/scripts/opdlisting/o...
20 http://www.gwpharm.com/Epidiolex.aspx
21 http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/ucm362986.htm;
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf;
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070491.pdf;
http://www.drugabuse.gov/drugs-abuse/marijuana;
http://www.deadiversion.usdoj.gov/drugreg/faq.htm#...
22 For information on these warning letters and the product testing, please see http://www.fda.gov/NewsEvents/PublicHealthFocus/uc...