What happen to the dog studies?

[Guest guest]

--- Lana Transue <lanadearest@...> wrote:

> From: " Lana Transue " <lanadearest@...>

> saxony01@...

> Subject: What happen to the dog studies?

> Date: Mon, 28 Nov 2005 00:27:25 -0800

>

> After trying to explain to a friend today why

> marijauna is illeagal, I

> decided to see what the FDA has to say about it. I

> found it very interesting

> that the first step in an approval process is to do

> a study on dogs. Now I

> am not saying that they should use dogs for the

> implant research but it is

> suppose to be the FIRST STEP of the approval

> proceedure. What happen to the

> dog studies on the implants? I know how bad the

> original dog studies were,

> but what happen to the studies being done on dogs

> before th current approval

> applications were submitted? Lana

>

> 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.

>

> What about the enconclusive tests that have been

> done on secondary exposure?

>

>

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>

> Testimony by

> 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

> Committee on Government Reform

> House of Representatives

>

> April 1, 2004

>

> INTRODUCTION

>

> Good afternoon, Mr. Chairman and Members of the

> Subcommittee. I am Dr.

> 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( 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.

>

>

>

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