Marijuana and Medicine Assessing the Science Base (1999) / Chapter Skim
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5 Development of Cannabinoid Drugs
5 Development of Cannabinoid Drugs
Pages 193-222
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From page 193... ...
The future of medical marijuana lies in classical pharmacological drug development, and indeed there has been a resurgence of scientific, as well as public, interest in the therapeutic applications of cannabinoids. After an initial burst of scientific activity in the 1970s, today's renewed interest has been fueled by major scientific discoveries discussed in previous chapters: the identification and cloning of endogenous cannabinoid receptors, the discovery of endogenous substances that bind to these receptors, and the emergence of synthetic cannabinoids that also bind to cannabinoid receptors.
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From page 194... ...
Food and Drug Administration Under the Federal Food, Drug, and Cosmetic (FD&C) Act, the FDA approves new drugs for entry into the marketplace after their safety and efficacy are established through controlled clinical trials conducted by the drugs' sponsors.23 FDA approval of a drug is the culmination of a long, research intensive process of drug development, which often takes well over a decade.~9 44 Drug development is performed largely by pharmaceutical companies, but some targeted drug development programs are sponsored by the National Institutes of Health (NIH)
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For every drug that ultimately reaches clinical testing through an IND, thousands of drugs are synthesized and tested in the laboratory. And only about one in five drugs initially tested in humans successfully secures FDA approval for marketing through a new drug application (NDA)
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In general, collecting new data for FDA approval of an efficacy supplement is not as intensive a process as that for an NDA; it generally requires the firm to conduct two additional Phase III studies, although under some circumstances only one additional study of the drug's efficacy is needed.24 The preclinical studies, for example, ordinarily need not be replicated. The average cost to the manufacturer for obtaining approval for the new indication is typically about $10-$40 million.33 The review time to obtain FDA approval for the new indication can be considerable; a recent study of supplemental indications approved by the FDA in 1989-1994 found the approval time to exceed that for the original NDA,~8 a reflection, in part, of the lower priority that the FDA accords to the review of efficacy supplements as opposed to new drugs.23 The manufacturer also must apply to the FDA to receive marketing approval for a new formulation of a previously approved drug.
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From page 198... ...
to allow patients with serious and life-threatening diseases to obtain experimental medications, such as marijuana, before their general marketing.) Treatment INDs may be issued during Phase III studies to patients who are not enrolled in clinical trials, provided among other requirements that no comparable alternative drug is available.22 32 33 Thus, the treatment IND program can provide a mechanism for some patients to obtain a promising new cannabinoid before its widespread commercial availability if it reached the late stages of clinical testing for a serious or life-threatening disease.
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From page 199... ...
Abuse liability testing is not a single test; it is a compilation of several in vitro human and animal studies, of which some of the best known are drug self-administration and drug discrimination studies. 34 The secretary's recommendation for scheduling is formally guided by eight legal criteria, including the drug's actual or relative potential for abuse, scientific evidence of its pharmacological effect, risk to public health, and its psychic or physiological dependence liability (21 U.S.C.
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From page 200... ...
Prompted by a 1995 petition from Ton Gettman, a former president of the National Organization for the Reform of Marijuana Laws (NORML) , to remove marijuana and THC from Schedule I, DEA gathered information which was then submitted to DHHS for a medical and scientific recommendation and scheduling recommendation, as required by the CSA.
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From page 201... ...
and the process outlined above. The possibility of scheduling is a major determinant of whether a manufacturer proceeds with drug development.33 In general, pharmaceutical firms perceive scheduling to be a deterrent because it limits their ability to achieve market share for the following reasons: restricted access,
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From page 202... ...
It was approved by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy. In 1992, the FDA approved marketing of dronabinol for the treatment of anorexia associated with weight loss in patients with AIDS.45 The preclinical and clinical research on THC that culminated in the FDA's 1985 approval was supported primarily by the National Cancer Institute (NCI)
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: anxiety, confusion, depersonalization, dizziness, euphoria, dysphoria, somnolence, and thinking abnormality.8 9 45 59 In two recent clinical trials, CNS adverse events occurred in about one-third of patients, but only a small percentage discontinued the drug because of adverse effects.89 Lowering the dose of dronabinol can minimize side effects, especially dysphoria (disquiet or malaise) .47 Abuse Potential and Scheduling On commercial introduction in 1985, Marinol was placed in Schedule II.
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From page 204... ...
The latter group is thought to consist of Alzheimer's patients drawn to the drug by a recently published clinical study indicating Marinol's promise for the treatment of their anorexia and disturbed behavior.58 As noted earlier, Unimed cannot promote Marinol for this unlabeled indication, but physicians are free to prescribe it for such an indication. Unimed is conducting additional research in pursuit of FDA approval of a new indication for Marinol in the treatment of Alzheimer disease.
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From page 205... ...
Marinol appears to have a dual effect, not only stimulating appetite but also combating the nausea and vomiting associated with combination therapy. Unimed is supporting a Phase II study to examine this combined effect and, with promising results, plans to seek FDA approval for this new indication.
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From page 206... ...
Unimed and Roxane are developing, or considering development of, five new indications for Marinol: disturbed behavior in Alzheimer's disease, nausea and vomiting in HIV patients who are receiving combination therapy, spasticity in multiple sclerosis, intractable pain, and anorexia in cancer and renal disease. Costs of Marinol and Marijuana During the IOM public workshops held during the course of this study, many people commented that an important advantage of using marijuana for medical purposes is that it is much less expensive than Marinol.
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From page 207... ...
But if the full cost of Marinol is borne out of pocket by the patient, the cost comparison is not so unambiguous. In this case the daily cost in relation to marijuana varies according to the number of cigarettes smoked: If the patient smokes two or more marijuana cigarettes per day, Marinol might be less expensive than marijuana; if the patient smokes only one marijuana cigarette per day, Marinol might be more expensive than marijuana, according to an analysis submitted to the DEA by Unimed.
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From page 208... ...
Economic Factors in Development The outcomes of preclinical and clinical research determine whether a drug is sufficiently safe and effective to warrant FDA approval for marketing. But the decisions to launch preclinical research and to proceed to clinical trials if early results are promising are dictated largely by economic factors.
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From page 209... ...
None Multiple sclerosis HIV-related appetite stimulation IND Migraine pending aClinical trials are to proceed In the next few years under a license from the British Home Office.~° SOURCES: Glain, 199827; Atlantic Pharmaceuticals, 19977; Striem et al., 199755; Nainggolan, 199737; Zurier et al., 19986~; D Abrams and E
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From page 210... ...
Without the benefit of sales revenues, small companies are able to fund their research through financing from venture capital, stock offerings, and relationships with established pharmaceutical companies.43 Second, with the exception of THC, no constituents of the marijuana plant appear to be undergoing development by pharmaceutical companies. A number of plant compounds have been tested in experimental models and humans.
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From page 211... ...
Excess release of glutamate, which acts by binding to the NMDA receptor, is associated with trauma and disease.54 As an NMDA antagonist, HU-211 blocks the damaging action of glutamate and other endogenous neurotoxic agents.5255 After having been studied in the United Kingdom in Phase I clinical trials, HU-211 progressed to Phase II clinical trials in Israel for treatment of severe closed-head trauma (Knoller et al., 1998~.35 Market Prospects It is difficult to gauge the market prospects for new cannabinoids. There certainly appears to be scientific interest, particularly for the discovery of new cannabinoids, but whether this interest can be sustained commercially through the arduous course of drug development is an open question.
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From page 212... ...
prescription and over-the-counter analgesic market in 1997 was $4.4 billion.49 Given the long-standing need for less addictive, safer, easier to use, and more effective drugs for acute and chronic pain, it would not be surprising to see cannabinoids developed to treat some segments of the current analgesic market, if their safety and effectiveness were clearly established in clinical trials. In addition to cannabinoid receptor agonists, two classes of cannabinoid-related drugs might prove therapeutically useful: cannabinoid antagonists and inverse agonists, compounds that bind to receptors but produce effects opposite those of agonists.
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From page 213... ...
A researcher can obtain marijuana free of charge from NIDA through an NIH-approved research grant to investigate marijuana, or through a separate protocol review.39 Research grant approvals are handled through the conventional NIH peer review Under the CSA, its only legal use is in research under strictly defined conditions. iThis is also the program through which several patients receive marijuana under a compassionate use program monitored by the FDA.
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From page 214... ...
The plants contain a consistently "clean" phytochemical profile and a higher * It might eventually be possible to import HortaPharm's marijuana from England, where HortaPharm is growing its marijuana strains for research use in clinical trials for multiple sclerosis (Boseley, 1998~.~° England, as the country of origin, would have to provide appropriate authorization for export of the strains to the United States.
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From page 215... ...
The difficulties of conducting research on marijuana were noted in the 1997 NIH reporter that recommended that NIH facilitate clinical research by developing a centralized mechanism to promote design, approval, and conduct of clinical trials. Regulatory Hurdles to Market For marijuana to be marketed legally in the United States, a sponsor with sufficient resources would be obliged to satisfy the regulatory requirements of both the FD&C act and the CSA.
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From page 216... ...
That is because a new drug approval satisfies the "accepted medical use" requirement under the CSA for manufacture and distribution in commerce.~3 But a new drug approval is not the only means to reschedule marijuana under the CSA.~4 For years advocates for rescheduling have argued that marijuana does enjoy "accepted medical use," even in the absence of a new drug approval. Although advocates have been unsuccessful in rescheduling efforts, their actions Promoted - rip r*
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From page 217... ...
The oftencited cost of new drug development, about $200-$300 million, might not apply, but there are probably additional costs needed to satisfy the FDA's requirements for a botanical product. As noted above, no botanical products have ever been approved as new drugs by the FDA under today's stringent standards for safety and efficacy.
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From page 218... ...
The cost of bringing dronabinol to market, for example, was reduced dramatically as a result of clinical trials supported with government funding. Nevertheless, it is impossible to estimate the cost of developing marijuana as a new drug.
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It is too early to forecast the prospects for cannabinoids, other than to note that their development at this point is considered to be especially risky, to judge by the paucity of products in development and the small size of the pharmaceutical firms sponsoring them. The market outlook in the United States is distinctly unfavorable for the marijuana plant and for cannabinoids found in the plant.
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From page 220... ...
1996. An analysis of regulatory review times of supplemental indications for already-approved drugs: 1989-1994.
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1995. Pharmacology of cannabinoid receptors.
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From page 222... ...
1996. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures.
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