The FDA Process and Modern Medicine

1. The FDA Process and Modern Medicine Bertha K Madras, PhD Professor of Psychobiology Department of Psychiatry Harvard Medical School February 18, 2013

2. The Food and Drug Administration (FDA) • Plant products as medicines • Food and Drug Administration: approval process • Marijuana History • The FDA and Marijuana • Without FDA Process, What are Conceivable Consequences?

3. Plant Products As Medicines

4. Plant Products as Medicines Composition unknown, unregulated Treatment of symptoms, not illnesses Poor understanding of pathology Poor understanding of mechanisms Quantities inconsistent, unregulated

5. Modern MedicationsActive chemical isolated from plants Digitalis Aspirin • Highly purified and defined • Treat specific illness • Mechanism of action known • Controlled, consistent, regulated doses Atropine Quinine

6. Food and Drug Administration, approval process Scientific, regulatory, and public health agency • In 1862: a single chemist in the Department of Agriculture: Now: > 9,000 (25¢ of every $ spent by consumers). • Jurisdiction: drugs, foods, additives, infant formula bio-therapeutics, medical devices, radiation-emitting products, cosmetics, animal feed. • The staff: Chemists, pharmacologists, physicians, microbiologists, veterinarians, pharmacists, lawyers, etc. • What FDA does: Monitors manufacture, import, transport, storage, sale of ~$1 trillion products annually. • What FDA does: Investigates and inspects >16,000 facilities

7. How Do Drugs Get Approved in the United States? Food and Drug Administration • FDA is the sole Federal agency that approves drugs as safe and effective for intended indications. • The Federal Food, Drug, and Cosmetic (FD&C) Act requires: new drugs be shown safe and effective for their intended use before US marketing. • FDA approval process requires: controlled research, clinical trials to base approval on safety, efficacy and labeling decisions. • To bypass the FDA drug approval process might expose patients to unsafe and ineffective drug products. • LAETRILE

8. The FDA Ensures Drug Safety

9. Food and Drug Administration Drug Development ProcessTest Tube to New Drug Application Review: ~12 years; ~$350 Million • 3.5 years + • laboratory testing • application to FDA for human testing • 1/1000 compounds go to human testing • 1 year: PHASE I • 20-80 healthy volunteers to establish safety and profile • 2 Years PHASE II • 100’s patient volunteers determine if drug is effective for a specific disease state • 2.5 years • Application for approval • < or > 100,000 pages!!!!! • 3 years PHASE III • 1000’s patients • multiple sites • different populations, doses, effectiveness • Drug combinations adverse reactions • PHASE IV • If approved, requirement to report cases of adverse reactions, other clinical data to the FDA.

10. Food and Drug Administration Drug Development Process • 2.5 years • Application for approval • < or > 100,000 pages!!!!! • Review meeting: discuss drug and data • New Drug Application (NDA) submission: animal, human data, analyses, drug behavior in body, manufacturing process. • FDA Review: decide to review (60 days); review (several years) • Drug labeling: is information accurate (indication, dose, side effects, proscriptions, drug interactions? • FDA Facility inspection: Inspects facility where drug is manufactured • FDA Decision: approve or reject

11. PHASE IV or Monitoring PhaseEven with 12 years of discovery, not possible to predict all drug side effects • Drug manufacturer: submits required periodic safety updates (new risks) • MedWatch: Physicians and consumers can report adverse events www.fda.gov/medwatch • New risk disclosures: drug labeling changed, public & physicians informed, drug use may be restricted or withdrawn • PHASE IV: • If approved, requirement to report cases of adverse reactions, other clinical data to the FDA.

12. Marijuana History

13. Marijuana History Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras

14. Marijuana History Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras

15. FDA and Marijuana

16. Has FDA approved pure products from marijuana plant? Marinol

17. FDA and Marijuana: Criteria

18. Pure compound, with predictable chemistry, manufacturing, and composition of matter

19. OH O Phyto- and synthetic cannabinoids Phytocannabinoids: plant-derived 80 or so phytocannabinoids made by marijuana plant Cannabis Sativa D9-TetraHydroCannabinol or THC is highest D9 refers to double C=C bond in 9-position of THC Synthetic cannabinoids: 1,000s made by chemists Δ9-THC (Gaoni & Mechoulam, 1964)

20. Endocannabinoids produced by brain, other organs Anandamide:arachidonoylethanolamide 2-AG: 2-arachidonoylglycerol 7 or more made in brain and in other tissues

21. Is Marijuan a Pure Compound?Marijuana Smoke and Tobacco Smoke Moir et al, A Comparison of Mainstream and Sidestream Marijuana and Tobacco Cigarette Smoke Produced under Two Machine Smoking Conditions. Chem. Res. Toxicol., 2008, 21 (2), pp 494–502 Standard conditions employed a puff volume of 35 ml, a puff duration of 2 s, and a puff interval of 60 s. These conditions are termed “ISO” throughout. Conditions more reflective of marijuana smoking employed a puff volume of 70 ml, a duration of 2 s, and a 30 s interval. These conditions are referred to as “extreme” and differ from the Health Canada “intense” tobacco smoking conditions, which employ a puff volume of 55 ml

22. Is marijuana smoke “cleaner” than tobacco smoke?

23. Chemistry, manufacturing, and composition of matter predictable?

24. Clinical data: dose response, effective, safe

25. The Gold Standard of Evidence: Randomized, Double-blinded (and cross-over) Multi-Center Controlled Trials

26. Center for Medicinal Cannabis Research (California) • > 36 scientific reports • Minus abstracts (or proceedings) • = 24+ publications • 5 performed with patients, medical conditions • according to ballot initiative Neuropathic Pain: Wilsey et al, J Pain, 2012 Wilsey et al, J. Pain, 2008 Ellis et al, Neuropsychopharm., 2009 Abrams et al, Neurlogy 2007 Spasticity: Corey-Bloom et al, CMAJ 2012 (30 patients) • 5 clinical studies • discontinued • 4/5 studies used EXPERIENCED MARIJUANA USERS

27. Center for Medicinal Cannabis Research • INVESTIGATOR: Donald Abrams, M.D.PROJECT TITLE: Marijuana in Combination with Opioids for Cancer Pain • PROJECT TYPE: Clinical Study • STATUS: DISCONTINUED • RESULTS: The study experienced difficulty with recruitment of participants, in part due to the 9-day hospitalization required for study participation. A variety of recruitment strategies were employed, including outreach to local oncologists, advertisements in local print media, and presentations at various related functions. None of these strategies were successful and the trial was discontinued.

28. Center for Medicinal Cannabis Research • INVESTIGATOR:MarkAgius, M.D. • PROJECT TITLE: Cannabis for Spasticity/Tremor in MS: Placebo Controlled Study • PROJECT TYPE:Clinical Study • STATUS: FUNDING DISCONTINUED • RESULTS:This study sought to evaluate the safety and efficacy of smoked cannabis in relieving the spasticity associated with multiple sclerosis (MS) as measured by a new objective measure of spasticity. Unfortunately, recruitment for this study proved to be difficult for many reasons, including a prohibition on driving throughout the 16 weeks participants were enrolled in the study. The study was reviewed by the CMCR Scientific Review Board and Data Safety Monitoring Board who both recommended discontinuation for lack of feasibility. No preliminary analyses of safety or efficacy were possible.

29. Center for Medicinal Cannabis Research • INVESTIGATOR: Dennis Israelski, M.D. • PROJECT TITLE: MMJ for HIV-associated DSPN: Adherence & Compliance Sub-Study • PROJECT TYPE: Clinical Study, Sub-Study • STATUS: DISCONTINUED • RESULTS: Recruitment for this sub-study stemmed from the parent study. Methods for recruitment included: dear doctor letters, flyers, and postings on San Mateo Medical Center and Center Watch clinical trials websites. A series of focus groups were organized to get community input regarding the study. • Changes were made to the study as a result of the focus groups with the intent of improving recruitment, but no such improvement occurred. In total, only three patients were recruited into the sub-study, and thus did not provide enough data for analyzable results.

30. Center for Medicinal Cannabis Research • INVESTIGATOR: Suzanne Dibble, DNSc, RN • PROJECT TITLE: Treating Chemotherapy-Induced Delayed Nausea with Cannabinoids • PROJECT TYPE:Clinical Study • STATUS: DISCONTINUED Unfortunately, recruitment proved more difficult than anticipated and the study was discontinued. In total, 172 people were screened, but only 6 completed the study. Most people who could not participate in the study lacked a "moderate amount of nausea." This may be in large part due to recent advances in anti-nausea drug treatments. As the target for enrollment was 81 patients, the 6 who completed were not sufficient to produce analyzable results.

31. Center for Medicinal Cannabis Research • INVESTIGATOR: Mark Wallace, M.D. • PROJECT TITLE: Analgesic Efficacy of Smoked Cannabis in Refractory Cancer Pain • PROJECT TYPE:Clinical Study • STATUS: DISCONTINUED • RESULTS: Recruitment for this study was difficult. Typical methods for recruitment, including posters, newspaper advertisements, and community referral were unsuccessful. Very few cancer pain patients were being seen in the UCSD Pain Clinic during this recruitment period. Local hospice agencies were willing to refer potential subjects, however, these subjects were often already smoking cannabis for pain control. To avoid potential complications from off-study cannabis use, these participants were not recruited. Only one subject was enrolled in the study, and was withdrawn for non-compliance with study procedures. No unexpected or unusual adverse events were noted in this subject.

32. Clinical Trials: other

33. States with Marijuana Approval as Medicine

34. Dose: How Much Can Public Possess?

35. Side effect profile

36. What Does Marijuana (THC) Target in Brain, Blood Cells, Tissues ? Marijuana Targets Brain, Blood Cells, Tissues CB1 receptors CB2 receptors brain Hematopoietic cells IMMUNE CELLS Adrenal Ileum Jejunum BRAIN Heart Testis Uterus Prostate Vascular tissue Immune cells

37. Marijuana distributes to many regions (CB1) of Human Brain Red, yellow regions have high concentrations of CB1 cannabinoid receptor Left: PET image to probe CB1 Center: MRI to define brain anatomy Right: MRI, PET combined GE Terry et al., Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand. Neuroimage 48 362, 2009

38. Marijuana Affects Many Brain Regions

39. Smoked, Intravenous THCProduce “High” And Perceptual Changes THC produces euphoria THC produces perceptual changes THC produces depersonalization, derealization, distorted sensory perceptions, altered body perception, feelings of unreality, and extreme slowing of time in both healthy individuals and patients with schizophrenia . Subjects were reported as being ‘‘spaced out,’’ looking ‘‘separated or detached,’’ and as if they said or did ‘‘something bizarre,’’ or if they needed redirection. Source: D'Souza DC. Cannabinoids and psychosis. Int Rev Neurobiol. 2007;78:289-326.

40. 12 11 10 9 8 7 6 5 4 3 2 1 Smoked THC Impairs Verbal Memory Maximum Score - Placebo - THC 2.5 mg - THC 5 mg/kg # Correct Words Recalled Minimum Score Immediate recall Trail #1 Immediate recall Trail #2 Immediate recall Trail #3 Delayed Free Recall Delayed Cued Recall Delayed Recognition Recall D’Souza, 2005

41. Long Term Marijuana Use Affects Cognitive Function • Performance of frontal-executive tests lower in heavy marijuana users • (Pope and Yurgelun-Todd (1996) • Performance on neurocognitive tests - attention, memory, and executive function - worse in heavy MJ smokers • (Solowij et al. 2002, Fletcher et al., 1996; McHale and Hunt,2008) • Cognitive deficits in heavy marijuana users • after 28-day abstinence • (Porter, & Frampton, 2007; et al., 2002) • MJ use impairs memory, attention, inhibitory control, executive function, decision making; effects can persist beyond acute intoxication for days, weeks, or longer, with long-term heavy MJ use • (Solowij & Pesa, 2010).

42. Marijuana use is associated with increased risk for psychosis, hallucinations, delusions Odds ratio NO RISK Adapted from Nat Rev Neurosci. 2007 Nov;8(11):885-95. Cannabis, the mind and society: the hash realities. Murray RM, Morrison PD, Henquet C, Di Forti M. McGrath et al, Association Between Cannabis use and Psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry 2010: 67: 440-447

43. Long term Marijuana Use is Associated With • Changes in brain structure, activity, gene expression • Negative long-term educational, career achievements • Addiction 9-10%, and higher prevalence with early onset • Impaired learning, cognitive, executive function • Compromised measures of reproduction Impaired school, work, social life • Higher Risk for Adolescents • Pathology in lung, compromised cardiovascular function • Increased risk of psychosis, schizophrenia, other psychiatric symptoms Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med. 2011 Mar;5(1):1-8; many other sources

44. Marijuana and the Developing Adolescent Brain

45. Adolescent Marijuana Use Escalating Monitoring the Future, 2011

46. Marijuana’s Effects are Greater in Adolescents Than Adults

47. Regular Marijuana Use by Adolescents…(20-30 Days/Month) • Arseneault et al., 2002; van Os et al, 2002; Zammit et al., 2002; Henquet et al., 2005; • Stefanis et al., 2004; Rubino and Parolaro, 2008; Konings et al., 2008; Andreasson et al., 1987; • Moore et al, 2007; McGrath J, et al. Arch Gen Psychiatry. 2010 May;67(5):440-7. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults

48. The Prevalence Of Addiction to Marijuana or Alcohol is 5-6 Times Higher if Teenagers Start Using at Age 15 or Less Age at first use and abuse/dependence as adult 2010 National Survey Drug Use and Health, NSDUH Sept 2011

49. Does Marijuana Fulfill FDA Criteria?

50. FDA Statement on Marijuana For Medical Purposes • Marijuana is in schedule I of the Controlled Substances Act (CSA), the most restrictive schedule. • The Drug Enforcement Administration (DEA) continues to support that placement and FDA concurred because marijuana met the three criteria for placement in Schedule I under 21 U.S.C. 812(b)(1) • 1. Marijuana has a high potential for abuse, and no currently accepted medical use in treatment (US). • 2. Lacks accepted safety for use under medical supervision. 3. There is sound evidence that smoked marijuana is harmful. • A past evaluation by HHS agencies, FDA, SAMHSA and NIDA, concluded that no sound scientific studies supported medical use of marijuana for treatment in the United States • No animal or human data supported the safety or efficacy of marijuana for general medical use. • There are alternative FDA-approved medications in existence for treatment of many of the proposed uses of smoked marijuana • A growing number of states have passed voter referenda (or legislative actions) making smoked marijuana available for a variety of medical conditions upon a doctor's recommendation. • These measures are inconsistent with efforts to ensure that medications undergo the rigorous scientific scrutiny of the FDA approval process are proven safe, effective with FD&C Act standards. • FDA, the federal agency responsible for reviewing the safety and efficacy of drugs, DEA the federal agency charged with enforcing the CSA, the Office of National Drug Control Policy, the federal coordinator of drug control policy, do not support the use of smoked marijuana for medical purposes.