A Non-Profit Approach to Developing Ibogaine into an FDA-Approved Medication

1. A Non-Profit Approach to Developing Ibogaine into an FDA-Approved Medication Rick Doblin, PhD Multidisciplinary Association for Psychedelic Studies

2. Three Basic Points 1) FDA can be trusted to evaluate data based on science rather than politics. 2) Cost of research to evaluate safety and efficacy of ibogaine-assisted psychotherapy in reducing drug abuse $5 million in 5 yrs. 3) A non-profit approach is best strategy.

3. FDA�s Track Record Since 1990, FDA has approved human studies with: DMT MDMA* Ibogaine* Psilocybin* Mescaline Marijuana* * = studies in patients.

4. FDA is our Ally FDA is our main ally in the federal bureaucracy. It�s institutional mission is to develop medicines to reduce suffering. NIDA�s mission focuses on harms of illicit drugs, and drug treatment. FDA is not in favor of psychedelics or marijuana, just in favor of research.

5. FDA Organizational Change The Division at FDA that blocked most psychedelic research throughout the 1970s and 1980s had the review of Schedule 1 Drugs taken away in 1989. Authority given to new experimental division called Pilot Drug Evaluation Staff. However, we weren�t aware at this time of this change, or its positive implications.

6. FDA Institutional Change July 14, 1992. NIDA convenes Technical Review on hallucinogenic research in animals, to meet day before FDA meeting. Sasha Shulgin courageously speaks out. NIDA recommends human research resume so animal data doesn�t become meaningless.

7. FDA�s New Policy for Psychedelic Research July 15, 1992: FDA convenes Drug Abuse Advisory Committee to review policy toward research with Schedule I drugs, and to review Dr. Grob�s MDMA/cancer study. Advisory Committee recommends that Schedule I research to be evaluated with the same rigorous standards FDA uses for other drugs. OK with DEA and ONDCP observers.

8. FDA Follows Through: MDMA July 15, 1992. FDA approves, in principle, Phase I MDMA study, to be conducted prior to MDMA/cancer patient study. November 5,1992. MDMA study approved.

9. FDA Follows Through: Ibogaine August 25, 1993. FDA Advisory Committee recommends approval of ibogaine dose-response study by Sanchez-Ramos, Mash. FDA approves 1, 2 and 5 mg/kg dose groups, with prior approval by FDA required before each higher dose can be administered.

10. NIDA: Just Say Maybe, Not. By March 1995, NIDA�s Medications Development Division (MDD) had invested over $1 million in preclinical research with ibogaine. March 8, 1995. NIDA/MDD convened an ibogaine protocol development meeting, but decides not to fund human studies or invest further in ibogaine preclinical research.

11. FDA Input to NIDA After NIDA decision, FDA still encouraged NIDA to allocate funds for a small Phase I ibogaine safety study. March 10, 1995. FDA�s Dr. Curtis Wright sent a memo to Dr. Frank Vocci, NIDA�s Director of MDD, urging NIDA to facilitate ibogaine research.

12. Dr. Wright�s Letter to NIDA �I believe that it is in the public�s best interests that research with ibogaine go forward�The methods of the major pharmaceutical firms are without equal in developing a new drug in a manner that produces a safe and effective pharmaceutical�Unfortunately, they do not usually produce breakthrough products for new indications.�

13. Dr. Wright�s Letter to NIDA �The normal process of peer review is excellent at deciding how best to undertake research in a new area, but often not a good way to decide if to undertake original new research. My recommendation is to use your strength to help those [such as venture capital firms, subsidiaries of major firms formed to take risks, iconoclasts within industry, or individual physicians] who will undertake such risks.�

14. NIDA: Just say No! NIDA/MDD doesn�t agree with Dr. Wright�s advice, ceases investments in ibogaine research.

15. Ibogaine Research:Not Enough $$$ May 27, 1995. FDA reviews 1 mg/kg data, approves 2 mg/kg. MAPS donated $50,000 toward costs of 2 mg/kg dose group. 2 mg/kg data used by Mash/Sanchez-Ramos as part of another NIDA grant application. Grant rejected. $500,000 not available. Research/treatment moves off-shore.

16. NIDA in 2003 More than 8 years after NIDA decided not to invest further in ibogaine research, situation remains the same. No realistic hope for NIDA-funding in the near future unless NIDA presented with promising data from clinical research and new political support for ibogaine research.

17. Privately-Funded Ibogaine Research Is a 5-year, $5 million Clinical Plan designed to develop ibogaine into an FDA-approved prescription medicine a reasonable estimate of time and expenses?

18. The Costs of Drug Development: A Stretch but Within Reach Pharmaceutical companies estimate it costs about $250 - $800 million to develop a drug into a prescription medicine. Where does this number come from? Does it apply to ibogaine for heroin withdrawal, reductions in drug abuse?

19. Drug Development $ Estimates Most reliable, trusted, informed source is: Center for the Study of Drug Development (CSDD), Tufts University, Dr. Louis Lasagna, Founder. Funded by a consortium of pharmaceutical companies. Given proprietary data to analyze but cannot reveal to competitors.

20. Major Papers DiMasi J, Hansen R, Grabowski H, Lasagna L. Cost of innovation in the pharmaceutical industry. J Health Econ 10 (Jul 1991) 2:107-42. DiMasi J, Hansen R, Grabowski H, Lasagna L. Research and development costs for new drugs by therapeutic category. A study of the US pharmaceutical industry. 7 (Feb 1995) 2:152-69. DiMasi J. Lasagna L. The Economics of Psychotropic Drug Development. in (eds.) Bloom F, Kupfer D. New York: Raven Press, 1995:1890.

21. Most Recent Estimate In 2003, Dimasi estimates total average cost of 68 randomly selected new drugs from survey of 10 pharmaceutical company firms is $802 million (2000 dollars). DiMasi J, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ March 22 (March 2003) 2: 325-30.

22. Industry Insider View Dr. Nelson Levy, ex-head of research and development at Abbott Laboratories remarked, �That it costs $500 million to develop a drug is a lot of bull.� NY Times, April 23, 2000.

23. Whittling Away 1. Opportunity Cost on money invested, often for longer than 10 years, at 11% discount rate. 2. The cost of developing all the drugs that never were approved,amortized over approvals 3. Cost of all preclinical, safety, efficacy studies. 4. Large-company overhead, no volunteers.

24. Opportunity Cost �income foregone from investing in development for a period before returns are earned (time costs).� When opportunity costs of 11% are subtracted from Dr. DiMasi�s 2003 estimate of $802 million, the estimate is reduced to $403 million, about a 50% reduction.

25. Cost of Failures �The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval.� DiMasi. J. et al.

26. Number of Failures Per FDA-Approved Drug For every new drug approved: 5000 chemicals synthesized and screened 250 brought into animal testing 5 into human testing 1 approved by FDA Pharmaceutical R & D: Costs, Risks and Rewards, Office of Technology Assessment, Washington, DC, 1993.

27. Cost of the Failures In the 2003 paper, DiMasi estimates that the success rate is 21.5% Mean cost of failures is $155 million, further reducing the cost of development by about 40%.

28. Preclinical v. Clinical Costs About 1/3 of remaining research costs are from pre-clinical research, of which FDA doesn�t need much if any more for ibogaine.

29. Cost of Success Mean cost of clinical research totals $127 million. Median cost of clinical research is $96 million. Cost for smaller firms is lower.

30. Small firm/Non-Profit Advantage Costs still include R&D-Related Overhead, which is substantial. Cost savings from motivated volunteers or paid staff. For example, bid for Contract Research Organization (CRO) monitoring of MDMA/PTSD pilot study was $175,000. Volunteer with better credentials will donate monitoring services for $5,000 costs.

31. Still Big Numbers, But... There is one more factor to take into account. Psychedelics are pariah drugs!

32. The Advantage (Finally) of working with Demonized Drugs Governments around the world spend tens of millions every year to find out what�s wrong with Schedule I drugs. NIDA�s budget is $950 million a year! MAPS FY $ was less than .1%. There is an large body of prior research published in peer-reviewed journals. This data is in the public domain and can be submitted to FDA as evidence of safety or efficacy.

33. Medline Papers on Ibogaine May 4, 2003. Medline lists 226 papers. 202 of these papers are from 1990 or later, virtually all on some aspect of ibogaine�s potential as an anti-addictive agent. Cost to conduct this research difficult to estimate, but assuming $50,000 average per study total equals more than $10 million. However, most are preclinical studies.

34. Quasi-Underground Research For pharmaceutical companies, all data must come from government-approved studies. For ibogaine, some safety data can be gathered from quasi-underground clinics and submitted to regulatory agencies. Data will not be used directly but can increase FDA�s comfort level in approving research.

35. Estimating Number of Subjects: Pilot Studies Initial pilot studies with patients will require 10-50 subjects, a low number due to all the other research that has been conducted. Treatment needs to be standardized and a �treatment manual� developed that can be used to evaluate therapists to ensure consistency.

36. Patients to be Enrolled in Phase III Clinical Trials Proposed Phase III study design includes 4 groups (placebo, medium dose, high dose, and best available approved medicine). 80 subjects in three groups and 40 in the placebo group, would be sufficient for FDA, 280 subjects per group. This was the size of the studies for the recent FDA approval of Zoloft for PTSD.

37. Patients Enrolled in All Studies Two Phase III trials will be required by FDA to demonstrate safety and efficacy. Two studies of 280 subjects each is 560. Add 50 for pilot studies and we have 610. Of course, this depends on how useful the test drug turns out to be. Larger effects and smaller variances = smaller studies required to prove significance.

38. Cost per Patient in US Clinical Trials Mean US cost per patient in FDA-approved research was $5,434 for 1994 and $4,904 for 1995. In 1996, the mean cost was $6454, in 1997 it was $7,123. Parexel�s Pharmaceutical R& D Statistical Sourcebook 1998. Waltham, MA: Parexel, 1998: 47. MAPS� MDMA/PTSD Pilot Study is about $10,000 per subject, larger studies cost less.

39. Summary Estimates Assume $8,000 per subject (economies of scale) and 610 total subjects. Cost =$4.88 million. Add $620,000 for consultants, lawyers, lunches, and we need $5.5 million, over 5 years, or: BOTTOM LINE $1.1 million per year.

40. Relative Costs $9 million or so spent on State Medical Marijuana Initiatives of non-deductible $$ Canadian Government allocated $5 million just to grow marijuana. NIDA Annual Budget over $900 million.

41. Step 1: Comprehensive Literature Review MAPS spent almost two years and $100,000 on a comprehensive review of the published, peer-reviewed scientific literature on MDMA, for submission to the FDA and for the MAPS website. However, there are over 1300 MDMA papers in medline, compared to 226 for ibogaine. Total cost $20,000.

42. Step 2: Obtain Independent Supply 1985: I had 1000 grams of MDMA manufactured by Dr. Dave Nichols for use in research, at a cost of $4 gram! Not sure what ibogaine costs, $50-$100 per dose.

43. Step 3: Complete Phase 1 Study. Dr. Mash estimates it would cost about $125,000 to complete the Phase 1 dose-response safety study. Reduced from $500,000 because data from St. Kitts could be provided to FDA, decreasing the number of dose levels and reducing the number of subjects.

44. Step 4: Standardize Additional pilot studies with about 30 or so subjects to standardize therapeutic approach. This is a necessary step in all NIMH-funded research that involves psychotherapy.

45. Step 5: Conduct Phase 3 Studies Once the treatment is standardized and dose is selected, research can begin on the Phase 3 studies. If promising results are obtained from the first study, it should be easier to raise funds for the second study.

46. Non-Profit v. For-Profit Ibogaine soon to be off-patent, no monopoly opportunities. For-profit can focus on 18-MC and noribogaine. Large number of patients treated in quasi- underground clinics around the world. This generates successfully-treated subjects who may wish to donate, and further reduces profit potential for FDA-approved drug.

47. Final Thought From Albert Einstein �If at first the idea doesn�t sound absurd, then there is no hope.� Albert Einstein.

48. If Psychedelics Become Prescription Medicines, How Should They be Regulated? Certainly this question is many years away, yet it is still worth a bit of time to consider. For some regulators, this eventuality may seem so frightening that research might be halted prematurely so that the data cannot be generated to argue persuasively for prescription availability.

49. DEA Fear: Legalization for Medical Use = Legalization for All uses. For example, the possibility that the medical use of marijuana could be approved by FDA drives DEA nuts. From DEA�s perspective, legalization for medical use by prescription is virtually the same as legalization for non-medical use since there are few effective ways for it to limit use to certain classes of patients.

50. The Issue of Off-Label Prescriptions The central issue is that physicians can prescribe drugs off-label, for purposes for which the drugs were not tested and approved, and in different doses or schedules. DEA cannot control off-label prescriptions. DEA tried that with Marinol the oral THC pill, but lost the battle. Physicians, Patients, FDA, and Pharmaceutical Companies lined up against DEA. Psychedelics are powerful, and carry risks. Should any doctor be allowed to prescribe them or should there be special training required.

51. DEA Relatively Weak After Drug Approved for Marketing DEA does hassle physicians who prescribe large amounts of pain meds, but DEA usually has to obtain the support of State Medical Boards to punish the physicians if theft or direct diversion is not involved. Unlike DEA, FDA does have substantial regulatory authority to impose requirements on the marketing of drugs that pose special risks to consumers and society.

52. Key FDA Regulatory Issues Should psychedelics be treated like any other prescription medicine with an abuse potential? Prescriptions monitored, but any physician could still prescribe them for anything they wish?

53. Strategic Approach: Incremental Change The reintroduction and reintegration of psychedelics into our culture must be done gradually, so as not to catalyze a counter-reaction, an immune response so to speak, similar to what transpired during the 1960s. Should drugs be legalized? Yes, but let�s argue that one directly, and let patients benefit from limited medical uses.

54. Limits Imposed by Regulatory System I�d prefer to design a regulatory system that would be capable of limiting use to: Narrow classes of patients Specially trained practitioners Settings that are most conducive to beneficial outcomes

55. Limits Can Be Relaxed Over Time Such a system would allow for gradual expansion over time as data built up and as society grew accustomed to the sanctioned use of alternate states of consciousness. The struggle for religious freedom to use psychedelics could move forward in parallel, as well as efforts to legalize non-medical and recreational uses .

56. Contingency Plan in Case of Success If ibogaine is approved for the treatment of substance abuse, or MDMA is approved for PTSD, or psilocybin approved for OCD or for anxiety in cancer patients, what happens next?

57. Putting on My Authoritarian Hat Rule 1. Only specially trained psychiatrists, physicians, or psychologists can treat patients with the approved psychedelic for the approved use. Training provided by the psychiatrists and psychologists who conducted the Phase III clinical trials that convinced the FDA to approve the drug.

58. Rules for Radicals Rule 2. Psychologists or physicians who are not psychiatrists could deliver the psychedelic-assisted psychotherapy, but they would need to work under the direction of a psychiatrist. In order to reduce the risks of adverse medical and psychological complications, power should rest in a psychiatrist to authorize prescriptions and treatments.

59. Are you experienced? Rule 3. Psychiatrists, Physicians and Psychologists would NOT be required, to have their own psychedelic experiences. We run the risk of creating an isolated and feared medical priesthood that excludes skeptics and the risk averse if we mandate that every treating psychiatrist, physician or psychologist must try psychedelics.

60. Are you experienced? Rule 4. There should be two distinct looking diplomas for treatment providers, one for those who tried psychedelics and a different one for those who didn�t. Patients should be able to determine whether or not their therapists have taken their own medicine.

61. The Psychedelic Clinic Rule 5. Psychedelic sessions should generally take place in specially licensed and equipped facilities. Requirements would include emergency equipment, music capability, private bathrooms for the treatment rooms. Treatments can take place in the patient�s home or hospice center only in instances where the patient is too ill to travel to a licensed treatment facility.

62. Staffing Requirements Rule 7. The patient shall never be left alone during the active phase of a treatment session. A minimum of two treatment professionals should be present in the facility during the active phase of the treatment session, though they need not both be in the treatment room.

63. Staffing Requirements Staffing requirements would be designed to reduce opportunities for sexual abuse of patients in vulnerable and trusting states .

64. National Patient Registry Rule 7. A report about every treatment session must be submitted to FDA. This is the way thalidomide is handled. Off-label use can take place, but it is reported and monitored. New clinical trials could be initiated for new patient populations if there are sufficient treatments for new indications.

65. Mail - Order Prescriptions Only Rule 8. Psychedelics would be available only by mail from one central pharmacy. This will facilitate enforcement of reporting requirements and reduce opportunities for diversion or theft (As with Oxycontin).

66. Advertising Rule 9. Advertisements, if any, should be targeted to patients or their physicians, with a voluntary restriction on ads in general media. This is to be sensitive to the mostly irrational concerns about �sending the wrong message� to adolescents.

67. Gradual Expansion of the Function of the Clinic Patients only treated in initial stages. Patients� family members next. Then, non-patients, healthy normals wanting to learn more about themselves. After first exposure in clinic, then people can obtain a license to purchase and use outside of the clinic for recreational use. Misbehave during recreational use, lose license to purchase the drug.