Transcript Three Basic Points

A Non-Profit Approach to
Developing Ibogaine into an
FDA-Approved Medication
Rick Doblin, PhD
Multidisciplinary Association for Psychedelic Studies
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.
FDA’s Track Record
• Since 1990, FDA has
approved human
studies with:
• DMT
• MDMA*
• Ibogaine*
• Psilocybin*
• Mescaline
• Marijuana*
• * = studies in patients.
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.
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.
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.
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.
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.
FDA Follows Through: Ibogaine
• August 25, 1993. FDA Advisory Committee
recommends approval of ibogaine doseresponse 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.
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.
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.
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.”
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.”
NIDA: Just say No!
• NIDA/MDD doesn’t agree with Dr.
Wright’s advice, ceases investments in
ibogaine research.
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.
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.
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?
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?
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
Still Big Numbers, But...
• There is one more factor to take into
account.
• Psychedelics are pariah drugs!
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Step 3: Complete
Phase 1 Study.
• Dr. Mash estimates it would cost about
$125,000 to complete the Phase 1 doseresponse 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.
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.
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.
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 quasiunderground clinics around the world. This
generates successfully-treated subjects who
may wish to donate, and further reduces
profit potential for FDA-approved drug.
Final Thought From
Albert Einstein
• “If at first the idea
doesn’t sound
absurd, then there
is no hope.”
Albert Einstein.
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.
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.
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.
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.
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?
Strategic Approach:
Incremental Change
• The reintroduction and reintegration of
psychedelics into our culture must be done
gradually, so as not to catalyze a counterreaction, 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.
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
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 .
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?
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.
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.
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.
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.
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.
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.
Staffing Requirements
• Staffing requirements would be designed to
reduce opportunities for sexual abuse of
patients in vulnerable and trusting states .
National Patient Registry
• Rule 7. A report about every treatment
session must be submitted to FDA.
• This is the way thalidomide is handled. Offlabel 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.
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).
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.
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.