BOTEC Analysis Corporation
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18 Brattle Street Cambridge, Massachusetts 02138
(617) 491-1277
Mark A.R Kleiman, President
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RESEARCH FUNDING FOR ABUSE LIABILITY
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Technical Report #3
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Prepared for the National Institute on Drug Abuse \ ,
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30 December 1985
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David E. Burmaster, Ph.D •
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TABLE OF CONTENTS
Section
-
Page
1.0
INTRODUCTION
1
2.0
THE SETTING OF ABUSE LIABILITY POTENTIAL TESTING
4
3.0
SOURCES OF FUNDS
4
4.0
DISTRIBUTION OF DRUGS FOR TESTING
6
5.0
ESTIMATED UNIT COSTS FOR TESTING NEW DRUGS
7
ESTIMATED UNIT COSTS OF TESTING NEW DRUGS WITH HUMAN VOLUNTEERS
8
ESTIMATED ANNUAL COSTS OF DAWN AND CEWG
8
8.0
DISCUSSION OF KEY ISSUES
9
9.0
SUMMARY
A.1
APPENDIX 1
A1-1
A.2
APPENDIX 2
A2-1
A.3
APPENDIX 3
A3-1
A.4
APPENDIX 4
A4-1
6.0 7.0 , .-
Topic
19
RESEARCH FUNDING FOR ABUSE LIABILITY
CHAPTER 4
" . • Abuse is used with reference to events that precede or accompany strong drugseeking, drug discrimination and drug-taking in association with self-administration of a pharmacological agent, often in a social context • . • • • .Tbe abuse concept clearly encompasses toxicity as well, i.e., adverse physiological and/or behavioral consequences . • • " -excerpted from' Joseph V. Brady, Ph.D. and Scott E. Lukas, Ph.D., Editors for The Committee on Problems of Drug Dependence, NIDA Research Monograph 52, Testing Drugs for Physical Dependence Potential and Abuse Liability, (1984).
1.0
INTRODUCTION Of all the research on drugs, only a small fraction of it
concerns the measurement of abuse liability potential for strong analgesics and other compounds with CNS activity.
-
The National
Institute on Drug Abuse (NIDA) and -- to a lesser extent -- the nonprofit Committee on Problems of Drug Dependence,
Inc.
(CPDD)
Funding
-- provide the bulk of the research funds supporting the key preclinical (animal) research programs at the Medical College of Virginia (MCV), Virginia Commonwealth University in Richmond, Virginia;
at the Medical School,
University of Michigan (Michi-
gan) in Ann Arbor, Michigan; and at the School of Medicine, Johns Hopkins University (Hopkins) in Baltimore,
Maryland.
Taken with
the clinical studies at the University of Chicago (Chicago) in Chicago, Illinois, the NIDA intramural research program at the Addiction Research Center (ARC) in Baltimore,
Maryland,
and the
Behavioral Biology Laboratories at the Johns Hopkins School of Medicine,
these three academic laboratories provide most of the
data and information in the abuse liability potential of new and old drugs in the United States -- indeed, most of the information in the world.!/ an
Over the years, these laboratories have created
incomparable
and
internally
consistent
database
by
methodically using double-blind experiments to test drugs on rodents, other small mammals, primates, and/or human volunteers. These studies have used small number of "duplicates" or "splits" to ensure the highest reproducibility and QA/QC (quality assurance/quality control) checks.
The MCV and Michigan programs
each test some 40 to 50 compounds per year in animals, the Hopkins program tests some 12 to 15 compounds each year in baboons, and the Chicago, ARC, and Johns Hopkins programs each test some 10 to 20 compounds each year in humans.
!/
There is only one other comparable program or laboratory in
the world -- in Japan. 2
Funding This report has 8 more major sections: 0
2.0
The Setting of Abuse Liability Potential Testing,
0
3.0
The Sources of Funds,
0
4.0
Distribution of Drugs for Testing,
0
5.0
Estimated Unit Costs of Testing New Drugs with Animals,
0
6.0
Estimated Unit Costs of Testing New Drugs with Human Volunteers,
0
7.0
Estimated Annual Costs of DAWN and CEWG,
0
8.0
Discussion of Key Issues, and
0
9.0
Summary
This report closes with 4 Appendices -- travel interview reports by
members of the project team concerning: o
the CPDD Annual Meeting in June 1985,
o
the Medical College of Virginia Program, and
o
the Michigan Program, and
o
the Hopkins Program.
3
Funding 2.0
THE SETTING OF ABUSE LIABILITY POTENTIAL TESTING Exhibit 1 shows a "Schematic Diagram of the Sources and
Users Research Funds" for abuse liability potential testing as compiled by Hsia (1985, unpublished) .
In terms of dollars, the
two largest sources of funds for this type of testing are NIDA
-
and CPDD.
Also in terms of dollars, the largest uses of funds
for this type of research are the academic laboratories at MCV/VCU, Johns Hopkins, University of Michigan, and University of Chicago,
3.0
and the ARC Laboratory (Baltimore).
SOURCES OF FUNDS The research funds for drug abuse liability potential
testing come from two major sources: 3.1
The National Institute on Drug Abuse NIDA, under ADAMHA in the Department of Health and Human
Services, supplies the bulk of the research funds for this type of testing.
As shown in Exhibit 2 for FY1985, NIDA signed grants
and contracts totaling $2.030 million,
with grants receiving the
far larger proportion, for abuse liability potential testing. Overall,
NIDA spent some $58.6 million in FY1985 on its
extramural research budget as shown in Exhibit 3.
Thus,
by
simple ratio, NIDA spent just under 3.1 percent of its extramural research budget on abuse potential testing.
4
Funding 3.2
The Committee on Problems of Drug Dependence, Inc. After more than 40 years service as a standing committee of
the National Academy of Science, CPDD is now an independent, nonprofit corporation.
CPDD functions as a loosely-organized
professional society with an unpaid Board of Directors served by an unpaid Executive Director (usually a professor at a major universi ty).
Each year,
CPDD collects voluntary donations
totaling approximately $200,000.
from approximately 40 licensed
drug companies. In the year 1984,
the firms listed in Exhibit 4 donated
funds to support the work of the CPDD.
The Committee allocated
its funds as estimated and shown in Exhibit 5.
Each year, the
Committee spends at least half its budget on its Annual Meeting (not counting the value provided indirectly by NIDA when the agency pays for the printing and distribution of the Proceedings of the Annual Meeting).
For a typical year, Dr. Harris at MeV
estimates that the Committee may spend up to $70,000. on
-
research,
providing base funding for abuse potential testing at
both the MCV and Michigan programs and sometimes providing onetime funding for a special project.
-
5
Funding 4.0
DISTRIBUTION OF DRUGS FOR TESTING As an adjunct to his regular, full-time job at the National
Institutes of Health (NIH) in Bethesda, Dr. Arthur E. Jacobson plays a key role in the testing of drugs for abuse potential. Basically, Dr. Jacobson receives newly synthesized drugs from various sources identified below, codes them in a double blind method,
and sends vials (with only solubility data) to the
laboratories at MCV and Michigan for initial testing.
At his
discretion, Dr. Jacobson may send "duplicates" or "splits" of the samples to the same or different laboratory at the same or a later time as an internal QA/QC check. During a telephone interview in September 1985, Dr. Jacobson reported the numbers shown in Exhibit 6. approximately 100 drugs per year,
Basically, he receives
with 70 percent of the
submissions arriving from academic or governmental laboratories. The pattern of submissions appears roughly constant over the last 7 years.
6
Funding
5.0
ESTIMATED UNIT COSTS FOR TESTING NEW DRUGS During four separate interviews, members of the project team
explored various estimates of the "unit cost" of testing a new drug for abuse potential.
In order, we interviewed:
o
Dr. Scott Lukas, McLean Hospital,
o
Dr. Louis Harris, Medical College of Virginia,
o
Dr. James Woods, University of Michigan, and
o
Dr. Joseph Brady, Johns Hopkins University.
The "unit costs," as estimated by each individual, are shown in Exhibits 7 through 10, respectively.
In broad review, the
estimates all look similar -- although they are not disaggregated on a common basis, laboratory
animal.
and although they do not assume a common In broad generalities,
one
may
(over)
simplify these data to remember that "preliminary testing" may cost up to $10,000. per compound and that "full testing" may cost up to $35,000. per compound.
-
Each of the interviewees voluntarily stressed the fundamental and powerful economies of scale.
In essence, there is a high
fixed cost per year to keep a team of researchers and a colony of trained animals assembled in a laboratory tory tests one or many drugs per year.
whether the laboraIn a crude sense, the
marginal cost of doing the second through last drug each year is zero after paying the set-up costs.
The four interviewees
stressed that the current arrangements maximize the economic efficiency of using scarce resources and talented researchers. They also emphasized that the present arrangements minimize the 7
-
Funding
number of animals needed,
a positive point in an era of
increasingly vocal animal protection groups. interviewees stressed that the present,
Finally,
the four
double-blind QA/QC con-
troIs force continued high accuracy across a wide range of doses, thereby insuring comparability of results among laboratories and over time.
6.0
ESTIMATED UNIT COSTS OF TESTING NEW DRUGS WITH HUMAN VOLUNTEERS Since the passage of the federal legislation in the 1970s
banning the testing of drugs on inmates, humans are conducted each year.
far fewer tests on
In the US, human testing occurs
mainly in three laboratories, those at ARC, the University of Chicago,
and the Johns Hopkins School of Medicine.
In an interview this summer, Dr. W. Robert Lange estimated that 2 of the 18 beds at the Addiction Research Center are used, on average, for abuse potential testings. ~
Pro-rating from the
annual ARC budget, Dr. Lange estimated that those beds cost some $240,000. per year -- a small fraction of the ARC's annual budget of
approximately $6
million.
Exhibi t
11 shows the
annual
figures.
7.0
ESTIMATED ANNUAL COSTS OF DAWN AND CEWG Among other programs,
NIDA supports two efforts to collect
data on the street-use of drugs, the Drug Abuse Warning Network (DAWN) and the Community Epidemiology Work Groups (CEWG).
8
DAWN
Funding costs more than $1 million per year; CEWG costs a comparable amount of money (Exhibit 12). Briefly, through the DAWN, NIDA collects data on drug abuse incidence from 760 participating hospital emergency rooms and 76 medical examiners (1983 figures) in major metropolitan areas. design,
DAWN has several objectives,
By
especially to monitor drug
abuse patterns and to detect new abuse entities and new combinations.
Each year,
a contractor prepares an elaborate
"Statistical Series" report, disaggregating (and correlating) the "mentions" by drug, factors.
sex,
age,
city,
combinations,
and other
While the medical examiners' data are based on
laboratory tests, the ER "mentions" are usually based on selfreports only. annual reports,
Finally, given the time lag for proposing the the DAWN program has a reputation more as a
chronicle than as a tool for current analysis.
The CEWG program operates in a fundamentally different way. Twice a year, NIDA convenes a group of knowledgeable people from approximately 50 major metropolitan areas to discuss recent trends and patterns on drug availability and street use in that city.
These reports, while less statistical in nature, have the
reputation of providing an "early warning network" of emerging street practices and problems.
8.0
DISCUSSION OF KEY ISSUES In this section, we discuss several key issues concerning
drug abuse liability potential testing. 9
Funding
8.1
Subsidization of Abuse Potential Testing Issue: Should the federal government continue to pay for
most of the costs of drug abuse potential testing? pros and cons of the current situation?
What are the
What are the pros and
cons of various alternatives?
Discussion: At present, the federal government pays for most of the abuse potential testing in the country, with some money contributed indirectly by pharmaceutical companies through voluntary contributions to the CPDD.
New drugs -- in blinded protocol
are sent to the Medical College of Virginia and the University of Michigan by Dr. Arthur Jacobson after he receives them from university, government, and pharmaceutical laboratories. Michigan conduct tests on about 90 drugs each year, bined annual
MCV and
at a com-
cost to the government of approximately S750
thousand per year -- or a little over S8,000. per compound. As an alternative, Dr. Jerome Jaffe has suggested that all _
persons submitting compounds to Dr. Jacobson for testing enclose a check to cover the costs, say SlO,OOO.
As a possible variation
on this basic alternative, Dr. Jaffe suggests that only commercial companies, i.e., the licensed pharmaceutical companies, send checks with their submittals.
Dr. Jaffe's suggestions are based
on considerations of both equity and efficiency. o
First,
should the federal government provide the ser-
vices free when the submitters could pay a fee? 10
Funding
o
Second, in a normal market sense, are the submitters
sending too many compounds to Dr. Jacobson because the service is a free good? On balance,
in view of the benefits received by the
government, we believe the present practices and subsidies are appropriate.
First, we found no abuse of the present system.
While zero-cost services do encourage overuse, evidence of such.
we found no
Second, the amount of the present subsidy,
perhaps $750,000, is small compared to other subsidies or grants given to the submitters by the federal government.
For example,
the federal government provides some or all of the operating funds for the university and government laboratories, and the federal government gives large tax incentives to ethical pharmaceutical houses to encourage research and development of new drugs.
Third, fewer than 30 percent of the compounds submit-
ted to Dr. Jacobson come from commercial companies, meaning that the government might net only a 30 percent recovery of current funds.
To effect such a large change in practice, the government
should want to recover more than $250,000. per year net.
Fourth,
the government benefits strongly from the expenditure of funds. Each year, the laboratories at MCV and Michigan add compounds to a growing "database" that is (i) consistent within and between laboratories, (ii) consistent from year to year,
(iii) subject to
rigorous QA/QC checks, and (iv) covers wide ranges and doses, well outside what could be called a "normal therapeutic dose." Fifth, the government buys the assurance that the data will be
11
Funding publicly available. While the status quo has many attractive features, alternatives to it raise many disturbing questions.
the
Fundamental-
1y, if a price schedule were set for some or all of the submi tters to help defray costs, it can be assumed that some or all of the charged submitters would seek to have the tests performed by other laboratories, either commercial or academic.
This breaking
of the monopoly implies the likely occurrence of several events. First,
the data will no longer meet the criteria mentioned
in the last paragraph as points (i) to (iv). may no longer be publicly available. of all,
Second, the data
Third, and most troubling
low-bidding laboratories may cut costs by lessening QA/QC
procedures and by narrowing the range of doses considered to include only doses in the "normal therapeutic range."
This point
is most troubling because most drugs show strongly nonlinear behavior,
and it is crucial to explore the location and shape of
the dose-response curve above the "break-point" or "knee." Thus, on balance we believe that the government receives fair value for supporting the current testing procedures, and that efforts to modify the system will likely backfire,
causing
lasting damage to the integrity of abuse potential testing.
8.2
Reality and Appearance of Abuse Potential Testing Issue: In reality and appearance, are the present programs
for
drug
efficient?
abuse
potential
testing:
accurate
and obj ective?
Are there ways to increase the accuracy, objectivity, 12
Funding
and/or efficiency of the present arrangement.
Discussion:
Over the summer, we heard no allegations or
assertions disputing the fundamental accuracy and objectivity of -
the abuse potential testing at MCV and Michigan.
While "absence
of evidence is not the evidence of absence," in this case we have no reason to doubt the fundamental integrity of the results because Dr.
Jacobson does send blinded "splits" and "duplicates"
to the same or alternate laboratory from time to time.
This
QA/QC procedure provides a positive incentive to maintain high standards.
By way of new ideas, we can only suggest that Dr.
Jacobson publish an occasional research paper to report the resul ts of these QA/QC checks in addition to the papers that he already publishes on the compounds tested at only one laboratory. On the third concern,
we are persuaded that the present
system makes efficient use of scarce and costly resources -highly trained researchers, colonies of trained animals, expensive equipment.
and
Many people commented on the strong
economies of scale in this type of testing,
and some people
talked of the "critical mass" needed to launch and maintain a stable,
successful
specifically,
laboratory for these purposes.
More
there is a high market entry cost in terms of
people, animals, equipment, and plant.
Thus the first test costs
a great deal, but subsequent test have a low (annual) marginal cost.
The present laboratories
have
adjusted their
carefully -- especially the sizes of their animal colonies make most efficient use of their resources. 13
sizes to
The laboratories do
Funding
receive considerable pressure from members of animal welfare groups,
so the laboratory directors are careful to use the
animals efficiently.
8.3
Allocation of Research Funds Issue: Are research funds currently allocated well across
drugs, among facilities, and by types of research?
Are improve-
ments needed? Discussion:
Again, over the summer, we heard no allegations
or assertions disputing the present allocation of funds across drugs, among laboratories, or by type of research?
Here, the
truism about the "Absence of evidence ••• " is far more telling. We found that
few data are available which dis aggregate budgets
into these types of cross tabulations.
While the cognescenti of
the field may know these comparisons implicitly or explicitly, we cannot demonstrate the fairness of the allocations On
the
contrary,
we
found
little
prim~
research
facie. at
the
laboratories on two topics of central concern to our overall national program to control drugs, namely (i) mixtures of pure compounds, and (ii) street buys, often formulated as mixtures (with impurities and extenders).
While "Ts and Blues" (and a few
other mixtures) and "China White" (and a few other street buys) have received research funding,
academic researchers vocally
argue against testing for either category.
Why?
For the first category -- mixtures -- the researchers argue
14
Funding combinatorics.
If there are 90 new drugs to test each year, and
a large number of drugs already in the pharmacopoeia, then there are an even larger number of pairs and triples to consider for testing.
No one has a good idea on how to begin, and the resul t
is no action.
Nonetheless,
it remains true (i) that mixtures of
pure drugs may have important properties that are qualitatively different from either component alone and (ii) that mixtures play an important role on the street per the results from DAWN and CEWG.
This topic needs further discussion within the field. For the second category -- street buys -- the researchers
argue the futility of analyzing potentially transient impurities and extenders.
Not withstanding the transient nature of the
task, it would be important to learn, for example, whether the idiosyncratic and intermittent effects of street "Angel Dust" come from the pure PCP (phencyclidine) or from the impurities.
8.4
Research Incentives Issue:
Do present policies and regulations encourage (or
require) enough abuse potential research on compounds? Discussion:
Strictly, the answer is no.
Generally, several
people commented that present federal policies do not encourage or require enough abuse potential research. cannot require abuse potential research,
For example, the FDA
so if a pharmaceutical
company does not voluntarily submit this type of data, the agency staff members must make decisions on the basis of best professional judgment.
As a second example -- in the absence of
15
Funding adequate data -- the DEA must also make difficult decisions on the basis of professional judgment concerning compounds showing up in street traffic.
8.5
Scientific Basis of the Scheduling Process Issue:
Do decision makers base
their policies
and
recommendations on science, combining full information from the drug abuse liability potential testing programs at MCV, University of Michigan, University of Chicago, Johns Hopkins University, DAWN, and CEWG? Discussion:
This is a difficult question, with different
answers valid from different pOints of view.
On the one and,
policy makers at DEA and FDA too often say that they are required to make tough decisions or recommendations on a dearth or an absence of appropriate scientific data and information.
In such
situations, they say, they do the best they can, interpolating and extrapolating from data and information on similar compounds.
On the other hand, senior scientists seem reasonably well informed on the functioning of the policy machinery of the federal government and on the policy implications of current research work.
By maturi ty
and by style,
these
senior
researchers have formal and informal access to high government officials and tribunals, and they use their influence quietly but effectively.
Their more junior colleagues, by contrast, seem far
removed from the concerns of Washington, DC, at present.
Whether
these individuals will fill the roles left empty as the more 16
Funding
senior people retire remains to be seen. In the last 5 to 8 years,
the researchers -- junior and
senior -- have focused increasingly on the "high science" of differentiating antagonists,
types
of
opioid
receptors
and mixed agonists/antagonists.
by
agonists,
This approach has
proved enormously fruitful in beginning to elucidate some fundamental aspects of neurophysiology and CNS activity.
To a casual
observer, mu-agonists and kappa-antagonists seem far removed from the day-to-day reality of government policies and programs to schedule drugs.
Some observers suggest that these avenues of
research will lead to powerful analgesics with zero abuse potential, while other observers suggest that these pursuits will lead only to more "high science" without pOlicy applications.
Time
will tell.
Recent events show that the federal government need not have solid scientific evidence before placing a compound in Schedule 1.
In June 1985,
the federal government used the recently-
enacted emergency scheduling amendments to the Control Substances Act to place MDMA in Schedule 1.
This action has provoked much
debate, but essentially all parties on all sides of the issues agree that no one has the proper scientific information and measurements that would have been needed to justify such an action before the amendments on emergency scheduling. the fundamental
In fact,
scientific studies only began after the
government's decision.
17
Funding Several senior researchers deplored the MDMA emergency decision, not
because the outcome was correct or incorrect, but
precisely because the process proceeded to a conclusion without the proper scientific underpinnings.
These individuals argue
that the emergency scheduling provisions essentially uncouple federal policy decisions from proper research,
thereby crippling
the process and undoing years of efforts to rationalize the decision making apparatus.
Further, they add, this style of
decision making will only signal junior researchers to pursue basic research on, say, receptors, rather than follow in the footsteps of their more senior colleagues. scheduling is valid for only 18 months, Again,
Because emergency what happens next?
time will tell whether the federal government intends to
uncouple decision making from science, or whether MDMA represents an isolated event. Finally,
it is difficult to discern any direct coupling
between the decision making process for scheduling drugs and the DAWN and CEWG programs.
The federal government spends more on
these two programs than on the drug abuse potential testing programs per se,
so one marvels at the looseness of the coupling
and the interaction.
While this question lies almost strictly
beyond the scope of this present project, we encourage others to review the programs -- with an eye to using the information effectively and efficiently.
18
Funding 9.0
SUMMARY
Of all the research on drugs,
only a small fraction of it
concerns the measurement of abuse liability potential for strong analgesics and other compounds with CNS activity.
NIDA spends a
few percent of its annual budget on abuse liability testing (approximately $2 million/year of approximately $59 million/year) and CPDD may spend some $70,000. on abuse liability testing in a typical year.
In addition,
the federal government spends a
comparable amount of money to gather data on street abuse through the DAWN and CEWG programs.
The present funding
mechanisms work
smoothly, and the QA/QC system for laboratory research (with double-blind testing) works efficiently and effectively. Nonetheless, present academic research funded under the aegis of abuse
liability testing is not
tightly coupled to
current
problems on the street -- in terms of mixtures, contaminants, and/or new ("designer") drugs.
Without changing the present
funding system which is fundamentally sound, researchers and regulators need to find ways to improve the usefulness of basic and applied research in the regulatory arena.
19
,
} ~
\
Exhibit 1 Schematic Diagram of Sources and Uses of Research Funds
Sources
NIH, NSF, and FCUldations
Researcher
Acadenllc laboratories
Reviewer
Research Type :
J
~
Peers/Publications
t
8aslc Science
Source: Adapted from Dr. David C. Hsia, tqltbl tshed 1985.
DAS of FDA
1
Specific Drugs
,
, \
Exhibit 2 NIDA Research Grants and Contracts, FY 1985
Dollars/Year [Total] 419,456.
Grants Dr. Woods
Screening new analgesics
Dr. Harris
Performing a wide range of multi·disclplinary tests
346,416.
Dr. Schuster
Evaluation of anorectics and anxlolytics
274,930.
Dr. Cole
Abuse liability of sedatives and stiMUlants
234,681.
Dr. OVerton
New behavioral methods for categorizing coqxuds
136,464.
Dr. Griffiths
Abuse liabH Ity of benzodiazeplnes
128,478.
Dr. Moreton
Abuse liability of PCP analogs
101,919.
Dr. Wenger
Abuse potential of barbltuates
52,732.
Subtotal
1,695,076.
Dollars/Year [Abuse Potential Deternlinations for Scheduling Decisions] 355,000. 325,000.
Subtotal
680,000.
Contract Dr. Brady
334,929.
Testing on primates
Subtotal
334,929.
Grand Total
M~.
Jacquilin ludford, NIDA, September 1985.
Subtotal
300,000.
Grand Total 2,030,005.
Source:
300,000.
980,000.
I
l
Exhibit 3 NIDA's Extramural Research Budget, FY 1985
Basic Biomedical Research; Biomedical, Neuroscience, and Chemistry
50
Clinical Research: Treatment, Prevention, and Behavioral Pharmacology
36
Epidemiology
14
Total
100 Dollars/year 58,640,000.
Source: Ms. Jacquelin Ludford, NIDA, September 1985.
I Exhibi t 4 Firms Contributing to the Support of the CPDD, 1984-1985 Abbott Laboratories Arthur B. Little Corporation Ayerst, Canada Boehringer Ingelheim International Burroughs Wellcome Company Clba-Geigy Corporation Clin-Midy of America, Inc. DeGussa Corporation Endo Laboratory, Inc. (Dupont) Glaxo Hoffman-La Roche, Inc. ICI Americas, Inc. Imperial Chemicals, Great Britain Johnson & Johnson, Inc. Key Pharmaceuticals, Inc. Knoll Pharmaceutical Company Lilly Research Laboratories McNeil Pharmaceuticals Merck Sharp &Dohme Research Labs Merrell-Dow Pharmaceuticals Miles Laboratories Monsanto Company Or tho Pharmaceutical Corporation Pfizer Central Research Reckitt & Colman, Pharmaceutical Div. Sandoz, Ltd. (Basle) Sandoz, Inc. (New Jersey) Scherlng Corporation Searle Research &Development Servier Amerique Smith, Kline &French Laboratories Sterling Drug, Inc_ Syntex The Upjohn Company Warner Lambert (Parke-Davis) Wyeth Laboratories Zambon s_p_a_
/
Source:
CPOO. Inc_
{
, Exhibit 5 Estimated Annual Budget for CPDD Oollars/Year CPDO Annual Meeting
100,000.
Grant to University of Michigan
25,000.
Grant to Medical College of Virginia
25,000.
Special Research Grants
20,000.
Administration, Other Expenses, and Endowment
30,000.
Estimated Total
Source: Dr. Louis Harris, August 1985.
S200,000.
\ Exhibit 6 Sources of Compounds Tested at the Medical College of Virginia and University of Michigan
NlIli:Jer of Compounds Tested per lZ·Month Period
93
Percentage 7-Year Mean
University laboratories
44
Goverrment laboratories NIH DEA NSF DOO WHO
Z6
commercial Drug companies
Z9
Total
99
* * * * *
* Note: 7-year means are not available.
Source:
Or. Arthur E. Jacobson, September 1985.
{
Exhibit 7 Estimated Unit Costs of Testing for Abuse liability Potential of a Compound
Dollars/Compound Direct Dependence Testing (4-6 primates)
15, 000. - 20,000.
Substitution Dependence Testing (4-6 primates on morphine)
25,000 •• 30,000.
Self-Administration (4-6 primates)
40,000. . 45,000.
Clinical Testing (8 -10 people, 10 weeks)
80,000. • 90,000.
Source
Dr _ Scott E_ lukas, August 1985_
J
(
\
Exhibit 8 Estimated Unit Costs of Testing for Abuse liability Potential of a Compound
Dollars/Compound
Dependency using Morphine·Addicted Rhesus Monkeys·
Full Battery of Tests .• Dependency, Discrimination, and Self·Administration with Rhesus Monkeys
6,000. . 10,000.
25,000 •. 35,000.
* Note: Estimated at scale of 50 compounds/year at approximately S325,OOO./year.
Source:
Dr. Louis Harris, August 1985.
1
I
Exhibit 9 Estimated Unit Costs of Testing for Abuse Liability Potential of a Compound
Dollars/Compound Dependency and Self·Admfnistration (Rhesus Monkey)
4,500.
Binding Assays
700.
Smooth Muscle Test
800.
Other Costs
1,800.
Total*
7,800.
* Note: Estimated at scale of 45 compounds/year at approximately S355,OOO./year.
Source:
Interviews at University of Michigan, August 1985.
1 '
1
1. Exhibi t 10 Estimated Unit Costs of Testing for Abuse Potential of a Compound
Dollars/Year
Test
Conpounds/Year
Dollars/Compound
Intravenous Drug Self-Injection
75,000.
3 or 4
18,500.
Drug Discrimination
40,000.
8 to 10
4,500.
Primary Dependence
65,000.
2 or 3 (naive animals) 3 or 4 (experienced animals)
Cross-Dependence
60,000.
8 to 10
6,500.
Sensorimotor Effects
45,000.
3 or 4
12,500.
Total*
15,900.
285,000.
* Note: Estimated at current scale (50 baboons in colony).
Source: Dr. Joseph Brady, September 1985, and letter to Dr. James Cooper from Dr. Joseph Brady dated August 16, 1985.
I
1.
L Exhibit 11 Estimated Cost of Clinical Research on Abuse liability at ARC, FY 85
Dollars/year Estimated Abuse liability Testing
Total ARC Budget
* Note: Estimated as 2 of 18 total beds at ARC.
Source: Dr. W. Robert lange, ARC, 1985.
240,000.*
6,000,000.
I .
Exhibit 12 Estimated Annual Cost of the Drug Abuse Warning Network (DAWN) and the Community Epidemiology Work Group (CEWG)
Dollars/year
NIDA administration and contracts Hospital reimbursements Annual reports
Subtotal
860,000. 340,000. NA
1,200,000.
NIDA staff and operations Contractor support
4,000. 130,000.
Subtotal
Total
*
134,000.
1,134,000.
Note: The CEWG and State Epidemiology Work Groups (begun in 1983) are funded jointly. Total annual funding is $219,329 for FY1985. Mr. ' Cozell estimated that 60 percent (approximately $130,000) funds the CEWG.
Sources:
Ms. Janie Dargin and Mr. Nicholas Cozell, 1985.
APPENDIX 1
20 June 1985
-
MEMORANDUM
TO:
W. Robert Lange, M.D. Addiction Research Center National Institutes of Drug Abuse
FROM:
David E. Burmaster, Ph.D.
SUBJECT:
Preliminary Report on the Research Project and Travel Report on the Forty-Seventh Annual Scientific Meeting of the Committee on Problems of Drug Dependence (CPDD,Inc.)
The Committee on Problems of Drug Dependence (CPDD), Inc. held its Forty-Seventh Annual Scientific Meeting in Bal timore, 10-12 June 1985.
--
In this memorandum, I report on the meeting and
on my initial observations concerning the nature and extent of the linkage between: o
Current scientific research on abuse potential testing of drugs, and
o
The federal bureaucratic process for scheduling drugs.
This memorandum addresses some of the issues raised in evaluating current drug testing and scheduling against the notion of an ideal.
As paraphrased from the original project document, an
A1-1
appropriately designed drug abuse potential testing program would spend the right amount of money on the right mix of sources on impartial,
"-
accurate,
and timely research at laboratories run by
companies, universities, and the government to support a federal regulatory program that is predictable, assessing risks.
prompt,
and accurate in
This original definition of the ideal
presupposed a strong and bi-directional link between research and regulation.
OBSERVATIONS Researchers from the United States and Canada presented some 63 talks and 33 poster sessions: o
A majority of the presentations and poster sessions
concerned some aspect of laboratory research on -- and clinical
-
treatment of -- addiction to related drugs.
heroin,
morphine,
and closely
In the last several years, using agonists and
antagonists, researchers have focused heavily on understanding the (four) different types of receptors for the opioid drugs. --
times,
this
research becomes
indistinguishable
research on
neuropharmacology
and
brain
from
transmitters.
At
basic As
practitioners of high science, many reseasrchers in this field no longer focus on the practical problems of drug abuse.
Al-2
-"
o
Most of the papers on the clinical treatment of drug
abuse focused on (i) methadone or LAAM maintenace for heroin addiction or (ii) cocaine abuse, today.
the two hot topics in the field
In a sense, heroin addiction is easy to study becausue
addicts and former addicts can be found in almost every large city and because researchers have fewer practical problems in meeting recent federal requirements for full disclosure and informed consent.
-
Meeting,
In terms of the papers at the Scientific
most of the clinical research on cocaine abuse (i)
relies on subj ects (mostly men) who volunteer for treatment at established programs,
or (ii) involves women who enter programs
for prenatal or obstetric care. o
Only a few papers at the Scientific Meeting focused on
problems related to non-opioid drugs, depressants,
marijuana,
alcohol,
stimulants,
inhalant solvents, polydrug abuse among
heroin addicts, and surveys to study the epidemiology of drug abuse. o
In the formal talks and in informal discussions later,
most of the researcherrs expressed strong preferences for two types of experiments once the LD50
and ED50 values are
established for a drug: (i) drug-discrimination tests and (ii) self-administration
tests -- usually conducted on small mammals
in the laboratory and/or on consenting, former addicts in pre-
Al-3
-
clinical settings.
By hypothesis,
these tests measure,
respectively, (i) the distinctions between and (ii) the abuse potential of various drugs -- albeit in highly controlled, mostly solitary, Skinnerian settings. o
Some purely scientific topics did not arise at the
Annual Meeting.
First,
and most noticeably,
few if any
researchers reported on mixtures of drugs -- other than the biochemical competition between agonists and antagonists.
Given
that enforcement officials report that young and not-so-young abusers often mix drugs, remains unexplained.
--
especially with alcohol,
this gap
Second, only one or two researchers made
serious analysis of chemical
shape
and
structure
activity
relations (SARs): no researchers reported on computer modeling of the 3-dimensional
shapes of agonists,
antagonists,
and/or
receptors in terms of their "backbones" and "active sites". view of recent progress in organic chemistry,
biochemistry,
In and
computer graphics, and in view of the recent restrictions on human testing, this gap also remains puzzling.
Third, given the
high science outlook of the Annual Meeting, it was surprising not to have more reports on concentrations at active sites, metabolic pathways,
and degradation products.
Fourth,
certain classes of
scheduled drugs, e.g., the hallucinogens, were not discussed at all.
Finally,
there was no in-depth discussion of "designer
Al-4
drugs"
in terms of their chemistry,
structure,
effects,
or
sociology. o
Overall,
the Annual Meeting had few reports on the
sociology of drug abuse, especially on the effects of set and setting.
This reflects the primary interests of many of the
participants in biochemistry. o
Given the high science focus of the Annual Meeting, it
is important to note that policy topics were not discussed formally or informally: - budgets, in absolute or relative terms, for research, etc. ; - manpower needs; - resesarch funding, management, and administration; + enforcement, and/or + criminal importation and distribution;
- evidence from enforcement agencies, and the DAWN Network:
street clinics,
federal policies towards: + leakage, + diversion, and/or + "bad doctoring";
- related research in other countries or international laboratories; and\or Al-5
- the scheduling process, in terms of science or bureaucratic politics and policies.
TENTATIVE CONCLUSION From
the vantage point of the
Forty-Seventh Annual
Scientific Meeting of the CPDD last week in Baltimore, I observe that the connection between current scientific research on abuse potential testing of drugs and the federal bureaucratic process for scheduling drugs is tenuous at best.
Anecdotes from the
Annual Meeting also lend support to this preliminary conclusion: o
One
conferee
noted
that
the
Drug
Enforcement
Administration (DEA) had just initiated emergency scheduling for the drug MDMA, called "Ecstasy" on the street, even though very little is known about the drug scientifically.
-
He hypothsized
that DEA pre-emptively scheduled the drug in the face of public pressures and that the research may follow. o
A second conferee noted the scheduling process, after
all, is "highly political" in nature.
He quipped that drugs only
get scheduled if and when "a pharmaceutical company wants to market a drug in a big way" or if the "son or daughter of a Representative in Congress gets hurt or hooked."
At the least,
this comment shows the distance and misperception between the researcher and the official process. Al-6
Pending the completion of interviews with federal officials directly involved in inter-agency task forces and committees that do the scheduling itself, I tentatively conclude that there is no bi-directional link between research and regulation.
Al-7
APPENDIX 2
2 September 1985
MEMORANDUM
TO:
NIDA Project Group
FROM:
David E. Burmaster, Ph.D.
SUBJECT:
Report on Visit to the Medical College of Virginia to interview Doctors Louis S. Harris, M.D. Aceto, and Robert L. Balster
I traveled to Richmond, Virginia on Thursday, 29 August 1985 to interview Doctors Louis S. Harris, M.D. Aceto, and Robert L. Balster in the Department of Pharmacology and Toxicology, Medical College of Virginia (MCV), Virginia Commonwealth University.
Dr.
Harris met me at the airport and we spent approximately 7 hours together going over background material for our summer proj ect for Dr. Jerome Jaffe and NIDA.
BACKGROUND ON THE MEDICAL COLLEGE OF VIRGINIA The Department of Pharmacology and Toxicology is a large operation. members;
It has a staff of approximately 26 full-time faculty 15 jointly appointed faculty members (including local
physicians, researchers from federal agencies with offices in A2-1
Washington,
and
research
staff
from
the
A.H.
Robins
Pharmaceutical Company); 15 adjunct faculty members; and 25 postdoctoral fellows.
This staff teaches and does research,
typically with a 40-60 percent split across the department: o
Overall, the Department's budget is approximately $5 to
$6 million per year. o
The Department of Pharmacology and Toxicology has 4
Divisions:
Central Nervous Systems (with perhaps 0.5 of all
funding), Toxicology (with perhaps 0.25 of all funding), Cellular Pharmacology (with perhaps 0.125 of all funding),
and Biochemical
Pharmacology with perhaps 0.125 of all funding). o
On the teaching side, the departmental staff is part of
the overall MCV faculty which overall admits 170 medical students per year, 100 dental students per year, >100 pharmacy students per year, 100 nursing students per year, 75 allied students per year,
and 5-10 Ph.D. candidates per year. o
On the research side, the department raises over $3.0
million per year in research grants and contracts and perhaps S350K per year in training grants, largely (perhaps 75 percent) from federal agencies in descending order:
A2-2
ADAMHA (read, NIDA) > NIH> DOD (unclassified) > EPA> NSF In the past, FDA supplied research funds for some projects.
DEA
has not supplied research funds for this group for at least 10 years, if ever. o
Industrial companies provide some $200K per year in
support of basic research contracts and/or grants for postdoctoral fellows and visiting professors.
Industrial companies
provide no direct support in any form for drug abuse liability testing, but they may indirectly contribute funds donated to the CPDD (next). o
The nonprofit Committee on the Problems of Drug
Dependence (CPDD) gives a grant of approximately $20K to the department each year for drug abuse liability testing on opiate agonists and antagonists.
This does not cover all the costs of
the testing program, especially for other classes of drugs.
In
addition, the Department has a one-time research contract for $17K funded by the CPDD for work on a special topic (the pharmacological profile and physical dependence potential of stimulants and depressants). o
MCV does only animal tests.
Johns Hopkins,
(Professor Joseph Brady at
Professor Schuster at the Unviersity of Chicago,
and researchers at the Addiction Research Center in Baltimore do most of the clinical testing of drugs.) A2-3
BACKGROUND ON THE CPDD Because the Executive Secretary of the CPDD (Dr.
Joseph
Cochin of the Boston University's Medical Shcool) is ill and will not soon return to active duty,
Dr.
Harris gave us some
background on the current operation of the organization. Approximately 35 ethical drug companies contribute a total of approximately $200K per year to the CPDD with no strings attached; CPDD receives no direct federal funds at this time. a typical year,
In
$lOOK goes to the support of the annual meeting,
equal amounts of about $20K go to the MCV and the sibling program at the University of Michigan,
and the balance goes to
operations, special projects, and the endowment. NIDA indirectly subsidizes the CPDD's operation by publishing the proceedings of
-
the Annual Meeting (>400 pages thick) each year.
BACKGROUND ON TESTING AND UNIT COSTS Dr. Harris had no specific numbers on the unit costs of testing drugs in their laboratories.
At the crudest level of
estimation, MCV tests perhaps 50 new compounds each year for dependency in morphine-addicted rhesus estimated cost of $325K per year.
monkeys
at
a
total
These numbers fluctuate from
year to year, but simple division yields an approximate cost of $7K per drug on average.
In conversation,
A2-4
Dr. Harris later
estimated the costs at $6K to $10K per drug for simple dependency (i.e.,
single dose suppresion (SDS),
withdrawal (PPTW»
and or precipitated
testing with rhesus monkeys.
Dr. Harris also
estimated that it may cost an additional $25K to $35K per drug for a full battery of tests for dependency, primary
physical
that is,
dependence, discrimination,
and
adding self-
administration in one common species (the rhesus monkey again). The MeV maintains monkey, rat, and mouse colonies for use in more elaborate tests. The Mev and the Michigan programs receive all of the drugs for dependency testing from Dr. Arthur Jacobson at the NIH in Washington.
The drugs come in small vials, coded by a serial
number to make the experiments doubleblind.
Dr.
Jacobson sends
duplicate vials of some of the drugs to the Mev and Michigan programs as a quality control check. Dr. Harris asserts that the 60 to 70 percent of the drugs received and distributed by Dr. Jacobson originate from academic and government laboratories, companies.
with the balance from ethical drug
Dr. Harris says that researchers at the academic and
government laboratories have no other way to have tests performed on their new syntheses but that private companies do considerable amount of their own testing in-house.
a
Dr. Harris
further states that the large majority of the drugs tested
A2-5
represent "triumphs of a synthesis" (my phrase), i.e., unique drugs, not for commercialization. In approximate sequence, a new drug is tested for these properties in this order: o
mouse hot plate, tail flick, (mouse analgesia),
PPQ abdominal stretching
o
narcotic antagonist (mouse tail flick vs. morphine),
o
monkey single dose suppression test,
o
monkey precipitated abstinence test,
o
rat substitution or precipitation test (ip),
o
primary physical dependence test (naive animals), and
o
self-administration test on one of several species.
All drugs are tested for their analgesic and/or antagonist activity.
Only some drugs make it past the first one or two
tests, and a small fraction make it to the self-administration tests.
-
Dr. Harris says that the MCV works only with pure samples of single compounds.
He denied interest in testing (i) mixtures of
drugs or (ii) street drugs containing (unknown) contaminants on various grounds.
Concerning mixtures,
he made a scientific
argument: researchers must study the effects of pure compounds to learn their true properties.
Concerning street drugs with
contaminants, he made a practical argument: researchers cannot A2-6
possibly study all of the possible contaminants in all of the possible relative concentrations.
BACKGROUND ON NEW TESTING METHODS Dr. Harris said indirectly that he thinks it will take many years before new techniques become practically important in drug design and/or abuse potential testing.
Concerning computer
modeling of molecular shapes as a branch of structure-activity research, he suggests that one really needs to know the shape of the
receptor
before
this
will
yield practical
results.
Concerning electrical signal processing of EEG traces, he says that the techniques are more expensive that behavioral tests on animals and that they yield no better evidence of changes in the animal. on new
Further, he argues that by repeating standard protocols drugs,
databases,
researchers add information to standardized
thereby facilitating comparisons across time and
between laboratories.
As a practical matter, the MCV has no
people investigating either computer modeling or electrical signal processing.
A2-7
COMMENTS ON INTER-AGENCY RESEARCH Dr. Harris believes that NIDA is the proper lead agency for drug abuse 1iab1i ty testing and that
FDA and DEA now have
appropriate inputs to the process.
COMMENTS ON ROLES AND RELATIONSHIPS Dr. Harris commented on the Addiction Research Center.
As
that organization becomes the Intramural Research Program of NIDA, Dr. Harris suggests that a blue-ribbon commi ttee ought to advise NIDA to map the future role of the laboratory.
Dr. Harris
reports that some people in the field think that the reorganized facility should focus on basic animal and clinical research in the future -- thereby diminishing its role in applied research. Dr. Harris did not reveal his personal preference on this issue, but he believes that this is a fundamental question. COMMENTS ON THE RELATIONSHIP BETWEEN SCIENCE AND REGULATION When asked about the controversy about MDMA,
Dr. Harris
commented negatively on the new legislative amendments giving DEA the power to schedule drugs on an emergency basis.
He feels that
the legislation is ill advised because -- in the extreme -- it allows DEA to make regulations without any scientific data support the decision.
A2-8
to
OVERALL COMMENTS BY DEB
Overall, I had a delightful visit with Dr. Harris and his colleagues.
At the end of our conversation and after he neatly
fielded some tough questions,
I came home with this overall
impression: "If it ain't broke, don' fix it."
A2-9
APPENDIX 3 4 September 1985 MEMORANDUM TO:
NIDA Project Group
FROM:
Chris Putala
SUBJECT:
Report on visit to the University of Michigan to interview Dr. James Woods and his colleagues
On Thursday, 29 August 1985 I met with Dr. Woods and his colleagues at the Department of Pharmacology of the Medical School at the University of Michigan.
I spent about 5 hours at
the University going over their participation in the drug
--
scheduling process for our summer project for NIDA. OVERVIEW The five researchers responsible for drug abuse liability research form a loosely organized team. This team makes up less than one-half of the full-time, Department of
professional staff at the
Pharmacology of the
University of
Michigan.
Research associated with drug scheduling decisions is some of the research done by each of the members.
Drugs routed from CPDD do
not go through a standardized testing process: they pass through four types of tests and each of the researchers may divert any drug to specialized tests at their own discretion.
A3-l
'-
STAFF Four Ph.Ds/MDs are supervised by Dr. James Woods.
All five
are specialists in biochemistry, pharmacology, and behavioral psychology.
Each of the four researchers has no more than two
full-time lab technicians.
They, and Dr. Woods, are employed by
the Department of Pharmacology of the University of Michigan
-
School of Medicine.
Two have teaching duties in the Department.
The entire Department of Pharmacology consists of about a dozen professors.
BUDGET Dr. Woods estimated the 1984 budget of the abuse liability potential testing program at approximately $355,000.:
* * *
$200,000. for primate research; $65,000. for in vivo research ($35,000. for smooth muscle testing-an~$30,000. for binding tests); and $90,000. for administrative costs.
CPDD supplied only $18,000. to the annual budget in 1984. The remaining $337,000. came from various government agencies, chiefly, NIDA and NIH. About 45 drugs are processed at the University of Michigan each year.
By simple division I estimate that it costs the abuse
liablility testing program about $7,800. per drug for the entire
A3-2
series of tests to be conducted, analyzed, and reported:
* * * *
Primate research averages about $4,500. per drug; Binding assays cost about $700 per drug; and Smooth muscle tests cost about $800 per drug. Admistrative tests cost make up the remainder.
These are only proxy measures, for there is no set number or type of testing for any drug.
Each researcher stressed the
freedom they had to conduct different experiments if their interest was piqued by the results of another. Moreover, these figures do not account for all the money, from other grants and from the University of Michigan, raised for drug research carried out by this team.
Equipment purchased for
(and by) projects other than abuse liability potential testing is often used to collect drug abuse liability data. laboratory space
are
other expenses
Office and
defrayed by the other
supporters of Dr. Woods and his colleagues.
In some instances,
such as when results of a test for drug abuse potential are particularly interesting to a researcher, money from the other sources might pay for some of the additional research necessary to study the drug.
A3-3
SOURCES OF DRUGS Dr. Arthur Jacobson, under the CPDD umbrella, coordinates the flow of drugs from (in approximately equal proportions): government agencies and laboratories;
-
pharmaceutical companies;
and academic and medical chemists from the U.S. and around the world -- over 100 labs rely on the facilities at the University of Michigan. PROCEDURE Each drug, accompanied by some basic information such as solubility data, is received by Dr. Woods. in turn, to each researcher.
The drug is assigned,
They will run their own specialized
analysis: dependency tests; self-administration tests; binding
-
assays; or smooth muscle tests. Dr. Woods monitors the results as they filter back to him (largely through informal channels) from his colleagues.
He
is
often called on to make suggestions for further research or to shed light on substances which defy analysis.
-~
When tests are
completed, Dr. Woods collects and reports the results through Dr. Jacobson.
Dr. Woods stresses that the report is just that: he
classifies
the
drug
as
to
its
effects
in
relation
to
pharmacological standards, he does not suggest any particular schedule.
The pharmacists and chemists at DEA, at other labs, or
at private companies are responsible, "bottom line" on any drug.
A3-4
according to him,
for the
Reports on each compound are used by the FDA, DEA, and WHO. The Food, Drug and Cosmetics Act mandates that abuse potential data be collected by the FDA.
The DEA is similarly instructed by
the Controlled Substances Act. Woods,
Information collected by Dr.
et. ale must be provided to the WHO since the United
States is Signatory to the Convention in Psychotropic Substances.
POSSIBLE VARIATIONS If the results of the four types of tests do not confirm each other, a second series of tests will be conducted in an attempt to find the common thread. Anytime the results of a test are interesting to anyone of the four researchers (or to Dr. Woods), the drug will be diverted to other tests.
[This freedom to do basic research is the most
often cited positive characteristic of the testing program.] If a drug is found to have particularly interesting characteristics,
test results may be published by these
researchers immediately.
Dr. Woods cited the example of a drug
which mimicked morphine withdrawal synthesized by the HoffmanLaRoche Company.
Through Dr.
Jacobson,
Hoffman-LaRoche was
contacted and they permitted the immediate publication of the resu1ts.
[Of course,
such a drug wou1d have no commercia1
appeal.]
A3-5
TYPES OF TESTS Drug Dependence
*
Between 20 and 30 morphine dependent rhesus monkeys and 15 to 20 non-dependent rhesus monkeys are used in this research at one time.
*
A single rhesus monkey costs between $1,000 and $1,200, some have been at the lab for more than a decade.
*
No animals other than rhesus monkeys are used in this, or any other research for abuse liability testing research. Humans are not used as research subjects.
*
Most of the research involves the injection of drugs into monkeys and observing the results, a basic and time-honored technique.
Self-Administration
*
Approximately 15 rhesus monkeys are attached to I.V. tubes and a computor monitors the regular injections of codeine the monkeys receive. At every fourth injection, the codeine is replaced by drug "X". Positive reinforcing effects are always tested, sometimes negative effects are as well.
*
Drug-discrimination tests are also performed by Dr. Gail Winger and her single full-time lab tech.
*
One behavioral psychologist reported that currently available EEG (computer modeling) technology is not as informative as behavioral analysis with monkeys.
[Primate research received about $200,000. of the drug abuse liability test budget of $355,000. in 1984.
Perhaps because the
other two researchers receive a lot more money from other sources -- which is probably due to the fact that the "hot science" in the field of pharmacology is in the opiate, receptor research conducted by Drs. Smith and Medzihradsky.]
A3-6
Binding Tests
*
Comparatively little of Dr. Medzihradsky's research budget comes from the drug abuse liability testing program, in 1984 he received about $30,000. In his own words, he is "sufficiently funded".
*
Dr. M. has teaching duties for the Departments of Biochemistry and Pharmacology. His research is supported not only by the University of Michigan, but by a variety of other grants from the federal government.
*
He has one and one-half full-time lab techs. His lab will soon be able to assay three compounds in a single day, each compound is assayed in at least three different ways. Dr. M. commented that his work was sometimes slowed down by incomplete initial data (such as solubility data) from the suppliers. Dr. M. had no idea, indeed no interest, in whether or not any particular sources (drug companies, government labs, etc ••• ) were consistently lax in their preliminary information.
*
Dr. M. uses rat brain membrains for his tests. So, the fixed costs of his supplies, technical labor, and equipment are the major expenditures, performing the tests is relatively inexpensive.
Smooth Muscle Tests
-
*
Dr. Smith's 1984 budget from the abuse liability testing program was about $35,000. Like Dr. Medzihradsky, he has teaching duties for the Department of Pharmacology and most of his funding comes from other grants and from the University of Michigan. [He informed me that he was in the final stages of securing a $165,000. grant, which would be one of a small number of similarly sized grants he is likely to have over the next few years.]
*
Dr. Smith was very proud of the cost-effectiveness of his research -- as compared to the cost of studying monkeys. Of course, he could not deny that the equipment he needed to study rodent ileum or vas deferens was significantly more expensive than that used for primate research. So, it appears that the fixed costs are significant, but using the equipment is not especially costly. A3-7
*
Dr. Smith does smooth muscle testing on compounds for MCV that have been used in in vivo assays at MCV.
IMPRESSIONS AND ANALYSIS Since the researchers at the University of Michigan have a great deal of freedom built into their experimental process, they feel that they are uniquely qualified to do research which, though it has implications to the drug scheduling process, is really basic research to develop an analgesic with no abuse potential. More than 100 laboratories from around the world use the research capabilities of this team.
These researchers are
completely familiar (MeV probably has similar expertise) with these tests and with the drugs. In fact, Dr. Smith reported that he was experienced enough to accurately predict what tests and techniques would be the most informative after examination of the structure of a drug.
an initial
They believe [and I have
no reason to doubt] that they can perform the tests more efficiently and effectively than anyone else.
They were quick to
point out that the specialized equipment and techniques required for many of the experiments need not be bought or learned by other laboratories (many of which use government funds). [Although, most of the equipment I saw seemed to be the equipment used for a variety of purposes -- freezers,
A3-8
microscopes,
etc .•.. ]
Dr. Woods noted that while the Controlled Substances Act mandates that data be
collected about
the
abuse
liability
potential of a drug before a final scheduling decision is made, the information need not be used in the scheduling decision to satisfy the conditions of the Act.
The DEA has improved its use
of this information since the early 1970s, according to the older researchers,
however.
Dr. Woods was not particularly concerned
about the lack of attention paid to their research in some drug scheduling decisions,
he sees himself and his colleagues as
scientists whose responsibility ends after they have reported their findings.
In fact, he expressed concern that a mandated
role in the scheduling process could constrict the freedom he values so highly if it allowed bureaucrats to define the testing process.
So, the researchers were unanimous in their belief that
more science belonged in the scheduling process, but they were wary of bureaucratic regulations which would reduce the program's flexibility, hindering opportunities for basic pharmacological research. Each of the researchers felt that the laboratories run by pharmaceutical companies were under too many organizational constraints,
and,
consequently,
were unable to do a significant
portion of the basic research so often encouraged in the testing process.
Dr.
Smith recounted more than a
A3-9
few cases where
pharmaceutical companies had simply missed some interesting results in their smooth muscle tests, presumably because they did not have the time, money, or interest to study the drug to the
-
extent he had. Dr.
Woods thinks that the biggest problem with the drug
testing process is the lack of clinical testing (tests using human rather than animal subjects).
He criticized the CPDD and
ARC for their failure
the research (using drug
to replace
addicted federal prison inmates) conducted in Lexington, Kentucky until the mid-1970s. NIDA funding.
He thought that the program would need
He praised DAWN, but since it is not a predictive
force it is not a sufficient replacement. The CPDD is not a large contributor to their budget ($18,000. of $355,000. in 1984).
But, Dr. Woods reported that
they were an important asset, by virtue of the real and perceived impartiality gained by having the CPDD distribute drug samples.
A3-10
Conclusion The biggest mistake in drug liability abuse testing would be to limit the tests which could be performed by research teams to the minimum necessary to make a reasonable drug scheduling decision,
the great utility of these
pharmacology, to medicine, and to science. $350,000. per year.
-
A3-11
researchers is to And all for less than
APPENDIX 4 11 September 1985
TO:
NIDA Project Group
FROM:
David C. Hsia, M.D.
RE:
Site visit to Dr. Joseph V. Brady, Johns Hopkins School of Medicine, Baltimore, MD 20215 (201-955-3135). On September 10,
1985,
I spent approximately two hours
interviewing Professor Brady, Ph.D. and touring his laboratory. He supplied me with copies of his recent letter to Dr. Cooper enumerating his cost breakdowns and of his "Testing Drugs for Physical Dependence Potential and Abuse Liability."
The latter
contains excellent descriptions and citations of both CPDD and available laboratory tests. BACKGROUND
Dr.
Brady's drug abuse screening facilities consist
primarily of his Primate Facility (or Baboon Laboratory).
The
division of behavioral biology of which Dr. Brady is director also undertakes some small mammal experiments at Johns Hopkins, and conducts research in human residential facilities at John Hopkins Hospital and Francis Scott Key Medical Center.
These
additional research programs involve both basic and applied behavioral pharmacology including codeine and marijuana studies as
well
as
some
treatment
oriented
research
pharmacotherapy of drug and alcohol dependence.
A4-l
on
the
They operate on
funding unrelated to the Primate Facility.
Dr. Brady started his drug studies using baboons in the 1960's at Walter Reed.
He subsequently took all the baboons with
him first to the University of Maryland and then to JH.
The
baboons have worked on different facets of addiction research for decades.
He notes that some of the baboons have been on the
university payroll longer than the average tenured professor.
The old Bureau of Narcotics and Dangerous Drugs in the Treasury Department initiated support of the Primate Facility's abuse screening.
When drug enforcement was reorganized, DEA took
over supporting the work and selecting the compounds for investigation.
When NIDA came into being, it took over the drug
assesment function and supported the lab with a series of three year contracts.
Dr.
Brady was very concerned about NIDA's
current desire to shift from contract to grant support.
He notes
that drug evaluation studies do not fit into a grant style process that emphsizes basic research.
He discussed the
possibility of approaching DEA about reassuring support of the program. STAFF
The Primate Facility employs 5-6 professionals (2 associate professors, 2 assistant professors, 1-2 instructors, graduate fellows and graduate assitants)
and several
and veterinary
technicians and other support personnel totalling 12 to 15 full
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and part-time employees. university funds in part,
JH supports Professor Brady from despite his devoting the majority of
his time to running the primate laboratory.
Dr. Brady indicated
he would very shortly have to commence layoffs since the funding of his current NIDA contract expires this coming January and getting a grant will take 6-12 months, if approved.
The facility also "employs" 40-50 baboons. These live in large,
mobile cages distributed among six observation rooms
depending upon their current experimental protocols.
Their
quarters appear to be clean, well lit, ventilated, temperature controlled, standards.
and otherwise meet current day primate research The facility had little animal odor.
The baboons all
know to test any new levers in their cages to see what food or drugs they dispense.
The technicians fit them with intravenous
or intragastric cannulas as needed for drug administration. Recently,
some baboons learned to take drugs orally,
much
accelerating the protocols and simplifying their care.
Dr.
Brady reports baboon preferences to have a very high predictive value for human abuse potential,
particularly compared to small
mammal testing.
BUDGET The Primate Facility receives approximately $300,000. in direct costs anually from NIDA.
The Primate Drug Abuse Testing
Faci Ii ty receives no support other than its NIDA contract (that terminates in three months).
It has no NIDA or other grants.
It
receives no CPDD support, but Dr. Brady has been the Chairman of A4-3
CPDD. The letter to Dr. Cooper provides a unit breakdown of costs. However, Dr. Brady points out that the Primate Facility has to be purchased as a package to some extent.
The cost of testing the
first drug is very high, but the cost of remeshing groups of drugs are proportionately reduced.
The facility tests fewer
compounds per year than the two small mammal laboratories because baboon tests take more time and produce more sophisticated information, despite screens involving as few as four animals. For example,
the Facility tested 14 anorexics (basically all
amphetamine derivatives) for abuse potential and found a rank order and order of magnitude difference in baboon preference.
Dr. Brady discourages direct pharmaceutical company support for a different reason. modest level.
His lab needs constant support at a
NDA testing occurs episodically and his baboons
have to eat in the interim.
He is also concerned about
pharmaceutical houses setting up their own internal addiction laboratories.
He believes that an FDA abuse testing requirement
would eventually result in the industry setting "standards" that company laboratories would just barely meet. RESEARCH
The Primate Facility processes 10-12 compounds per year. Some have passed the University of Michigan/Medical College of Virginia small mammal screening (substances from government
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compound synthesis laboratories and some IND/NDAs) and some are selected
by
NIDA
for
study
(MDMA,
cocaine,
marijuana,
occasionally a commercial drug already on the market). usually does not receive totally blind compounds.
The lab
Knowing the
compound to be studied does not preclude double blind experiments.
The research involves all the usual variations on operant conditioning.
NIDA Research Monograph 52: Testing Drugs for
Physical Dependence Potential and Abuse Liability fully describes the options and gives citations.
1. Self administration: pushing a lever to get a drug dose.
The number of pushes per dose increases to see how hard the animal will work to get it.
2. Comparison: giving the animal two levers to push for different drugs (e.g. cocaine v. morphine) prefers.
See which one it
Reverse the levers occasionally and see how fast the
animal reverses its choice.
3. Drug discrimination: baboons excellent.
Could this be a
function of their long training, so that naive humans would do worse?)
4. Psychophysics: studying what price the baboons pay for drug use.
The animals learn to press a lever in response to a
light or sound cue. incl ude
Important measures of physical damage
their reaction time A4-5
(motor)
and abil i ty to detect
decreasing amounts of light and sound (sensory).
After
establishing a baseline, the animal can demonstrate motor v. sensory deterioration on the drug or after accumulating damage from repeated drug administration.
Interestingly, these tests
can quantitate the effects of hallucinogens (exclusively sensory) and
barbituates
(largely motor).
Cocaine
shows
little
psychophysical effect over the short run.
The Facility cannot readily increase the size of its effort to accommodate a larger flow of compounds.
University floorspace
and shortage of technical personnel would form the principal limitations.
Training more baboons would not constitute a
bottleneck (cocaine as a motivator).
Dr. Brady feels he could
handle a maximum of 30 compounds annually.
However, contracts
running longer than three years would help a lot.
POSSIBLE IMPROVEMENTS Dr. Brady noted three methodological problems in the present structure of the addiction research field. 1. Validity: relating laboratory results to the real world
of human addicts. mammal studies.
Baboon studes predict much better than small Resurrecting the Lexington prison program of
human screening and experimentation would produce the highest validity, but costs far more than current efforts.
2. Reliability: by screening the same compound, Michigan and Virginia act as quality controls on each other.
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No parallel
checks exist for primate research.
Establishing a second primate
facility at a second university would soon increase screening capacity and reproducibility of results by overlapping a quarter of the compounds.
3. Selection of test procedures: at present, deciding what tests to do on a blind compound after initial screening involves a degree of educated guesswork. and fast.
The sequence has not become hard
Addiction researchers need to undertake
investigation of controls and standards.
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further
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