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Appendix D
Survey of Pharmaceutical Companies
To aid the committee in assessing the incentives and disincentives to the
pharmaceutical industry's investment in research and development in the field of
anti-addiction medications, a questionnaire was sent by the Pharmaceutical
Manufacturers Association, the Generic Pharmaceutical Industry Association, and
the Biotechnology Industry Organization to their members currently involved
with central nervous system medications. The questionnaire was developed by the
committee and IOM staff in conjunction with the industry organizations.
Responses were blinded and the committee did not have information on the
company or the job title of the survey respondent. A total of 19 responses were
received, and the responses were viewed by the committee as indicative but not
definitive.
Figure D.1 indicates how respondents rated the uncertainty or risk involved
in R&D issues in the field of drug addiction as compared with the fields of
cancer, AIDS, and cardiovascular disease. Clearly, these results are not a
quantitative assessment of the industry, but the drug-addiction field is perceived
to be high risk in all areas except for likelihood of competitive advantage over
other treatments and likelihood of fast track FDA review. The committee used
the survey solely as a point of reference and a starting point for committee and
individual discussions with representatives of the pharmaceutical industry.
215
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216
DEVELOPMENT OF MEDICATIONS
Questionnaire on Factors Influencing Pharmaceutical Companies'
Investment in R&D in Medications for Treating Illicit Drug Abuse
The names of individual respondents or their f rms will not be given to the IOM
Committee or be included in the Committee's report.
(Responses are tabulated or are in bold type)
1. Has your company ever had a drug discovery pro gram in any of the following
areas?
a. cocaine/crack addiction Yes 3 No 16
b. heroin dependence Yes 4 No 15
c. alcoholism Yes 5 No 13
d. nicotine addiction Yes 3 No 14
2. Has your company ever had a drug development or in-licensina effort in any
of the following areas?
a. cocaine/crack addiction Yes 3 No 14
b. heroin dependence Yes 3 No 13
c. alcoholism Yes 6 No 11
d. nicotine addiction Yes 6 No 11
3. If your company has never had a drug discovery or drug
development/in-licensing program in one or more of these areas, please indicate
the area and the major reasoners) for this decision.
a. role of the potential market 6
b. federal regulations 2
c. state, local or community barriers 1
d. difficulty in conducting clinical trials 4
other reasons (please state/explain)
· Beyond current focus on neurological disorders
· Drug discovery (and development) is not defined in the current
mission of our business
Other project opportunities/priorities and resources
Not in area of expertise/experience
Lack of preclinical leads
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APPENDIX D
217
· Concern that use of a drug for "abuse" treatment might tarnish
its image for other uses
· Outside our area of expertise
· Indicationts) lay outside our areas of strategic interest.
4(a). If your company once had a drug discovery or drug
development/in-licensing program in one or more of these areas but no longer
does, please indicate the area and state the major reasoners) for dropping the
program.
.
Alcoholism program dropped due to market potential
High recidivism
Community concept that drugs shouldn't be used to cure an
addiction
· Nicotine addiction-loss of commercial interest due to
unfavorable marketing experience with other products (nicotine
transdermal patches)
.
No further leads at this time, would review alcohol or nicotine
programs for any leads.
(b). What incentives (including legislative proposals) would be necessary for your
company to renew its effort in those areas (please state area)?
R&D tax credits
· Guaranteed market exclusivity for ten years or more
· Availability of government sponsored patents on an exclusive
basis
· Guaranteed pricing freedom to achieve high margins to enable
re-investment in R&D, educational programs, and broad marketing
None, no commercial interest
Sponsor preclinical support
Reclassification of many schedule I drugs to schedule II
Indemnification for usage in subject populations
5. If your company has a drug discovery or drug development/in-licensing
program for medications to treat drug abuse please state the positive incentives
that attracted you to this field. (NOTE: We are referring primarily to medications
to treat cocaine and opiate addictions).
.
Drug being evaluated has potential for analgesia. This is our
primary commercial interest
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DEVELOPMENT OF MEDICATIONS
.
Urgency of medical need rapid approvability and demand for
effective therapy
· Our drug discovery program, re: cocaine abuse, involves
interaction with MDD-NIDA, and NIH to search our existing compound
file for potentially useful compounds. Incentive was statement by
Senator Biden to Mr. George Sella (then PMA chairman). Our only
current incentive is scientific interest, and good relations.
· We decided to invest $10M or so in alcohol and nicotine due to
good lead and its public health importance-program does work for both.
· Large patient population, public good.
· Large unmet medical need.
· Significant experience in treating nicotine addiction shows that
programs can be commercially viable.
6. Are you aware of NIDA's Medications Development Division (MDD)?
yesl4 no5
7. Are you aware of NIDA's preclinical screening program?
yes 12 no 4 vaguely 1
8. What is your perspective on the role of NIDA's MDD?
· MDD has expressed considerable interest, is in position to
provide considerable support for our project.
· No major accomplishments to date
· Could be very useful.
It is viewed as a major deterrent to discovery/development
efforts by companies like ours, because of 1) likelihood of government
involvement in pricing, 2) concerns re: government being involved in the
"go/no go" development decision-making and 3) involvement of taxpayer
dollars.
.
Excellent approach to this problem. Highly productive.
To evaluate potential drugs, particularly those well along in
development, for use in the treatment of cocaine addiction (antagonists
to cocaine, or drugs as adjuncts to psychotherapy).
· NIDA's investment is helpful to industry to explore uses of
drugs already in development as well as assist in exploration of early
leads from related research programs in industry.
· Very useful, underutilized.
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APPENDIX D
219
· Generally involve CRADAs with "fair pricing" provisions and
thus not usable.
Already working with NIDA in a constructive collaboration.
Waste of time. They are not effective. PMA companies could do
a better job if there were an incentive.
9. Please add any additional comments that you feel would assist the Institute of
Medicine's Committee on Medications Development and Research at the National
Institute on Drug Abuse to better understand the incentives and disincentives for
private sector R&D involvement in producing medications to treat illicit drug
abuse (particularly cocaine and opiate addictions).
· Development of medications to treat drug abuse is perceived to
be of low commercial value. Therefore, direct financial support or co-
development is essential to provide sufficient incentive.
· Speaking as a member of a firm not involved in any programs,
but strictly as an outside observer, disincentives are enormous when the
proposed new compound becomes entrapped in DEA's scheduling
system. These barriers should be changed.
efforts.
.
Increase transparency.
Offer consultative support to ongoing industrial research
We have concerns about handing over control of the product
development decision making to NIDA along with the official in-
volvement of pricing, plus the likelihood of "unofficial" pressures to
continue development even if the sponsor wished to discontinue. The
involvement of tax dollars in "for-profit" drug development projects by
pharmaceutical companies is also viewed as risky in today's political
climate.
· Adequate patent protection is essential.
· Avoidance of accusations of collusion with a government agency.
· Recognition of altruism in cooperative ventures.
· Have FDA run DEA.
· Change many Schedule I drugs to Schedule II.
· Eliminate "fair pricing" clause from HHS CRADAs.
· The primary disincentive is that your medication (the
company's) is the only one with a traceable history. The subjects treated
not only may have concomitant ethical pharmaceuticals, but also drugs
of questionable origin and purity. Drug/drug interactions, unexpected
adverse interactions due to prior history of usage leave only the
company vulnerable to litigation.
10. Please fill out Attachments 1 and 2.
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DEVELOPMENT OF MEDICATIONS
Attachment 1
The intent of this exercise is to gain information on how pharmaceutical
companies view the drug abuse area in relation to other project areas, with
respect to certain factors commonly used to judge R&D priorities. (NOTE: By
"drug abuse area" we mean illicit drug use, primarily in the form of opiate and
cocaine addictions, we do not mean use of alcohol, nicotine, or abuse of
prescription drugs.)
Please put a number from 1 to 5 in each blank, based on the scale below.
High uncertainty
or risk
Average uncertain
or risk
Cancer Drug Abuse AIDS
Low uncertainty
or risk
Cardiovascular
These four disease categories were repeated in the survey for each of the
following 12 areas. The responses are displayed in Figure D.1.
Sufficient scientific knowledge of disease to begin a drug discovery/drug
development program
Availability of screening techniques and animal models
Clear efficacy endpoints for ethical studies
Availability of qualified clinical investigators
Likelihood of fast track review or special handling by FDA
6. Patentability of product
7. Product liability risk
8. Sufficient market size
9. Likelihood of competitive advantage over other treatments
10. Adequate price and reliable reimbursement
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APPENDIX D
11 . Sufficient prod
221
ected return on investment
12. Good public image; intangible benefits to company or other company
products.
High 5
4
In
- 3
lo
~ 2
Law
High 5
4
3
1
o
- ._
_
_
_
_
_1 1
1 - 8111 1
_1 1
LOW _
Liability At ~Competi6 - Reimh~t Invoke ~ht~
O _
C ~_ -
_-
1
1 ~_
l ~_
l I~Im ~
~1
_~1
4@~
-
Scieno ~Screening Endpo nts Personnel FOA re~new P~entab~
1
1 1~
1 ~
_
_
(Ca~ ~ Den Ah - e O AIDS g' Cation
i
Figure D. 1 Survey results. Issues involved in R&D were ranked for four diseases: cancer,
drug addiction, AIDS, and cardiovascular disease (see Attachment 1 of the survey).
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222
DEVELOPMENT OF MEDICATIONS
Attachment 2
POLICY SUGGESTIONS
For each box in Attachment 1 in which you put a 1 or 2 for Drug Abuse, i.e.,
for each factor for which you think the Drug Abuse area is handicapped by
higher-tharl-average uncertainty or risk, please state briefly what you would
recommend to improve the situation. Suggestions should be one-liners (e.g.,
"amend the Orphan Drug Act to include all drugs intended for drug abuse",
"increase the basic science budget at NIDA by $50 million per year," "change
regulations requiring . . .", etc.~.
The intent is not to get fully evaluated policy recommendations that are fonnally
approved by your company but rather to get your personal ideas for further
consideration. Please treat this as a "brainstorming by mail" or a "public policy
suggestion box". No individual attributions will be seven to the IOM Committee
on Medications Development and Research at NIDA.
1. Basic scientific knowledge
· More emphasis on underlying biochemical mechanisms needed.
· Not a high profile research area, nor widely viewed as
attractive.
· Improve quality and focus of ongoing research, especially in
molecular biology of addictive process.
· What is molecular basis of addiction.
· Why will addicts relapse on drug therapy.
· Fund special NIDA extramural research efforts via executive
branch edict or legislation.
· Need further mechanistic work, availability of modern day
screens, etc.
Inter-company interaction should be encouraged.
Increase NIDA budget.
Increase NIH support of this domain of research.
Increase NIDA budget.
Fund biotech startups.
2. Screening techniques and animal models
· Technically demanding and applicability to humans not certain.
· Do not over-rely on these; expedite pathway to clinic with good
hypotheses.
Good models are lacking.
Fund special NIDA extramural research efforts.
Increase NIDA budget.
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APPENDIX D
3. Efficacy endpoints
223
More money to MDD-NIDA, the process is now painfully slow.
Primates too expensive-develop in vitro screens?
Start search for susceptibility genes.
Develop transgenic animals with increased "abuse liability."
· Since there are both psychological as well as physiological
dependencies at work, a clear endpoint especially on the psychological
aspects would- be difficult.
· Clear FDA guidelines would help.
· Do not ask drug to do everything- acute drug effects in many
cases will be combined with long term counselling to keep patient clean.
· Develop NIDA/FDA/industry consensus guidelines for study
requirements and officially-recognized endpoints.
Movement to clinical trials should be accelerated.
Very difficult to improve.
No clear standards except very expensive followup surrogates.
Need more validation of surrogate endpoints.
4. Availability of qualified clinical investigators
· The field is not one to attract the best medical school faculty.
· A general problem in psychotherapeutics-particularly acute
drug dependence. Need more physicians; scientists.
· Consider an investigative network similar to the ACTG
mechanism for anti-HIV treatments.
.
5. FDA review
.
Training and research support need improvement.
Not certain of FDA's view of this area.
· An FDA fast track is based on disease slate vs. availability of
existing treatments. This in my opinion, would not warrant FDA's
highest attention (over drugs in categories of AIDS or cancer
treatment).
· Expedite.
· Declare substance-abuse drugs and biologicals "AA" priority,
like AIDS drugs.
· Safety should be the major criterion, with efficacy being a
clinical finding; e.g. more flexibility in evaluating animal pharmacology
should be allowed.
· Automatic priority ranking for any drug with significant lower
abuse of target agents.
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DEVELOPMENT OF MEDICATIONS
· Safety a real problem in the treated population. FDA will be all
over drug interactions and serious adverse reactions.
6. Patent protection
· No special issues use patents for psychotherapeutics discovered
for other indications will be common.
.
Give (via legislation) substance-abuse drugs Waxman-Hatch
type exclusivity/patent life extension.
· The patent office must recognize the speculative nature of
current research when evaluating relevance of animal testing data.
7. Product liability
.
Side effects of CNS drugs used long term.
· High-unstable patient population leads to high potential for
adverse events (which can easily be non-drug related).
· Government indemnification, as for vaccines, should be
provided.
.
Insurance pool similar to vaccines for products intended to
treat drug liability.
· Government should subsidize insurance costs for adverse drug
effects during testing and clinical use.
· Government assumption of risk.
Tort reform.
Use legislation to eliminate lawyers.
Who do you sue the company or the guy on the end of the
block with the gun?
8. Market size
Hard to identify or characterize.
Potentially large, but returns on investments may be poor if
reimbursement not forthcoming in managed care most patients are
financially distressed.
· Supportive therapy is used to exclusion of drug therapy.
Candidates can't afford intensive medical therapy.
May not be a problem if government reimburses. Tied up in
health care reform, pricing, etc.
· Patient unreliability is the big problem, possibly address by
creating a national network between drug treatment centers and
programs.
· Out-licensing partners should be sought; smaller returns
become more meaningful (profitable) to smaller, lower overhead
operations.
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APPENDIX D
225
· If primary purchaser is government, insures no tax or rebate,
free market pricing.
· Increase percent of "war on drugs" billions that goes to
treatment. Spend less on enforcement reduce the demand for illicit
drugs by effective treatment programs.
9. Competitive advantage
No effective therapies available for any addiction.
Reduce the disincentive and sponsors may be willing to seek
products with advantages.
· Company that loses out because of competition by a selected
drug should receive some compensation.
.
Free market.
Try more experimental approaches.
10. Price and reimbursement
.
Not sure who is going to pay.
· Ensure pricing that would allow sufficient return on investment.
· Typically, it would be my opinion that these patients may not
be under routine care of a PCP or have their own insurance/ability to
pay.
Expect unreasonable political pressure to have low prices
because of government subsidy to research or reimbursement.
· Very uncertain, due to Health Care Reform, but protection
from direct and indirect price caps, e.g., by legislation exemption,
substance-abuse treatments, is essential.
· Government support for high prices.
· Tax advantages would have to support the low prices
necessitated by this class of drug.
· Make drug treatment programs mandatory part of HMO and
insurance industry payment programs.
· Federal and state government primary customer.
.
11. Retune on investment
· Not well understood.
R01
May be difficult to determine length of time of recovery for
Government interference and negative image of drug therapy
will not provide reasonable margins.
· Will this be completely reimbursed?
· Costs of development should be distributed among "partners"
e.g. government, venture capital.
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DEVELOPMENT OF MEDICATIONS
12. Public image and intangibles
· Publish NIDA's work at a more high profile level.
· A mixed area: charging the typical drug abuser for therapy will
be seen negatively.
· "Substitute addictions" will be invented by the press for
successful therapies.
· Remove the disincentives, so that the prospects of bad publicity,
poor pricing, etc. no longer outweigh the goodwill that would accrue
for sponsors of successful treatments or preventive measures.
· Could work around this problem if had clear benefits.
· Get the current administration to spend less time bashing the
pharmaceutical industry.
· Too visible an arena, much like AIDS. Too susceptible to
government/Congress trying to make "political" points on pricing at the
same time crying about lack of treatment. It's a no win situation.
Other comments:
· Drug efficacy must be assessed in the context of overall care for
the addict; clinical studies isolating drug from other modalities may set
unrealistically high hurdles.
· I think the major problem is no science in this area.
· The PMA seems to be focusing on the business aspect of this
project, while interactions are mainly at the scientific level. What is
absolutely essential at this time is a forum to share compounds and
data, and to worry about "who will develop?" later. NIH-Addiction
Research Center should also be involved with companies; that funnel
compounds to MDD-NIDA at this time. An excellent forum is the
College on Problems of Drug Dependence (CPDD). Their involvement
in any such venture is extremely helpful.
· Trials a special problem of compliance and longterm followup.
Although NIH could help fund, their behavior on CRADAs makes this
unattractive re #10 and #11 above.
· Make NIDA/industry collaborations better and really allow
industry to make a reasonable return on investment.
Representative terms from entire chapter:
drug discovery
