Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 69
ISSUE # 3:
OE=NIZP~IC~PL Si^JClURE OF CLINICAL
IN~G~CN IN quite:
W; 1 lion N. Halley
70
Elaine L. Iars<3n ~ ~ . ~ e e e 75
IS The - a
69
78
OCR for page 70
FE5CURCS C0NSIDERAIIONS AND SUPPORT OF CIINIC~L INVESTIGATION
OpkimF~ and Neared ry Organization and Structure of Clinical Research
William N. Halley
The cubical organization and structure-of that a ~ of clinical
investigation as defined by the Commitbee, i.e. patient related clinical
research, requires a program which is creative, coordinated, and
supportive of the clinical investigator.
_ Such a program most also
maximize the likelihood that intcorbant advances win 1 be translated with
all due speed from the rose arch laboratory to the alleviation of pain
and suffering for the individual patient.
1. Develop an RO-1 mechanism dedicated to patient related
clinical studies. Research grants which represent
studies ready for patient application should be reviewed
by study sections set up entirely for this purpc set The
number of study sections, as well as the qualification
of the members of these study sections would be
determined over time by the number and orientation of
the grants submitted, but in any romp, shall not be less
than one study section committed to this purpose for the
entire NIH. Since the studies under review would be
only those which are ready for patient application, the
basic bench research leading up to the proposal would
have to be supported by other mechanisms and, if such
research was incomplete, the studies would have to be
completed by other mechanisms. For consideration by
this (these) study sections, the studies would also
not be appropriate protocols for the CRC or for clinical
trials. Such studies also would be appropriate only for
those institutions with an established IRB and a funded
CRC, and all such proposals would be subjected to review
by the IRB and the CRC prior to submission for support
to the NIH. All such studies would be funded by the
appropriate institute using the standard cutting score
mechanism.
2. Expand the funding and the mission of clinical research
centers. The general clinical research center has
proven to be highly successful, if not critical, In the
application of basic research advances to the bedside.
While the most appropriate mechanism for support
oont~nues to be the NIH, methods must also be encouraged
to allow support from other sources, such as the
pharmaceutical industry. The CRC program also should
be expanded to non-haspit~l settings, such as nursing
homes, home care sites, and other non-traditional
settings. In addition, the responsibilities of the
70
OCR for page 71
Directors and other professional staff of the CRCs
should be expanded to include recruitment of the best
qualified students, postdoctoral trainees, and faculty
to a career in patient related clinical investigation.
Finally, funding of CRCs should be increased to support
these expanded responsibilities. Specific
recommendations are summarized in Appendix 1. scram==
or failure of The competitive renewal of theme CRCs
should be determined, IN part, by how well these goals
described in Appendix 1 are met.
3.
4.
Clinical Trials. Clinical trials continue to be an
extremely important aspect of patient-related clinical
research. While clinical trials are critical to this
structure and organization, they will be described in
detail by others.
Provide a funding mechanism to insure rapid
implementation of clinical advances that are beneficial
to human kind, but are not cost effective for
implementation by the pharmaceutics industry. There
have been many advances over The past century which have
proven to be extremely important but do not justify an
investment for profit. Perhaps vaccines and orphan
drugs represent good examples of this ph£ncmennn in the
pent. It is quite clod that this not only will
continue, but could be greatly expanded in the future.
For example, if human gene therapy proves to be as
surf as many believe it will, it may sell be
possible to develop an approach to cure a disease with
only a one time application of the appropriate
therapeutic modality at the time of birth. While this
example cculd be an exaggeration (at least in the early
years), it is difficult to envision how such an advance
could be able to generate a return on investment to even
recover develcpment costs. On the other hand, it is
quite easy to recognize how such an advance Night be
preventative or curative for literally millions of
patients, thus reducing dramatically the di=~hility and
death from a specific disea e, and perhaps saving
countless billions of dollars, in addition to untold
human despair. Pro vision of funding for this purpose
would need to be incremental to current NIH programs; it
would be highly inappropriate for programs to reduce or
displace the funding for basic research which is
nP-=c=~ry to achieve these advances. We would,
accordingly, recommend that one percent of the health
care expenditures of the United States be budgeted for
this purpose to be provided (on a voluntary basis) by
71
OCR for page 72
all entities which reimburse for health care, including
HCFA, Blue/Cross-Blue/Shield, the commercial in9uDers,
etc. It might also be reasonable to ask that financial
support be provided from the life Insurance industry.
In summary, it Is quite clear that the most rapid and appropriate
application of advances in basic bicmedic~1 investigation win 1 be
realized when support is combined four the NIH, the pharmaceutical
industry, the Insurers of health care and of life. We would summarize
our concept as follows:
Melanism: Nordic adva~lini~a1 R - l~lin.Trials Implantation
Source: NIH NIH NIH Industry Ir~stry
NIH Health Care
H - filth Care Payors
Payors
Wile the NIH aced continue to provide the major support in ~ of
these stops, critical support four other saris as appropriate wed
insure final sup at a maxim rate.
mere are several major issues which deserve consideration by this
committee relating to the above organization and structure. First, a
mechanism to assure that fraud is basically non-existent must be in
place, strictly adhered to, but not onerc us. Secondly, we must insure
That there is no conflict of interest among the investigators
participating in this program at any stage. m is could best be handled
by defining very clearly anything which might conceivably represent a
conflict of interest and asking the investigator to insure that such is
not the case. An important principle related to this would be full
disclosure of any consulting relationships, equity participation by the
investigator or by any family members, such as parents, siblings,
spouse, children, or a trust of any sort. The importance of such a full
disclosure and review by appropriate parties cannot be over emphasized.
72
OCR for page 73
OCR for page 75
OCR for page 76
OCR for page 77
OCR for page 78
OCR for page 79
OCR for page 80
Representative terms from entire chapter:
clinical trials
AE~IDIX 1
Nations for Nell S~r~ Cam;
M~i~1 Spends
0 Zymase personal ~olv~nt of CEtC physicians In nadirs ~ school
Farm pn~rmE; at each Apical school.
o
P - ;ident
o
o
o
o
Fellows
o
Nose fens available for sort of Vicar spent Nears
In He CRC Fox $4,000 to $15,000 a year and alias specific
pa ~ pective b ~getir~ for su ~ a pr~3rmn.
Consider the su~-cc of the CRC in supporting medical student
research as an important factor in competitive renewals (eg.
number of students supported, number of protocols involving
serpents, number of abstracts and publications involving
students, and, in the long run, number of students pursuing a
~r~
~ ~ ~ of ~~ _ ~~ ~ a _
Of 150 ~ ~ ~ 40 ~ e ~ ~ 1~ ~ 3
~ ~ ~~ ~ ~ ~ a ~ of 3 ~ a
of 5~
=1~ ~ too ~ $20~000 ~ at,
74
ORGANIZATION AND STRUCTURE OF CLINICAL RESEARCH
Elaine L. Larson
The sue of the NIH extramural programs as a catalyst for the
development of biamedical science has been phenomenal. Continued
sugary however' requires ongoing scrutiny of organizational structure
with appropriate and timely modifications made to assure continued
optional cat of clini`~1 investigation. Fair organizational
r~ations are made Scar Bite might Spat the potential for
economic ~~ of research facilities and the incorporation of basic
science into practice.
1. Develop mantes to facilitate more ~lticenter trials.
Although expertise and interests of indivir~ resealers are essential
to the creative pro; of science, sore clinical probed are better
addressed on a la ~ er scale. Major clinical trials design ~ to
characterize basic biologic phenomena or to test innovative
technologies, drugs or devices, could be centered in fewer federally
funded clinical ranch centers. Such centers could focus scarce
r;#~nroeS such as cadres of highly trained researchers and m~D~3ment
and analytic equipment within scientific settings best suited and
equipped to surY-y-"=cfully carry out rigorous clinical investigation.
Protocols could be standardized across such centers so that the
requisite sample sizes could be attained. Selecbed centers could assume
responsitili~ for certain aspects of Be study (e.g., tests which
require cc~;tly equipment or highly t~=in"1 staff Carla be conduct - 1 in a
few side: or complex statistical analytic :st~ategies cold be su~rvi~
freon orm or two site for an entire project). there are ongoing
un~ticenter clinical trials as well ~~ the General Clinical Pesea~h
centers funded through Nix that would sure as Gels and conduits for
this plan.
-
2. Develop mechanisms to facilitate Arch without walls and
expand sites available for clinical investigation.
Currently, the bulk
of federally funded Rae nch is conducted in large tertiary medical
institutions where rc£~undhers and facilities are centered. Ranch
conducted at such institutions is extrem ly costly. In addition,
certain types of arch are not appropriate within those settings
where funding has been traditionally allocated.
Examples include
evaluation of alternative therapeutic modalities or systems of care
delivery, aE~#R;ment of pro grams for disease prevention and health
prc motion (e.g., AIDS education for high risk populations, smoking
lion pro grams, prenat~l care deigned to reduce low birth weight),
and cast analyses of clinical therapies and programs. m ese types of
applied research link basic science to improvements in technology and
practice and may be conducted in a 1==c 006~1y, most efficient, and more
alps Striate marker In alternative sites like private and state~rated
ex~ed and Conic Ore facilities, cc~rn~ni~ agencies or schools.
75
Use of such alternative site= for clinical investigation has several
advantages. The selection biases inherent in the use of large mPd;~1
centers are reduced, access to study populations mare representative of
target populations but inarr~ccible in traditional research settings is
enhancer, and some of The mats associated with conducting clinical
research may be reduced. Mast importantly, use of these site= focuses
clinical investigation more Honestly on some of The major health care
needs of the nation.
Currently, the funding structure within the NIH is not well designed
to fact itate research in sites other than academic health ousters.
Mechanisms not only to allow but to actively encourage research without
walls should be designed. Tb assure that such clinical research is in
no way oompromised in terms of research design or scientific rigor,
There must be guidelines and protocols addressing issues which need to
be resolved such as how to develop research agreements among various
non-traditional research sites, how to deal with ethical and human
subjects considerations, and how to assure adequate scientific
supervision of decentralized projects.
3. Facilitate linkages for clinical investigators between
government, academia, and industry. On the research spectrum NIH
funding has placed emphasis on basic science whereas the focus of
industrial research and development is on technology and product
development. There are currently no adequate mechanisms in place to
assure smooth flow of scientific research to technologic innovation, nor
to facilitate joint sponsorship of clinical investigation by industry
and government. The need for increasing collaboration f ~ u all three
sectors has been consistently identified within the scientific community
(references below) but investigators will look to NIH for direction
regarding how and when to seek out such new relationships, since there
are many real misgivings about the issue. Important tasks include The
development of guidelines to protect the ~n~Pr~=ts and reduce conflicts
of all parties and the definition of roles of these parties within
research continuum from basic to applied research.
References
Clogston AM. Applied research: key to innovation. science 1987;
235:11-3.
Government-Un~versity-Industry Research Roundtable Council. A
Demonstration Project of New Federal-University Research Relationships:
A Cooperative Effort Among Five Major Federal R&D Agencies, Public and
Private Research Universities in Florida. W ~ n, DC, National
Academy of Sciences, March 1986.
Langfit, TO, Hackney, S. Fishman AP, Glowasky AV, eds. Partners in
the Research Enterprise. Fhiladelphia, University of Pennsylvania Press,
1983.
76
Ion, E . Guidelines for collaborative r~r~ with Wintry.
Nixing dynamic 1986; 5:131-3.
In KL. rim pains of biblical r~r~ furring: me
impact on ~ clinical investigator. Clinical harm 1983; 30:308-15.
Pullman AS. me new r~i~=l-ir~us~ial complex. New England Journal
of Medicine 1980; 303; 963-70.
me L. chic scier~x and African business. Bulletin of ~ New
York Academy of Medicine 1981; 57:493-502.
77
OIL AND Now OE~Z~CN AND
STRUCTURE OF CIINIC~L RESEARCH
Lcuis Tuna
The NIH is m a position to 1~d an effort that might correct some
glaring deficiencies and meet critically important national needs in the
general areas of clinical investigation. The problems that need to be
an cress ad are the following:
1. The decline of academic clinical pharmacology in the U.S.
2. The absence of specific braining programs for individuals
working in the field of drug development, be they in industry,
academia, or The government, and needing the background to
conceptualize the process of bringing a new drug to the public,
from its very beginning though to it usage in practice.
3. The paucity of attention to new techniques for amusing drug
benefits an] C06tS (both somatic and monetary) to complement the
well~workPd out techniques for controlled clinical trials which
suffice to gain regulatory approval but are inadequate to
address the issue that appear after registration is achieved.
Several decades ago, largely due to the leadership of Dr. Robert
Grant of the National Heart Institute, the U.S. led the world in
federally supported training of clinical pharmacologists. In time,
industrial support (Burrcughs Welcome, EM\, e.g.) augmented NIH
support. Today the number of such training programs of high quality and
critical mass is pitifully small, and the annual output of grad mate
trained in the discipline is minuscule. The U.K. and Sweden have
outstripped the U.S. in their support for academic units of this type.
The reasons for this parlous state are multiple: The failure of
clinical pharmacology to achieve a clear image in academia of its
potential value and the absence of academic support for such individuals
once past their training, the "taint" of "applied" research in academia,
and the recent worship of molecular biology as if somehow all scientific
progress could be achieved by focusing on molecular level research.
Industry and the FDA, unlike academic' appreciate the crucial
importance of clinical pharmacology to their daily activities, but
suffer from a lack of individuals well-trained for the process of drug
research and drug evaluation. There is very little in the formal
training of physicians or Ph.D.'s, e.g. that prepares them for such a
role. Pharm.D's and pharmacists are only slightly better off in some
Is.
78
m e back ground needed includes training in medicinal chemistry,
clinical medicine, pathology, toxicology, pharmacology (both
pharmacokinetics and pharmacedynamics), epidemiology, biostatistics,
experimental design, economics, ethics, food and drug law, r ~ k
perception, risk communication, and risk/benefit analysis.
m e evaluation of a drug prior to FD~ approval is not adequate to
define its proper use after marketing has begun. m e pre-apprcval
process focuses on "group" performance, in controlled trials, conducted
often by expert physicians, in patients whose heterogeneity and exposure
to other variables of importance are nec scary y limited. Once a drug
is approved, the sib mtion changes drastically: physicians of all
levels of training and expertise are free to prescribe The drug for
patients with other co-morbid stat==, or multiple drugs, variably
-liar with prescribing directions, and in outpatient settings where
condom and supervision are reduced. Reparative perforTnar~e (both wit
regard to quality and react) becomes more important. tact containment
pro; have an increasingly strong impact.
Mat could NISI do?
1.
Either alone, or in concert with academia, my, ir~try, FLEA,
etc., NO Id assess Mat is needed in the way of training and
post-training short, to revere U.S. clinical pharmacology to
a position of so.
2. A similar role Could be played by NIH in evolving a "curricula"
for training individuals for drug discovery, ~ search, arxt
evaluation. Since such a curriculum napes to be both realistic
and imaginative, the best brains in the several fields mentioned
earlier need to work out a syllabus which could not only build
on accepted lore and custom, but would revise current
inadequacies In concept or application. (Statistical thinking,
e.g., is desperately in need of reworking as it is currently
invoked.) Teaching materials could be prepared (written,
a~;o-visual, oomputer-linked learning, etc.) and periodically
updated, so as to maximize the utility of these new curricula.
3.
At the level of post-marketing research, much needs to be done.
The benefits of many drugs are now inadequately measured, while
their ousts (somatic and monetary) are often paid a lot of
attention. Tinge scale, lengthy, expensive controlled trials
Cannot possibly be done for every new drug marketed in such
areas as lipid-lowering, blood pr o reduction, or
thrcmbDlysis. Can we assess the putative long term benefits by
epidemiologic data: (It seems paradoxical that those who answer
"no" to this question are willing to concede that the pressure
to develop broad pressure lowering drugs or cholesterol-lowering
drugs comes preccminantly from epidemiologic evidence.)
79
A new drug is like a new surgical procedure; with time' the choice
of target population and the skill with which therapy is applied change,
as they should. "Fine-tuning" of treatment for individuals, hand on
data suggesting dine variables that predict response, is the goal,
not treatment of the "average person.!' There is probably as much good
to be gained from the wiser ~~. of drugs we already have as from new
drugs still to be developed.
The challenges are real, the potential benefits are enormous. WE 1
NIH lead the way?
80
