Click for next page ( 70


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



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 69
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 69
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 phncmennn 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 69
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 69
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~ OCR for page 69
~ ~ ~ of ~~ _ ~~ ~ a _ Of 150 ~ ~ ~ 40 ~ e ~ ~ 1~ ~ 3 ~ ~ ~~ ~ ~ ~ a ~ of 3 ~ a of 5~ =1~ ~ too ~ $20~000 ~ at, 74

OCR for page 69
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

OCR for page 69
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

OCR for page 69
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

OCR for page 69
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

OCR for page 69
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

OCR for page 69
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