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4. The Development of Clinical Procedures
The last 25 to 30 years have seen rapid advances in basic biomedical
researched, strengthening the scientific underpinnings for the development of
new clinical procedures in the years to come. A clinical procedure can be
defined as any practice of a health practitioner that involves a combination of
special skills or abilities and may require drugs. devices. or both. As clinical
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proceoures involving new Drugs or Devices, such as laser ang~oplasty, have been
considered in Chapters 2 and 3, this Chapter will especially focus on those
clinical procedures which are not to a large extent dependent on new health
care products but on the technique of the provider performing the procedure.
For example, the development of certain surgical procedures (although they
may involve the use of scalpels, clamps and drugs) or psychotherapy.
The development process of clinical procedures is very different from that of
drugs and medical devices. Analytically, the distinction between the
development of radical or breakthrough innovations and incremental
innovations is useful. Radical innovations frequently arise in academic or
academic-associated centers, where physical and professional resources are
available and clinical development is stimulated. The development of
incremental innovations usually occurs in a much more decentralized fashion,
involving numerous physicians refining and motiving an existing procedure in
everyday clinical practice.
In contrast to medical device innovation, which requires -- as C.P. Snow would
say -- the bridging of "two cultures" (that of engineers and clinical researchers),
the distinction between "developers" and "evaluators/users" may be very fine or
even non-ex~stent in the development of clinical procedures. Within the
hospital those involved in experimental medicine may be physically down the
hall from their clinical colleagues, but often they are embodied in the same
person. Physicians who treat patients may at the same time be engaged in the
development of clinical procedures. This sometimes-may lead to difficult
conflicts of interest between the therapeutic and investigational role of a
physician. As Swazey and Fox (132) observe "... their double-edged role causes
46 In absolute terms, the United States invest heavily in biomedical
research and development. Shepard and Durch (127), for example, indicate
that the U.S. account for 45% of funds spent in the OECD countries and the
top five countries -- US. Japan' The FRG, France' The United Kingdom
, . ,
, ,
account for 84% of all biomedical R&D expenditures. If considering per caput
spending, however, Switzerland and Sweden head the list.
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stress for most physician-investigators. The strains that they experience are
intensified by their typically close and continuous relations with the patients
who are also their subjects; by colleagues' scientific and ethical judgments of
their work; and by a certain vested interest not only in protecting their
professional reputations, but also, in advancing them through recognition for
being eminently successful with breakthroughs in knowledge or technique".
In spite of the enthusiasm and fascination generated by potentially radical
procedures, the initiation of first human application often remains inherently
premature (particularly in the absence of a satisfactory animal model) (132~.
Therefore this transition often is controversial, as recently illustrated by
transplants of dopamine producing cells into the brain region (in need of that
specific transmitter) of very severe Parkinson's disease patients. SIadek and
Shouison in a review of the initial clinical application of this procedure in
Science argue strongly that although "... the scientific rationale continues to
build for neural grafting as a therapy for neurological disease ... we could
benefit from more patience than pai'ents" (128~. Fox and Swazov. in their book
at_ ~~ a_ I_ ~ ~ a ~ .~ · .~.
one Courage to rail-, nave aescr~oea tne scenic and emotional controversies
that may arise during the development of clinical procedures such as kidney
dialysis and transplantation. Their work indicates that radical innovations
usually are first applied to life-threatening or very serious diseases, which often
have no alternative treatment (501. In these cases the considerable uncertainty,
and potential risks, associated with the clinical application of the innovative
procedure may be considered more acceptable.
Their analysis also indicates that during their development, procedures may
often be subject to a partial or complete "clinical moratorium", i.e. human use
of a still experimental procedure on patients is suspended (132~. For example,
mitral valve operations were performed on animals since the turn of this
century. The first application to humans occurred in 1923, but a clinical
moratorium was invoked in 192S, in part due to the high mortality associated
with the procedure. Following a series of drug, device, and surgical advances
such as those in cardiac catherization, anesthetic techniques for intrathoracic
surgery, ligation of the patent f]UCtUS, and antibiotic drugs, the clinical
development of mitral valve surgery was resumed in 1945 (despite initially high
mortality rates). Over time, as surgical experience increased and different
patient groups were accepted, mortality declined and the technique became
established. Comroe and Dripps have equally underlined how the development
process of procedures for cardiovascular-pulmonary medicine depended on
numerous advances in different areas of science and technology (30~.
In contrast to drugs or devices, no forma] governmental regulatory system exists
for the development and evaluation of clinical procedures. Their development
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has traditionally been placed in the context of the physician's clinical autonomy
and the trust relationship between patients and physicians. Evaluation of these
procedures cluring development therefore depends heavily on professional self-
regulation (for instance, through peer review and Institutional Review
Boards)47. In this respect, the difference between radical and incremental
innovations may also be of importance. In the case of incremental innovations,
the line between experiment and individualized therapy often is difficult to
draw clearly (101), and as such Institutional Review Boards (IRBs) are usually
not approached to give their approval for the evaluation of slight modifications
of existing procedures. This is different regarding radical innovations, and their
development and evaluation (at least those that are federally funded) is
generally subject to the approval of TRBs. IRBs, however, do not usually
conduct in-depth examinations of the research design (by.
To date, the potential safety, efficacy, and effectiveness of many procedures has
not been evaluated systematically during their development. Surgical techniques
in the first half of this century were developed by pioneering surgeons on the
basis of their intuition and insight, and were tested by trial and error. Many of
these procedures attained acceptance in the medical community and resulted
over time in useful treatments. A number were discarded, however, often after
years of clinical application, such as surgery for constipation. According to
Barnes, this pattern of development is due to a number of factors Air.
Historically, there was often a poor understanding of disease processes and an
uncritical acceptance of established dogma as dictated by leaders in the field.
In addition, the analytical underpinnings of clinical investigations, in terms of
sample bias, observer objectivity or standards for adequate follow-up, were
often still rather weak. As Bunker et al conclude in their important work on
the Costs, Risks and Benefits of SurgeIy: "In this respect, surgery shared with
other branches of medicine at the time a process for groping for effective
therapies, a process that did not have the help of extensive knowledge in the
basic biological sciences or the understanding of sophisticated experimental
designs to permit logical inductions from multivar~ate clinical circumstances"
(21~.
47 it iS within this context, that medical societies are increasingly issuing
guidelines regarding the use of a particular new procedure; however, usually
these guidelines emerge after a new procedure has already diffused more
widely into clinical practice. The NIH consensus development conferences may
issue similar recommendations regarding the appropriate use and effectiveness
of a new procedures in clinical use.
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In the second half of this century, rapid advances were made in the
methodological underpinnings of clinical investigations. At the end of the
1970s, however, Bunker, Hinkley and McDermott describe that surgical
development was still often based on inadequate evaluation (22~. Examples of
procedures that diffused into health care and only later were to be found
ineffective for treating certain conditions, include prefrontal lobotomies for
schizophrenia, colectomies for epilepsy, and more recently, EC/IC bypass
surgery to prevent stroke. In a recent article Eddy and Billings provide an
extensive argument for the often weak evidence underlying a number of
important present-day clinical procedures (36~.
According to Wennberg, many procedures have not received careful feasibility
studies during their initial application in humans (144), but have been
introduced on the basis of investigations, involving historical controls or more
anecdotal evidence. Generally, the results of such investigations tend to be
more optimistic regarding the benefits of a new procedure (57~. On the basis
of such optimism and a complex set of sociological, economic and scientific
factors a procedure then may diffuse into more widespread use. Over time,
uncertainty regarding the risks and benefits of a procedure, as used in specific
patient groups and for various indications, may increase and clinical trials may
then be undertaken (~10~. At this moment in time, however, the acceptance of
the trial results has become inherently difficult as an advocate group for a
procedure generally has been created48.
Chalmers, therefore, has proposed to "randomize the first patient" receiving a
new procedure(26~49. This proposal has not received wide acceptance, because
during the initial stage the practitioner's skills and expertise with a procedure
still evolve and the risks and benefits associated with the procedure may
change considerably. In view of this "learning cuIve" phenomenon, the initial
application of a new procedure will probably need to involve methodologically
sound non-formal experimental stuffiest. Such early careful and comprehensive
48 The heated debate in the American Association of Neurological
Surgeons and the New England Journal of Medicine illustrates the difficulties
of a number of prominent physicians to accept the EC/IC bypass trial results
(34,35), as well as the importance of ensuring "clear definition and relative
homogeneity of the patients to be randomized."
49 Inherent in his proposal is a fluid protocol that allows incremental
changes in techniques.
so Alternatively, Buxton -- in a three-year evaluation of heart transplants in
the UK -- uses cross-sectional analyses to estimate changes in benefit and cost
parameters over a longer time period than the study period directly allows
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reporting of clinical experience may form the basis for the design of subsequent
RCTs, if necessary, or of otherwise well-controlled trials to determine a
procedure's efficacy and safety.
The above does raise the question of the timing of these studies; when exactly
in the development process should RCrs or otherwise well-controlled studies
be undertaken? If a RCr is undertaken too early, the results may be obsolete
before the trial is finished. For example, 15 years ago a randomized trial was
initiated to compare the Vineberg procedure with medical treatment for
coronary artery disease. Two years later the triad was abandoned because the
tunnel implant had been replaced by coronary artery bypass grafting (44~. If a
RCI is delayed, however, a constituency for the procedure may have formed.
Bunker et al therefore suggested to initiate a reviewing authority to initiate and
coordinate such trials as appropriate (22~.
With regard to RCrs, one should bear in mind that some real conceptual,
practical and ethical difficulties may exist regarding their use in the
development of new clinical procedures (~S,19~. Double blinding, for instance,
is more difficult to achieve. One possible solution may be to have one
physician perform the procedure while another evaluates its effects. Controls
may include standard accepted surgery or alternative treatments involving drugs
or devices; it is generally accepted today that use of sham-operations is
unethically. Surgical procedures will also depend much more strongly on the
technical skills of the surgeon, who might be better at one Ape of surgery than
another. Van der Linden (88) suggested that patients should be randomized to
different surgeons who would perform the surgery they do best. Furthermore,
if alternative treatment modalities are being developed with the aim to improve
~ · . ~ ~ · ~ ~ ·~ . ~ ~ . rim . · . . · · . ~ · . ~ · ~ ~ . ~
quality ot life, while the different interventions are associated with variable risks
and benefits, randomization may be considered unethical. As Reiman noted:
from the patient's point of view, surgical and medical therapy are not simply
comparable arms of a clinical trial. They are vastly different treatments with
very different persona] consequences (35~. In these cases, Wennberg has
argued that assignment according to patient preferences may be the ethically
necessary choice. This would require systematic analysis of how patients value
different types of health outcomes (an understanding that today is not yet
available) and an in-depth examination of how one wall be able to understand
the "biases" associated with actual patient choice.
(23~.
5] The few clinical trials using sham operations clearly demonstrated that a
strong placebo effect can be associated with these surgical interventions, thus
underlining the importance of controls (324.
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Finally, as argued in Chapters, the full range of information on the
effectiveness and safety of a procedure may not emerge in randomized clinical
trials, as these trials may exclude a spectrum of at risk patients. For example,
Hlatly et al (70) compared the patient population in their cardiovascular
disease databank with the patients enrolled in some large RCrs of coronary
artery surgery. They found that only S% of their patients met the eligibility
criteria for the European Cooperative Surgery Study, 13% met the criteria for
the large Veterans Administration (VA) study, and 4% met those for the
Coronary Artery Surgery Study (CASS) (70~. This indicates that the trial
results may not always form a sufficient basis for clinical practice decision
making.
Therefore, following randomized or otherwise well-controlled efficacy and safety
trials, long-term surveillance should be undertaken of the safety and
effectiveness of new procedures as they are used in everyday clinical practice.
These studies may involve experimental or observational methods. In view of
some of the logistical problems involved, it may be especially useful to depend
on modern observational methods that enable one to monitor clinical practice
and changes in health outcomes. In recent years the use of such observational
studies for assessing outcomes of clinical procedures has increased. For
example, Wennberg (146) and Roos et al (122) have used claims data to
evaluate health outcomes following prostatectomy, hysterectomy and
cholecystectomy. Given the increased availability of computerized data banks,
the possibilities of inexpensive monitoring are appealing. -A-more extensive
examination of the advantages (such as low cost, ease of patient follow-up over
long periods of time, and the absence of reporting bias) and the disadvantages
(such as adequacy of the data to adjust for case-severity and lack of outcome
information on quality of life and functional status) is needed.
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Representative terms from entire chapter:
clinical practice
