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This note is intended to stimulate debate and discussion on a
topic that I consider very important for most HUM-MOLGEN
subscribers.

Rapid and efficient translation of preclinical data into
early clinical studies represents a critical problem in
biomedical research. Modern science is becoming more and more
specialized and focus demanding. In addition, clinical and lab
activity follow quite different and often contradictory rules.
Thus, it could seem natural that different individuals will deal
with preclinical (the "scientist") and with clinical (the
"clinician") research. Such an organization can work for basic
research and for advanced clinical studies (phase III-IV). In the
delicate field of "translational research" (pilot, phase I-II
studies), this separation of duties carries with it a significant
risk: to create two almost independent and mutually impermeable
systems. The field of molecular genetics is quite exposed to this
problem, since more and more techniques (usually developed by
people with little or no clinical experience) are entering the
clinical arena (where few people have consistent lab background).

In the extreme of this context (let's call it the "schizophrenic
theater") the two players have different goals: molecular
modeling (independently from its clinical relevance), papers and
grants on one side, tailoring of existing treatments
(independently from their often marginal value), patients and
money on the other. Paradoxically, the development of new
treatment modalities is not a first priority for anybody. The two
participants in this surrealistic game do not know each other
situation sufficiently well to perceive and understand the other
side problems and perspectives. Reciprocal misunderstandings and
distrust can develop. This results in an inefficient
translational research. I can supply interested readers more than
one such example.

Having worked both in Europe and in the US I think the
situation is different in the two continents, although a similar
trend is emerging.
In Europe this represents an endemic problem. The
organization of work tends to ask a 100% clinical commitment to
people in clinical departments (the concept of rotation is mostly
unknown) and to put non clinicians in separate departments with
their own structures, hierarchies and directors. It is usual
that clinical studies list the involved personnel in two separate
columns, one for the clinicians and one for the non-clinically
involved staff. While these divergent goals can (perhaps) be
more easily reconciled inside the management of a private
company, this is more difficult to be accomplished in entities
like research institutions and universities characterized by a
high degree of complexity and independence of different
departments. There is no defined granting agency or program,
specifically designed to fund clinical research or the clinical
component of a research project, whose cost usually rests over
the respective national health system, with all its pros and
cons. Some past attempts at creating clinical research centers,
on the example of american GCRC, have been found to be
incompatible with the existing structures or were mainly
"political" attempts (Nature, 369,92, 1994, Nature 361, Jan.21,
classified #2 and #5, 1993). The problem is more evident in
some
countries (Italy and Germany are to my knowledge the worst
examples) where a more pyramidal organization is present inside
hospitals and universities, and perhaps less in the UK.
In the US many of the above mentioned problems do not exist,
even if the situation for clinical research is far from optimal
there too (Nature, 371, 468, 1994). Rotations are usual in
clinical departments, thereby freeing research-protected time.
Clinical training usually include at least some research-oriented
time (in hematology and medical oncology for example). Programs
like the NIH-funded General Clinical Research Center (GCRC) do
exist and assure financial support and extra-mural peer review
for clinical protocols. Recently, however, a trend toward a more
demarcated separation between lab and clinical activity is
emerging. Most people working as "clinician-scientists", with
whom I recently spoke, find more and more difficult to remain in
this position, without losing competitiveness. There is a diffuse
feeling of inadequacy to compete for grants with PhDs, who do not
have any clinical burden and are often technologically more
experienced, on one side, and to compare with people on clinical
tracks, who have far higher clinical volumes and therefore carry
more clinical revenues to the institution.
This editor does not mean that everybody inside an
university hospital should become a physician-scientists, but
that a critical number of such professional figures should be
allowed to successfully work in an institution encompassing both
clinical and lab activity, to avoid or limit the above mentioned
difficulties.
Some publication data can be illuminating: I looked at the
first 3 months of MedLine 1995, and searched for all publications
with CLINICAL/RESEARCH (mostly pilot, phase I-II studies) among
keywords. Among the 208 papers, 2/3 come from North America (42%
of them acknowledging public support), 1/3 from the rest of the
world (31% with public funding). Data concerning publications
from more basic fields (like for example HLA/PEPTIDE), show
publication from North America (US + Canada) accounting for only
42% of total (68% of them with some public funding), the rest of
the world getting the remaining 58% (with 80% acknowledging
public funding).
What these data do tell us ? In my opinion four things:
1. original clinical research is best played in america (little
doubt about it), where, 2., it also gets a level of public
financial support higher than in the rest of the world (42% vs.
31%); 3. clinical research, however, is in general less likely
to get public funding than basic research, and this, 4. is
particularly evident for non american countries (31% vs. 80%).

Although there is wide acknowledgment on this issue (J.
Clin. Oncol., 11, 1639-51, 1993, Nature, 371, 468, 1994, American
Association for Cancer Research, Association News, March 29,
1994, pages 1-2, Nature Medicine, 1, 281, 1995), little (Nature,
376, 547, 1995) is being actually done.
I hope this short piece can result in an healthy debate.

Questions that interested readers could try to answer are:

1. do you agree in general with this analysis ?
2. do you think this trend represents an inevitable
development ?
3. do you have comments, ideas or proposals ?

Carlo Gambacorti MD, Editor,
Human Molecular Genetics network
Diagnostics/Clinical Research Section
HUM-MOLGEN@NIC.SURFNET.NL


Headings

Replies of readers:

From: Margit Burmeister

Dear Editor,

I enjoyed your analysis.

As a German working in the US, I whole-heartedly agree with the statement
about the difference between Europe and US, and Germany being one of the most
segregated societies in terms of research/clinic: My German friends ALWAYS
have a good laugh when I, a Ph.D., state that my tenure track faculty
position here in the US is in Psychiatry. That is inconceivable and
incomprehensable in Germany! I do think that the trend in Europe is towards
bettering the situation - the Max Delbrueck Center in Berlin specifically
claims that that's what it wants to achieve, and has a clinic with beds
connected to a basic research center, a rarity if not unique situation in
Germany. It is too early to judge its success, but at least the need was seen
and addressed.

It is my impression that the trend in the US is indeed such that it is
getting harder for M.D.'s and Ph.D.'s to get together. Due to tightening
funding and job opportunities, there is more animosity between M.D.'s and
Ph.D.'s - as there is a general trend of less cooperativity and more
competition among scientists in general - unfortunately. Ph.D.'s realize that
MD's usually have a better or far better salary, and often can fall back on a
higher percent clinical work if they are not funded for a while. On the other
hand, MD's feel that their time commitment for research is lower because of
their clinical duties, yet they are judged for their research at the same
level with Ph.D.'s when promotion and funding is concerned, and find it hard
to compete with them. They also often have to fight for their protected
research time - when an M.D. with a previous high clinical load gets an NIH
K-award for 75% research effort, I have seen calculations assuming 70
hours/week for faculty, so 25% clinical=17.5 hours =1 day plus two half days
which then get expanded due to "unexpected clinical load" from the morning
into the afternoon, leaving de factor 2 protected days for research that
equal 75% effort.

There is one factor you didn't mention, and that is MSTP's or MD/Ph.D.'s. I
have the impression that the best research at the border between basic and
clinical is mostly carried out by MD/PhD's, and is harder and harder to get
into by anyone else. I don't know the statistics but my impression is that
the number of MD/PhD's has increased significantly over the last few years,
and given that funding/jobs are tight, they are mostly the ones doing the
research that you are talking about. This is also where Europe is lacking -
M.D./Ph.D.'s are rare or non-existing there.

Funding? I am amazed about your conclusion that basic/clinical research gets
less well funded than basic even in the US - estonishing if correct. That
deserves a better look, especially which way the trend goes. I would think
that with NIH ear-marking more money for clinical (e.g. breast cancer/AIDS)
research with a basically zero-growth budget, there is a higher fraction of
money for clinical or clinically-oriented basic research. I fear that if the
impression from politicians agrees with your analysis, that there isn't
enough money in the more clinically oriented research arena that even more
money as already is taken away from basic research - we have to be careful in
promoting a shift without being sure that that is justified.

Margit Burmeister, University of Michigan (margit@umich.edu)

From: Segolene Ayme

Thanks for sharing your thoughts with us. I largely agree with what you
said, especially with the first part of your text, about the two separate
paradigms. I wish to add some information about what is going on in France.
I am the director of an INSERM unit (id supported by public funds), which
is totally dedicated to clinical research in genetics. Its name is "Gene
mapping and clinical research". We are not suppose to do the research
ourselves , but develop and distribute tools to facilitate the
collaboration between biologists and clinicians. We have created a
database, called GENINFO (http://www.infobiogen.fr) which contains all the
research projects, both biological and clinical, going on in France, to
stimulate the collaborations. We also advertize them by mailing to all
relevant clinicians in France.
INSERM has also created several other units called "centres for clinical
research" which are co-supported by the hospitals where they are located.
They are open to any project which requires a technical medical support.
The patients can stay for the day and have all the necessary exams,
performed by nurses and technicians in clinical research who are trained to
complete detailed questionnaires.
The Ministry of Research distributes also some funds specifically for
clinical research, but you are right to say that this type of research is
not supported enough.

Segolene Ayme, MD

From: Agnes Tay

I agree with most of the observations raised. As an MD/PhD spending more
time in the lab than the clinic, I have seen and heard both sides of the
story, in N America where I did my PhD and postdoc, and back home now in
Singapore, where the MD/PhD is still a rare (but growing) species.

The S'pore system is modelled on the UK one, where clinicians doing
research generally do so on their own time. Despite a continuing interest
in clinical practice, I sought employment in a research capacity so as to
ensure "protected time" in the lab. Thanks to a growing appreciation of the
need to bridge the 2 worlds of bench research and clinical medicine, I have
been allowed to retain clinical privileges.This arrangement is possible
only through the generosity of my fulltime clinician colleagues on the team
who provide cover during those times that I am unable to attend my clinical
responsibilities because of research commitments. I must emphasise,
however, that mine is the exception rather than the rule. In addition, the
decision to spend more time in the lab meant a significant salary decrease.

Since people in the clinical and research worlds each speak a different
jargon, it is not surprsing that there is often no communication,
miscommunication, and even hostility, between the two groups. My training
in both fields has allowed me to bridge this chasm to some extent, and it
is encouraging to be able to introduce friends from one world to the other
occasionally, and to find that with a little effort on each side, they can
begin to understand each other and even to co-operate and collaborate.

It would be unrealistic to recommend that everyone train as an MD/PhD but I
believe it would be useful for clinicians be exposed to some research
training during their training, and biomedical scientists be given some
understanding of the practical problems that exist in the clinical realm.

From: Malcolm Snead

Your analysis of clinical versus basic research trends was most
intersting and certainly worthy of concern and discussion. As you must
be aware, Dr. Varmus ordered a review of funding trends for clinical
versus basic research grants at the behest of clinical scholars who felt
that regular study sections (first level peer review in the NIH system)
were not "fair" to clinical applications or at the very least, tended to
fund less of them. This distinctive polarity tends to hit everyone
eventually, and create several camps that tend not to have the same
experiences in their professional lives and hence may have different
expectations and prejudices. I am fearful that the distinguished crop
of physician-scientists that spearheaded the NIH in the decades afters
its formation are few and far between today. I do not think that special
funding devices, such as the physician scientist awards from the NIH,
that provide greater levels of financial support to professionally
trained persons (e.g. MD, DDS, DVM, DO and etc) rather than "straight"
PhDs, or the NIH's intramural supplemental stipends to professionally
trained individuals or the disparate salary lines paid to professionally
trained members of house staffs help reduce the polarity. It does create
a conflict to pay a postdoctoral fellow more simply because they have the
MD degree than a similarly qualified individual with a PhD, even when it
is likely that the PhD fellow will at least initially be more productive
in a "cross-over" training experience. These are rubs that create
friction because they are obvious and not justified. As per the NIH
funding of clinical grants, it is my perspective that clinical
applications are very very hard to write and often fail in study section
because the hypothesis, methods of data generation, data analysis,
outcome predictions and hypothesis testing is not as rigorous as when a
"bench" trained scientist writes an application. In fact, when clinical
grants are well constructed and incorporate these points they do very
well in study sections and this was borne out by an ad hoc group who
examined this question for the division of research rants.

Still, we can hardly expect to make progress in the field unless we work
more closely with one another, bing mindfull of the differences among
training experience between bench or bedside researchers. One is not
better than the other, just different. In these times of diminished
financial support for NIH sponsored research projects, it is important to
present a unified front and to lobby American Congressman for more of all
types of support for meritorious studies. I refer anyone interested in
the marriage of basic and clinical research to the comments by Am. Soc
Cell Biol public policy chair, Dr. Marc Kirscher who addressed these
issues in a particularly stimulating statement, as did Dr. Phil Sharpe in
testimony to Congress (both of these are available from the Am Soc Cell
Biol by email at ASCBINFO@ASCB.FASEB.ORG It is important for all of us
to make our wishes known to American Congress persons and to help
diminish the growing gap between individuals with different raining but
the underlying desire to explore the unknown and help those who are ill.

From: Timothy Cox

Your analysis of the problem in clinical research was intriguing. However
there were a number of points that I found to be contradictory to my
experiences working in biomedical research in Australia, the United States
and Italy. In this field (perhaps not true for "clinical research" as such)
the problem is relatively straight forward -- "Clinicians" trained for
clinical work should not venture into an arena where they do not have the
skills and training. The laboratory interests they have should be bridged
by the appropriate means of communication; be it frequent meetings with the
scientists or through appropriately trained "mediators" To follow the trend
in Law over the past decade or more, specially trained lawyers have been
required to bridge the gap between "scientific" data and jury comprehension
during trial. Although most may consider that perhaps not such a large gap
needs to be bridged in the "clinician" / "scientist" context, a similar
opening for specialised "mediators" may be appearing.

A scientist spends 7 to 10 years gaining the experience and qualifications
to head a research project. These qualifications do not allow the
"scientist" to do clinical rounds or clinical research just because he/she
may have an interest in patients!!! Why then does the "clinician"
(qualified only for the clinic and/or clincal research) feel suitably
qualified to wander to the bench? Does clinical training also permit the
"clinician" to work at any other "bench" say if he/she is interested in
Law? Or, for those wishing a more pertinent example: why then is an
experienced theatre nurse not permitted to operate on patients? -- the same
reason... The knowledge is probably more than adequate but the
"qualifications" and, importantly, the "details" are missing. I am not
saying that "clinicians" are not capable of performing one or both tasks:
in fact there are endless cases where this is more than exemplified.
However, one must choose between "clinician" and "scientist" -- in the long
run there is nothing worse for both professions (and separate professions
they are), and "professionals", than to have a "clinician" having his/her
time distracted from the tasks for which they are qualified and spent on
things for which they may have only adequate knowledge -- TWO 50% EFFORTS
IN DIFFERENT "PROFESSIONS" DOES NOT MAKE A PROFESSIONAL! There are ample
opportunities (e.g. in the US - see below) for one to further their
education to deal more appropriately with the more "specialised and focus
demanding" requirements of their chosen profession.

Certainly in Australia (which follows effectively the English style of
Post-graduate programs), university qualified researchers (PhDs in
particular) are the primary "directors" of research ("scientists") -- both
biomedical and basic. In the areas of Medical Genetic Research these
scientists are frequently found in the hospital-based environment or at
least have a direct connection with relevant "clinicians". As a general
rule (as emphasised above), no "clinician" is permitted to enter the
biomedical research "domain" unless he/she returns to university to gain
the appropriate theory and practical skills necessary. And, obviously, the
converse holds true.

In the States, although undeniably the best place for interactive,
supportive biomedical research (and similarly could be said perhaps for
other areas of research) the problem you describe is becoming apparent
particularly in a number of the more notable medical colleges. Also, in
accordance with your comments on the Italian system, this problem is most
noticeable in this country - at least in the hospital based research
settings on which I can only comment. Here, in many labs, the PhD (whether
US, UK or Aust) appear to be the hands of the "clinicians", who frequently
have given up their clinical duties (if ever initiated - and majority I
have met fall into this category) to "devote themselves to scientific
research". "Clinicians" surprisingly consider themselves the "thinkers" and
are motivated by the "political appearance". The nearly non-existent
funding for non-medical research, however, may be one cause of this
"acceptable inter-profession migration". However, the beleaguered higher
education system here must take the brunt of the blame for the appalling
status,in recent years, (certainly not true a decade or more ago) of
"scientists" from this country. An "internationally-recognised" equivalent
of, for example, the UK / US / Aust PhD does not appear to exist these days
in Italy.

Any gap between existing "clinicians" and scientists surely then only
highlights the shortfall of the higher education system in all the
countries where a widening gap is appearing. The US seems to be (and have
been doing so for some time) buffering themselves against such a occurrence
by having in place specialised tertiary (and other postgraduate) courses
such as in Clinical Genetics. This, I believe, is one of the major reasons
behind the success and "dominance" of biomedical (and perhaps clinical)
research in the US. When will other countries wake up?

Timothy C Cox, PhD

Visiting Postdoctoral Fellow
Tigem - Telethon Institute of Genetics and Medicine
Via Olgettina 58
20132 Milan - Italy
tel 39-2-21560221
fax 39-2-21560220
tcox@andromeda.hsr.it

From: Barbara Zehnbauer

In general I agree with your assessment and believe that some of
this is a result of which professional activities are valued and
endorsed by our (US) academic institutions. However as public
funds become even more difficult to obtain and health reforms are
implemented, the balance is chaging somewhat. It seems that more
PhD's are looking for applied or clinically relevant diagnostic
positions and clinical activities are more valued.
One positive development to maximize the expertise of each group is
evolving in the creation of multidisciplinary approaches in the
genetic predisposition to inherited neoplasias. Geneticists,
molecular diagnostic labs, medical oncologists, and surgeons are
creating comprehensive care programs for patients with MEN, or
inherited forms of breast and colon cancer. As the human genome
project elucidates more gene-disease correlations the integration
of genetics into many medical disciplines will become necessary.
As professionals we have a tremendous responsibility of education
of ourselves, colleagues, and the public.
Thank you for reminding those of us in the US that we are still
fortunate to be working in our system, imperfect as it is.

Barb Zehnbauer, PhD FACMG
Molecular Diagnostic Lab
Washington University Medical School
bzehnbau@imgate.wustl.edu

From: Kathy Momtahan

I just thought that you might like to have the perspective of a parent
with a 2-year-old girl who has either Infantile Adrenoleukodystrophy or
Infantile Refsum's. I am also doing a Ph.D. thesis in the area of
organizational psychology.

I think that it is wise for scientists and clinicians to work together to
improve the lag time between laboratory experiments and clinical trials.
The general public has easier access to clinical information than ever
before. It seems to me that clinical medicine is not keeping up with the
information age. I found a researcher in another country
who happens to also be a clinician to treat my daughter; something my
daughter's pediatrician wouldn't have done. As a result, my daughter is
no longer completely blind (she sees well enough to track her toys), her
motor development has improved, as has her cognitive functioning. Her
prognosis may or may not be the same, but her quality of life, and thus
her parents' quality of life has improved. This is also likely the most
cost-effective treatment as well since her physical health is also better;
she has not had any hospitalizations, and no doctors visits other than
for immunization.

Having said this, I still have a daughter who is two and doesn't walk and
doesn't talk. I keep hoping that a gene therapy trial will be available to
my daughter while she is still a young child. I hate to think that poorly
organized information transfer could mean the difference between a child
having a life and not having a life.

Kathy Momtahan

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