DUSAN PETRICIC

Understanding
CLINICAL TRIALS
The journey from initial medical research to the bottle
in your family’s medicine cabinet is complex, time-consuming
and expensive. Can the clinical trial process be refined?
by Justin A. Zivin

O ne of the biggest stories in medicine of the past five years is surely the furor over angiostatin and
endostatin, compounds heralded by some media reports as the cure for cancer (a premature
claim, to be sure). The two substances— which dramatically reduced tumor size in a group of
laboratory mice—made headlines for a few weeks in the spring of 1998 but then faded from public view.
Scientists, however, continued their slow, methodical study of the potential drugs. A year and a half later,
in September 1999, doctors were at last ready to begin testing endostatin in humans. At press time, phase I
of a clinical trial was under way in Boston, Houston, and Madison, Wis.; barring unforeseen complications,
testing should continue through most of this year. But even if all goes smoothly and endostatin proves to be
a safe and effective treatment, it will not be available to patients for several more years.
Another story that often makes the evening news is the promise of gene therapy, but almost half a cen-
tury after the revolution in molecular biology began, no such treatments are available. Testing of gene

Understanding Clinical Trials Scientific American April 2000 69

Copyright 2000 Scientific American, Inc.
therapy is under way, however— and is ten with little time to make weighty de- for a contract research organization, a
currently the subject of intense scrutiny. cisions. Furthermore, in recent years company that can be hired by drug
The complaint this time is not about the human trials have become more than firms to organize clinical trials. During
slow progress of research but about just a way to screen new drugs. They these years, those of us involved in clini-
whether the research is actually harming have taken on an important role in the cal trials have tried to develop improve-
patients. In September of last year, a delivery of health care: many patients ments or alternatives to the traditional
young man participating in a phase I tri- view participation in a trial as the only clinical trial. Some of these techniques
al of gene therapy for a rare metabolic way to obtain experimental medications may help resolve current dilemmas, but I
disorder, ornithine transcarbamylase de- they consider potentially lifesaving. believe that on balance the three-stage,
ficiency, died as a result of complica- Concerns about the way clinical trials randomized, controlled clinical trial re-
tions caused by the treatment. In the are conducted have surfaced regarding mains the most reliable way to test new
subsequent months, reports of addition- the money, time and potential conflicts drugs and medical devices.
al deaths in gene therapy clinical trials of interest involved. Do drug companies
have also been made public. Much of push researchers to report results in Protecting Patients
the discussion of these tragedies has fo- only the most self-serving way? Is it re-
cused on how the trials were run and
whether misconduct on the part of the
researchers could have led to the deaths.
ally feasible to explain all the potential
risks to a patient (a requirement for se-
curing his or her “informed consent”)
A leading complaint about the current
formula for testing experimental
therapies on humans is the need for so-
The three-part clinical trial process re- when the purpose of the trial is to learn called blinded, controlled clinical trials.
quired to judge the efficacy and safety of about such risks? How do you balance Ideally, neither physicians nor patients
potential treatments is a major under- the desire to test a drug candidate com- know whether a subject is part of the
taking. The necessary trials may require prehensively with the desire to make treatment group or the control group
more than a decade to complete and lifesaving treatments available to pa- (which receives either a placebo or the
cost hundreds of millions of dollars. (For tients quickly? The list of questions goes best available proven therapy)—they are
more detailed descriptions of the three on. Under pressure from the public, the “blind” to whether the test drug is being
phases of a clinical trial, see the boxes on government and the companies funding administered. Complicating the issue is
pages 71, 73 and 75.) Trials that fail to medical research, clinical investigators the idea of randomization, the practice
show that a treatment works outnum- are continually striving to cut the cost of randomly assigning patients to either
ber substantially those that prove that and length of the process—without sac- the test group or the control group. Be-
one does work, but both can cost the rificing the quality controls set up to cause of this practice, patients often
same. Although the precise numbers are protect patients and to ensure that new complain about being powerless “guinea
not available because pharmaceutical treatments are safe and effective. pigs” for the far more powerful drug
companies do not like to report their For more than 20 years, I have ob- companies. They argue that patients
failures, it is safe to say that thousands served hundreds of clinical trials from a whose only chance could be the latest,
of drugs and medical devices have been variety of perspectives: as a bench re- cutting-edge treatments should have
evaluated in the past decade alone. searcher, a clinical neurologist and an guaranteed access to them.
Most people know very little of how investigator in clinical trials. I have served If researchers somehow knew a drug
trials are conducted or what their scien- as a consultant to the National Insti- candidate truly was a better treatment,
tific foundations are. Yet they may be tutes of Health, the U.S. Food and Drug however, there would be no need for a
asked to risk their health, and possibly Administration and several pharmaceu- trial. It is scientifically essential that the
their lives, to participate in a trial— of- tical companies. I have also consulted division of subjects into the test or con-

TIMELINE FOR DRUG DEVELOPMENT typically spans many and Drug Administration) and, finally, monitoring of drugs on the
years, stretching from preliminary research in the laboratory through market. Efforts by the FDA and clinical investigators have short-
human trials, review by a regulatory agency (such as the U.S. Food ened the process somewhat, but a thorough trial takes time.
File ”Investigational New Drug” Application with FDA

PRECLINICAL RESEARCH CLINICAL STUDIES REVIEW POSTMARKETING

• Discovery and early BY FDA SURVEILLANCE
screening of compound • Watch for
File ”New Drug Application” with FDA

Phase I adverse reactions,

• Large-scale synthesis
product defects
• Animal testing 1.5 YEARS

Phase II
Approval

2 YEARS
DUSAN PETRICIC (drawings); HEIDI NOLAND

Phase III
3.5 YEARS

AT LEAST 5 YEARS 7 YEARS 1.5 YEARS ONGOING

70 Scientific American April 2000 Understanding Clinical Trials

Copyright 2000 Scientific American, Inc.
trol groups occur and that it be entirely
random. Otherwise the final results will
be skewed. If the test group were to con-
sist mainly of patients for whom all oth-
er drugs had failed (and thus were more
likely to be among the sickest patients),
the drug candidate being screened could
appear to be less effective than the place-
bo, even if it were not, simply because
the patients receiving the drug started off
in worse health. Conversely, if the lead-
ers of the clinical trial consciously or un-
consciously administered the test drug to
healthier patients, it could appear to be
more effective.
What is essential for science does not
always make sense to patients, however,
especially those with life-threatening ill-
nesses. To protect patients from poten-
tial abuses and address their concerns,

DEL BROWN Gamma Liaison

trial organizers incorporate many levels
of oversight into their planning. First,
doctors are bound by their ethics to pro-
vide patients with the best care possible,
whether or not they are part of a trial.
Physicians are never required to enroll ENDOSTATIN, a potential anticancer drug, is now in phase I testing at the Univer-
people in an experimental study, and sity of Wisconsin Comprehensive Cancer Center.
patients cannot be forced to join. When
someone does decide to enroll, doctors
must provide a complete explanation, PHASE 1: Screening for Safety
both orally and in writing, about the na-
ture of the study and all available infor- Number of volunteers: 10–100 people, typically healthy
mation about the potential risks and
benefits of participating. If patients or What researchers hope to learn: Maximum safe dose of drug
their responsible guardians agree to con-
tinue, they must do so in writing. This Typical length: 1.5 years
process is called obtaining informed
Typical cost: $10 million
consent. Patients always have the right
to refuse to participate or to withdraw
from a trial at any time.
But because of the impossibility of I n the first stage of a clinical trial, researchers gather information about
whether a drug is safe to give to humans and, if so, how much they can toler-
ate. Administering a drug for the first time can be a frightening experience be-
knowing in advance all possible side ef-
cause the volunteers (who are usually perfectly healthy and are also usually
fects of an experimental drug, hospitals
paid) are taking a very real risk. The initial dose is typically very low, to minimize
in the U.S. that run clinical trials operate
the possibility of a major reaction, but as doctors escalate the dose the poten-
Institutional Review Boards, or IRBs.
tial for problems increases. If the possibility of extremely serious side effects ex-
This second level of oversight usually
ists,phase I testing is conducted in patients with the condition that the medica-
consists of a committee of caregivers,
tion is intended to treat. Potential harm then is balanced by potential benefit.
patient advocates and other interested Of course, before human testing begins, the general safety of the drug has
nonprofessionals (for instance, lawyers been established in animals. But animals cannot express whether they are
or members of the clergy). The IRB dizzy, nauseated or experiencing psychiatric symptoms; humans can and fre-
must agree to a trial before it can begin quently do. And although such an outcome is extremely rare, volunteers occa-
at a site, and if the members become sionally suffer life-threatening side effects that were not apparent during ani-
concerned about how a trial is progress- mal testing.
ing they can stop the trial at their hospi- The trial team monitors the participants closely,constantly observing their be-
tal or request changes in procedure. havior and asking how they feel. Additionally, to spot problems early the re-
As an additional layer of patient pro- searchers usually measure blood pressure and temperature, collect blood and
tection, each trial usually includes a urine samples, and monitor for any other danger signs warranted by the animal
Data Safety Monitoring Board, or studies. The scientists also measure the level of drug in the bloodstream or tissues
DSMB. This group of physicians and to determine how it is distributed in the body,how rapidly it reaches a therapeu-
statisticians works independently of the tic level and how the body eliminates the compound. When combined,these data
sponsors of the drug trial and the scien- help to determine the safe dosing regimen. — J.A.Z.
tific investigators. They monitor the tri-
al, continually checking safety and peri-

Understanding Clinical Trials Scientific American April 2000 71

Copyright 2000 Scientific American, Inc.
odically evaluating other aspects. If nec- from entering patients into the trial—
essary, the board can be unblinded dur- drug companies typically pay doctors
ing the course of the trial. If the DSMB for each new patient enrolled. And as
finds that the treatment group is doing the events of the gene therapy trials re-
substantially better than the control veal, professional pride can be at stake
group (or vice versa), the board can rec- as well. Pharmaceutical companies, of
ommend the trial be terminated. course, have a definite financial interest
In some instances, physicians can offer in moving trials along rapidly: the
experimental treatments to patients out- longer a trial runs, the more it costs
side of a clinical trial. Therapies that them. In addition, a short successful tri-
have not been approved by the FDA can al allows a company to start selling its
be made available to people who are ex- product sooner (and take advantage of
tremely ill for what doctors call “com- patent protection on its drugs for a
passionate use.” But because such treat- longer time).
ments have not been adequately tested in
humans, recipients have no assurances Speeding Up the Process
that the drug or new medical procedure
will help— or that it is safe. Moreover,
the results of such experiments will not
help anyone else, because they were not
T he rate at which a trial can be con-
ducted depends predominantly on
the number of participating investigators
part of a properly designed clinical trial. and patients. The faster the data are col-
From what we now know about the lected, the sooner researchers can begin
phase I gene therapy trials that involved to interpret the information. This is par-
the deaths of some subjects, oversight ticularly true for therapies that may offer
committees can be misinformed [see important benefits to only a relatively
“Gene Therapy Setback,” by Tim small number of patients and for those
Beardsley, News and Analysis, Febru- that provide only modest benefits for
ary]. In several of the trials now under many people. For instance, taking aspirin
investigation (several of which have been daily prevents strokes every year in ap-
halted), the researchers did not inform proximately 1.5 percent of patients who
the NIH of certain health hazards associ- have suffered a previous stroke. Only by
ated with the treatment— hazards they administering aspirin to a very large
had observed previously either in animal number of patients could researchers
tests or in other patients. (Most of the re- prove that such an effect existed. Al-
searchers had reported complications to though this benefit may seem small, as-
the FDA, but that agency does not release pirin costs only a few dollars a year,
data on trials.) whereas the costs of taking care of one
Such notifications—required by federal stroke survivor total about $50,000 a
law— could have stopped the trials and year. And viewed from a larger perspec-
prevented the deaths. Unfortunately, tive, out of one million cases, some
when researchers think they have discov- 15,000 people should benefit from as-
ered a “magic bullet”— a therapy that pirin treatment. and economics. Ensuring that patients
cures with complete safety— it may be As a way to enroll as many patients as can get needed medicines that they can-
hard for them to recognize the risks asso- possible, as quickly as possible, trial lead- not afford must and should be ad-
ciated with any clinical trial. But the diffi- ers now run their studies at numerous dressed by legal and financial means.
culties scientists will be most likely to en- sites around the world. More sites mean As trials grow in size, investigators ac-
counter in developing gene therapies are more patients and a diverse group of cumulate increasingly vast amounts of
similar to those considered common- people who are more representative of information. The reports generated for
place in the testing of more traditional those who will one day be taking the just one patient frequently consume
treatments. The recent deaths should re- medication or using the medical device. more than 100 pages of a notebook.
mind all clinical investigators how vital it Despite the benefits of international The process of collecting such a moun-
is to conduct our studies according to the trials, however, such efforts have come tain of data and checking it for accuracy
well-established rules. under criticism. Detractors argue that accounts for much of a trial’s price tag.
The public, physicians and pharma- some drug companies take advantage of An alternative approach, known as
ceutical companies all agree that drug people in the developing world, testing the large simple trial, attempts to reme-
candidates should be tested quickly yet new lifesaving therapies in these regions dy part of this problem. In this method,
thoroughly so that useful new medica- (particularly for HIV/AIDS) but then physicians collect only the absolutely
tions can be made available as soon as withdrawing access to treatment that is necessary details— usually just identify-
possible. The public’s considerations are too expensive for most patients to pur- ing information and a simple check-off
fairly clearly humanitarian. Physicians’ chase on their own. This issue, as trou- list indicating whether the patient ended
motivations may be mixed, however. bling as it is, does not reflect a poor clin- up better, unchanged or worse. The
They want patients to get the best treat- ical trial design; who has access to whole record can then be sent into the
ment, but they also benefit financially medicine instead reflects current politics coordinating center on a postcard. Large

72 Scientific American April 2000 Understanding Clinical Trials

Copyright 2000 Scientific American, Inc.
 PHASE 2: Establishing Protocol
Number of volunteers: 50–500 patients with the disease being studied

What researchers hope to learn: Who and how many people should be included in the final phase of testing; end
points of trial; preliminary estimates of effective doses and duration of treatment

Typical length: 2 years

Typical cost: $20 million

T he main goal of phase II testing is pragmatic: to find

the experimental conditions that will allow the final
phase of the trial to give a definitive result.(The purpose
account for people in whom health problems unrelated
to a drug candidate develop. For example, a medication
being tested for treatment of high blood pressure might
of a phase II trial is not, as some people assume, to prove be suspected of causing nausea. But nausea can occur
that a drug candidate is an effective treatment.) In partic- in just about anyone. Only if its incidence is significantly
ular, researchers try to establish an optimal dosing regi- higher in the treatment group than in the control group
men. One criterion that must be established immediate- will it be considered a problem.
ly is the primary end point. End points describe unam- Ideally, neither the physicians nor the patients know
biguous results that indicate exactly what the treatment whether they are part of the treatment group or the con-
can do. For instance, the usual end point sought when trol group— in other words, they are “blind”to the type of
screening a new antibiotic is whether a patient is free of therapy being administered. During phase II,investigators
infection after treatment. Many ailments cannot be so work hard to ensure that the blinding procedure is suc-
readily cured,however,so an alternative end point might cessful. For instance, if a placebo pill is used, it is made to
be whether the progression of, say, HIV/AIDS has slowed look exactly like the drug,and the patients are treated with
or whether the death rate from cancer has fallen. either the drug or placebo in exactly the same way.
Phase II marks the introduction of the control group Yet in some cases, keeping a trial blind is simply im-
to the trial. Almost all diseases are highly variable in their possible. If the test drug causes some kind of mild side
progression,with remissions sometimes occurring spon- effect, patients will quickly figure out that they are in the
taneously. Researchers must be able to distinguish be- treatment group. Also, it is usually considered unethical
tween a natural remission and the effects of treatment. to subject a patient to anesthesia and placebo surgery
Inclusion of a control group— which receives either a when surgical procedures are being evaluated. Re-
placebo or the best available therapy— makes it possible searchers can compensate for the loss of blinding, how-
to perform this comparison. ever, and phase II enables them to work out how to do
Similarly, having a control group enables doctors to so before entering phase III. — J.A.Z.

PATIENT RECORDS must be carefully reviewed during phase II, when trial organizers refine
CORBIS

the dose and duration of treatment to be used in phase III.

simple trials offer a far more economi- Center for the Study of Drug Develop- a collection of near-misses is strong. But
cal plan for collecting data on huge ment, the average length of all clinical questions remain about the validity of
numbers of patients; such trials routine- trials under way between 1996 and 1998 meta-analysis: the technique is subject to
ly enroll tens of thousands of subjects was 5.9 years— down from 7.2 years be- potential bias in terms of which studies
for a small fraction of what it would tween 1993 and 1995. But even with were selected for inclusion and the com-
otherwise cost. And with such large timesaving measures in place, clinical parability of those studies. The findings
numbers of people, even small effects of trials still represent a large investment of from a meta-analysis can be useful for
a medication can be detected. time and money. So when the results are interpreting a large amount of conflict-
Large simple trials have a major draw- ambiguous, leaders of a clinical trial ing data, but the results are not generally
back, however: they cannot be used to usually try to extract some useful infor- considered definitive.
test a new drug candidate, because the mation out of their hard work.
side effects are unknown. Giving large Often a phase III trial will show a Financial Dealings
numbers of patients an experimental trend in favor of a drug, but the effect
medication that has never been screened
for safety and has uncertain benefits is
unethical. As a result, researchers typi-
will be too small to serve as statistically
convincing proof. In many instances, ad-
ditional trials give mixed results as well.
M oney— who pays for the research
and who takes home the profits—
looms over every clinical trial. For many
cally run large simple trials to evaluate For such cases, statisticians have devel- years, the pharmaceutical companies
the relative effectiveness of known, ap- oped methods for pooling data from all have done most of the work of clinical
proved treatments. the previous trials to conduct what they trials themselves, hiring physicians to or-
Progress in accelerating the clinical term meta-analysis. Such evaluations re- ganize and run the trials, monitors to
trial process is already apparent. Ac- main controversial, however. The appeal verify that the data have been collected
cording to a 1999 report from the Tufts of trying to salvage a valuable result from accurately, statisticians to analyze the re-

Understanding Clinical Trials Scientific American April 2000 73

Copyright 2000 Scientific American, Inc.
 sults, clerks to enter findings into the been reserved for the trials of drugs that
databases, and a variety of support peo- are unlikely to result in substantial prof-
ple to handle the administrative func- its or for highly speculative studies that
tions involved in coordinating such a are too risky for industry to attempt.
massive endeavor. All of this is in addi- For example, the NIH sponsored the tri-
tion to the local physicians and nurses als indicating that aspirin reduced the
who care for patients enrolled in the tri- occurrence of strokes in patients who
al. The price tag for this enterprise had already suffered one. Although the
quickly becomes substantial, running number of patients who benefit from
into hundreds of millions of dollars. As a this finding is quite extensive, aspirin is
result, no one should be surprised that so inexpensive that none of the manu-
drug companies want to recover their facturers was willing to sponsor the
costs as expeditiously as possible. studies, because the subsequent profits
Stories of unethical behavior on the would not justify the costs.
part of the pharmaceutical companies A third approach to conducting trials
running clinical trials are relatively rare, has been tried in recent years: turning
but they do surface. Researchers involved them over to a contract research organi-
in trials have sometimes complained that zation, or CRO. These companies oper-
sponsoring drug companies restrict what ate independently from pharmaceutical
they can report to their colleagues and companies and are hired specifically for
the general public if a treatment appears conducting clinical trials. The CROs gen-
not to work. One alternative to having erally do nothing but manage trials and
the pharmaceutical industry finance so often have the capacity to test various
many studies is to have the NIH sponsor drugs in many countries simultaneously.
all clinical trials. Such an arrangement— Theoretically, then, CROs should be
which does happen on occasion even more efficient, and by relying on them
now— dramatically reduces the profit drug companies ought to be able to re-
motive of the people conducting the trial duce the costs of conducting large stud-
and usually assures that the resulting ies at numerous hospitals. Also, if a
studies will be of the highest quality. drug development program fails, the
But devoting tax dollars to research companies do not have to fire or transfer
into new drugs, many of which will the sizable number of people needed to less subject to conflicts of interest than
eventually result in large profits for conduct the research. the drugmakers are. They benefit finan-
pharmaceutical companies, is troubling. Because CROs do not profit from the cially only from the sale of their ser-
In the past, government support has sale of pharmaceuticals, they should be vices. Presumably, then, companies will
hire a CRO only if it conducts trustwor-
thy trials that stand up to FDA scrutiny.
In an attempt to minimize potential
174
HEIDI NOLAND; SOURCE: “SUCCESS RATES FOR NEW DRUGS ENTERING CLINICAL TESTING IN THE UNITED STATES.”

(100%) INDs filed problems over financial conflicts, most

1976 –1978 medical societies and major journals
now require from researchers a disclo-
150 sure statement that describes how the
(86%) Entered Phase I work discussed was financed, along
with any other details relevant to con-
flicts of interest. The U.S. government
requires a similar declaration from in-
124
(71%) Entered Phase II vestigators who participate in govern-
J. A. DIMASI IN Clinical Pharmacology and Therapeutics; JULY 1995

ment-sponsored trials or from consul-

tants involved in grant or regulatory de-
cisions at organizations such as the NIH
56
(32%) Entered Phase III or FDA. Some people even argue that re-
searchers who own stock in a drug com-
pany that supports their research should
48 sell it. These considerations are relative-
(27%) NDAs filed ly recent, and it is not at all clear yet
what— if any— effect they have.
For the near future, the basic frame-
35 NDAs approved work of clinical trials is here to stay, al-
(20%) though efforts are under way to fine-
DIMINISHING RETURNS are the norm in the clinical trial process. Only about 20 tune the process. But the extent to
percent of Investigational New Drug, or IND, applications filed with the FDA make it which it can be refined has limits. I like
to the final step, many years and many tests later: approval of a New Drug Applica- to say that we can describe the conduct
tion (NDA), which clears a treatment for marketing to the public. of a trial three ways: it can be trustwor-

74 Scientific American April 2000 Understanding Clinical Trials

Copyright 2000 Scientific American, Inc.
 PHASE 3: The Final Test
Number of volunteers: 300–30,000 or more patients with the disease being studied

What researchers hope to learn: Whether treatment is effective and what the important side effects are

Typical length: 3.5 years

Typical cost: $45 million

T he final stage of the clinical trial process,phase III,is

most familiar to the general public. Hundreds,
thousands,even tens of thousands of patients take part
the Evaluation of Medicinal Products. But if the first re-
sult is sufficiently persuasive,one trial can be enough. If
an agency is convinced, it approves the drug for sale as
in such tests, and results often receive much publicity. a treatment for the disease.
By this point, the scientists running the trial have de- If the results of phase III testing are not positive, sev-
fined at least one group of patients who are expected eral options remain. By poring over the tremendous
to benefit,how they benefit and the best way to admin- amounts of collected data, clinicians might be able to
ister treatment. The phase III trial can provide authorita- discover a cluster of patients within the larger group
tive confirmation that a drug works. who seem to have benefited. Researchers must then
If, after careful statistical analysis, the drug candidate conduct another full-scale phase III trial,this time with a
proves to be significantly more effective than the con- more restricted set of patients, to prove whether the
UNIVERSITY OF VERMONT/AP PHOTO

trol treatment, the trial is called pivotal. Ordinarily two drug actually did help. In practice, initial phase III trials
pivotal trials are needed to prove the value of a new frequently fail to show adequate proof of a drug candi-
therapy to regulatory agencies such as the U.S. Food date’s efficacy, and several follow-up trials must be car-
and Drug Administration or the European Agency for ried out. — J.A.Z.

HOPING FOR GOOD RESULTS, doctor and patient in this phase III trial of laser therapy for
Barrett’s esophagus disease await an answer to the crucial question: Does the treatment work?

thy, fast or cheap. Generally speaking, a Medicare? Going one step further, how tors and regulatory agencies around the
trial can have only two of these charac- well tested are other items that con- world, we can expect even better treat-
teristics. If a trial is fast and cheap, it is sumers purchase and how accurate are ments and continued elimination of old-
unlikely to be trustworthy. advertising claims? The validity of medi- er medications and procedures that do
No drug will ever be perfect, a com- cal claims is far better substantiated than not work. A long, dismal history tells of
plete cure for everyone with no side ef- in almost any other area of commerce. charlatans who make unfounded prom-
fects for anyone. The clinical trial re- The vast majority of the medical pro- ises and take advantage of people at the
mains a crucial proving ground for any fession accepts randomized, controlled time when they are least able to care for
new drug or medical device. A good way clinical trials as the required gold stan- themselves. The clinical trial process is
to evaluate the reliability of trials is to dard for deciding whether a treatment is the most objective method ever devised
compare them to matters requiring med- useful. The methodology is still evolving, to assess the efficacy of a treatment. It is
ical judgment. How often is unnecessary and some of the newer approaches to expensive and slow, and in need of con-
surgery performed? How often are false testing should prove to be of help. With stant refinements and oversight, but the
bills sent to insurance companies or increasing cooperation among investiga- process is trustworthy. SA

The Author Further Information

JUSTIN A. ZIVIN is a professor in the depart- Guide to Clinical Trials. Bert Spilker. Raven Press, New York, 1991.
ment of neurosciences at the University of Califor- Tissue Plasminogen Activator for Acute Ischemic Stroke. National Insti-
nia, San Diego. He is also a staff physician at the San tute of Neurological Disorders and Stroke rt-PA Stroke Study Group in New
Diego Veterans Affairs Medical Center. Zivin earned England Journal of Medicine, Vol. 333, No. 24, pages 1581–1587; December
his M.D. and Ph.D. at Northwestern University. Be- 14, 1995.
fore moving to California, he was a member of the International Stroke Trial (IST): A Randomized Trial of Aspirin, Subcu-
faculty at the University of Massachusetts Medical taneous Heparin, Both, or Neither among 19,435 Patients with Acute
School. Zivin has also served as a consultant to nu- Ischemic Stroke. International Stroke Trial Collaborative Group in Lancet,
merous pharmaceutical and biotechnology compa- Vol. 349, No. 9065, pages 1569–1581; May 31, 1997.
nies but has never owned shares in any of them. In Oversight Mechanisms for Clinical Research. Ralph Snyderman and Ed-
1993 he co-founded Cerebrovascular Advances, ward W. Holmes in Science, Vol. 287, No. 5453, pages 595–597; January 28, 2000.
Inc., which merged with the contract research orga- CenterWatch Clinical Trials Listing Service is available at www.centerwatch.com
nization Quintiles Transnational in 1997. on the World Wide Web.

Understanding Clinical Trials Scientific American April 2000 75

Copyright 2000 Scientific American, Inc.