It was November of 2001, shortly after the savage attacks of 9/11, and America was gripped with fear of illness and death from the anthrax envelopes sent to government officials. The U.S. government was concerned about a much larger biological attack against Americans with a more potent infectious agent – smallpox virus. Smallpox vaccinations had ended in 1972 after smallpox was eradicated in the U.S.A. Millions of Americans thus lacked immunity to the virus. To prepare for a possible smallpox attack, the University of Maryland School of Medicine opened a clinical trial. Because there was a limited supply of the smallpox vaccinia vaccine, the question was whether a reduced dose of the vaccine could generate a sufficient immune response to protect the population.
I was intrigued by
the research question and, like so many Americans post-9/11, felt very
patriotic; I wanted to contribute to the cause. Volunteering for the clinical
trial, I received a vaccine dose, and yes, the vaccine did render me immune to
the virus. The trial was later published in the New England Journal of Medicine (NEJM; Frey et al., N Engl J Med. Vol 346, 2002). Having been
vaccinated, I felt protected and could safely step into the breach to assist
should a smallpox biological attack occur. I use this personal vignette to
exemplify only two of the many reasons people will join a clinical trial:
wanting to contribute to the common good and satisfying a scientific curiosity!
From this personal
story, we see one main difference between regular medical care and a clinical
trial. A clinical trial seeks to answer a scientific question – for example, can
a diluted vaccine generate an immune response? There are many other clinical
research questions asked by the 421,000 research studies registered with clinicaltrials.gov. They are conducted in
more than 200 countries, with just under half being done within the U.S.A. (as of
07/14/2022).
There are many
scientific terms associated with clinical trials, and a good place to start in explaining
them would be to focus on a better understanding of the main clinical trial
types.* They are:
Interventional Study: Perhaps the type
of study with the broadest effects for science and for the participants (also
referred to as “subjects”), interventional studies assign the subjects – often randomly,
like drawing from a hat – into specific groups or “arms” of the trial. In any
given arm, they may receive one or more active interventions, standard of
medical care, or just placebo (e.g., a harmless pill). These interventions can
include drugs, biologics (e.g., a smallpox vaccine or a Covid-19 vaccine),
behavior modifications, surgeries, or new test devices and instruments. The
interventions can be invasive, being inserted within the body (like a
pacemaker), or non-invasive, such as dietary modifications.
To reduce various
types of biases, prejudice, or predilections, an important aspect of these
trials is that different levels of “blinding” can be expected. For example, in
my smallpox vaccine trial, only I was unaware if I was receiving an undiluted
or diluted dose. Afterward, I did find out that it was a 1-to-5 dilution. However,
in a double-blind trial, neither the subject nor the physician would know
what’s in that inoculation (undiluted or diluted vaccine, for example).
Investigators can evaluate and measure the effects of the intervention(s) on
health-related outcomes by following the study protocol exactly. This reduces
the chances of inaccurate or misleading conclusions. There are many more
aspects of interventional trials, such as phases or steps, and I hope to explain
more about them in future articles.
Observational Study: Also termed “natural
history,” “case-control,” or “retrospective” studies, the focus of the observational
clinical trial is to discover scientific or medical outcomes by just observing
the trial participants, in some situations against a control population without
the disease of interest. Usually, in observational trials, the participants do
not receive any interventions from the trial itself. Natural history studies
can function as “patient registries,” where investigators attempt to collect as
much relevant information as possible about the trial subjects and all aspects
of their disease and medical care. Participation in observational trials helps
expand the general knowledge about a syndrome, disease, or even human behavior.
Expanded Access (EA): These trials are a
necessary modification of interventional studies. Unlike interventional trials,
where the trial informs on and creates new science in the area that is the
focus of the trial, with EA trials, more stress is placed on providing any
measure of benefit for the patient, with science taking a back seat. For
example, in EA studies, also called “compassionate use,” patients with no other
resort for standard care – and usually in dire need of some yeshu’ah
(salvation) – will be given an unlicensed drug that is unproven, i.e., non-FDA
approved. There will be pre-clinical knowledge from the laboratory and animal
studies, perhaps, but no to very little data as to how safe and effective it is
in humans for a specific use.
The FDA provides
for different sized EA trials. They may even be administered to a single individual.
It is obvious, of course, that we cannot generalize any results to the entire
population. For more details about this type of study, go to www.FDA.gov and
search for “expanded access.” These are the trials that often make the news or
are passed on via social media.
* * *
Two examples of these trial categories can be found in the
recent edition of the NEJM (July 14th). It is a premier
journal for medical peer-reviewed scientific literature and has published much
on Covid-19 in the last two-and-half years. Indeed, of the four NEJM
articles in this issue, all reporting on clinical trials, one was on Covid-19
vaccination during pregnancy, another two on cancer (lung and myeloma), and the
fourth on neonatal hypoxic–ischemic encephalopathy (nHIE), where the baby did
not receive sufficient oxygen to the brain around the time of birth, resulting
in brain dysfunction.
The Covid-19 study
was a case-control trial showing the positive benefits of maternal vaccination
for babies less than six months old; the non-small cell lung cancer study was
an interventional trial investigating a positive response to the drug against
the disease; the third was an interventional trial evaluating two different
treatments for myeloma patients who had failed previous therapies (one provided
20 more months of life); and the nHIE interventional trial had disappointing
results, with no improved benefits observed with the experimental drug. (Actually,
there were worse side effects.) It is these clinical trials that ultimately
move their respective fields forward by either promoting new treatments or, as
in the nHEI trial, dissuading use of a drug that has no benefit to treat a
disease.
Although this is
by no means an exhaustive expose on clinical trial types and terms, I hope you
found this article helpful. In the next issue of WWW, I hope, G-d
willing, to explore Part II: Clinical Trial Basics: resources, finding trials,
and knowing what to ask. We remind our readers that, while clinical trials do
provide hope (as in the first three NEJM trials), expectations for a
positive outcome, much less a cure, cannot be guaranteed, and that there is
risk associated with participation (as in that fourth trial for nHEI). I would
offer, however, that whatever the outcomes of any given clinical trial, medical
education can be broadened, life given more purpose, and worlds of possibility
hugged tightly, only to then be released as additional light into our world. Hashem
ya’azor.
Daniel Edelman received his BTL from Ner Israel
Rabbinical College, his M.S. in Applied Molecular Biology from University of MD
Baltimore County, and his Ph.D. in Medical Pathology from University of MD
Baltimore. Dr. Edelman worked at the Food and Drug Administration (FDA) as a Scientific
Reviewer for a brief stint before moving to the NCI/NIH for 13 years as a
laboratory manager of a clinical laboratory supporting NCI cancer research and
clinical trials. While at NIH, he ran a science bridge program for seven years
for dozens of young Orthodox Jewish women seeking a mentored pathway into the
sciences; many have gone on to careers in science and medical fields.
Currently, Dr. Edelman is a Biologist/Policy Analyst at the FDA as part of the
Personalized Medicine Team where he and his colleagues seek to bring the right
test, to the right patient, at the right time, for the use of the right drug.
The views expressed in this series do not necessarily represent the views of
the FDA or the United States government.
* Clinical trial
definitions were derived and modified from clinicaltrials.gov_TypesofStudies.
