1. No category

BUT I SAW IT ON TV! HOW TO CRITIQUE CLINICAL
STUDIES AND COMMUNICATE THEIR RESULTS TO
QUESTIONING PATIENTS
DR. GASBARRO’S MONOGRAPH
BUT I SAW IT ON TV! HOW TO CRITIQUE STUDIES AND COMMUNICATE
THEIR RESULTS TO QUESTIONING PATIENTS
ACTIVITY DESCRIPTION
ACCREDITATION
The Internet may grab all of the attention these days,
but TV is still the media king. According to one
recent study, the average American spends over 4.5
hours a day in front of the tube, and a whopping
99% of all US households have at least one TV.
According to the A.C. Nielsen Co, the number of TV
commercials seen by the average person by age 65 is
approximately 2 million. A sizable chunk of these are
health-related. Pharmacists constantly get asked
questions about medications their patients have seen
on television or in magazines. Many of these
products promise to enhance some aspect of the
patient’s body, such as weight loss or recapturing
youth. The primary literature can be used to explain
whether or not the medications are useful and
properly studied in valid clinical trials. In this activity,
the accessibility of the primary literature will be
explained and the elements of a clinical study
defined. Examples of good, poor, and internal studies
will be cited.
PHARMACY
PharmCon, Inc. is accredited by the
Accreditation Council for Pharmacy
Education as a provider of continuing
pharmacy education.
NURSING
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Registered Nursing (Provider Number CEP 13649) and
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BN are accepted by most State Boards of Nursing.
CE hours provided by PharmCon, Inc. meet the ANCC criteria
for formally approved continuing education hours. The ACPE
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information, please visit
http://www.nursecredentialing.org/RenewalRequirements.aspx
Universal Activity No.: 0798-0000-13-176-H01-P&T
Credits: 1 contact hour (0.1 CEU)
TARGET AUDIENCE
The target audience for this activity is pharmacists,
pharmacy technicians, and nurses in hospital,
community, and retail pharmacy settings.
Release Date: June 17, 2014
Expiration Date: June 17, 2016
LEARNING OBJECTIVES
ACTIVITY TYPE
After completing this activity, the pharmacist and
nurse will be able to:
 Define the elements of a clinical study
 Interpret a clinical trial in terms of its design
and intent
 Analyze a clinical study without reading the
entire paper
 Determine if the results of a trial are clinically
relevant and applicable to one’s practice
Knowledge-Based Home Study Monograph
FINANCIAL SUPPORT BY
Pharmaceutical Education Consultants, Inc.
After completing this activity, the pharmacy
technician will be able to:
 List criteria for a clinical study
 Determine if results of a trial are clinically
relevant
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ABOUT THE AUTHOR
Ron Gasbarro is a practicing pharmacist with a strong
background as a medical/pharmaceutical writer
specializing in peer-reviewed journal articles as well as
many other aspects of medical communication. He has
long been interested in patient education. He earned
his Doctor of Pharmacy (PharmD) at the University of
Maryland at Baltimore, his MS in Science Journalism at
Boston University, and his BS in Pharmacy at SUNY
Buffalo. He has written on many topics including those
having to do with psychiatry, psychotropics,
cardiology/cardiovascular, antibiotics and infectious
disease, oncology (solid tumors; targeted therapies) as
well as a range of other subjects including
epilepsy/seizure disorders, pain management, and
HIV/AIDS.As a working pharmacist, he brings a specific
awareness to the production of educational webinars
that are meant to address the concerns and realities of
pharmaceutical work today.
Ron Gasbarro, PharmD
Rx-Press
FACULTY DISCLOSURE
It is the policy of PharmCon, Inc. to require the
disclosure of the existence of any significant financial
interest or any other relationship a faculty member or
a sponsor has with the manufacturer of any
commercial product(s) and/or service(s) discussed in
an educational activity. Ron Gasbarro reports no
actual or potential conflict of interest in relation to
this activity.
Peer review of the material in this CE activity was
conducted to assess and resolve potential conflict of
interest. Reviewers unanimously found that the
activity is fair balanced and lacks commercial bias.
Please Note: PharmCon, Inc. does not view the existence of
relationships as an implication of bias or that the value of
the material is decreased. The content of the activity was
planned to be balanced and objective. Occasionally,
authors may express opinions that represent their own
viewpoint. Participants have an implied responsibility to use
the newly acquired information to enhance patient
outcomes and their own professional development. The
information presented in this activity is not meant to serve
as a guideline for patient or pharmacy management.
Conclusions drawn by participants should be derived from
objective analysis of scientific data presented from this
monograph and other unrelated sources.
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Ask your pharmacist (aka street doctor)
Because we are available, free and not far off the sidewalk, pharmacists like ourselves
constantly get asked questions about medications or supplements their patients have seen on
television or in magazines. Many of these products promise to enhance some aspect of the
patient’s body, such as weight loss or recapturing youth. Well-designed clinical studies with
solid data and conclusions, published in the primary literature, [Table 1] can be used to explain
whether or not the medications are useful and properly studied for both safety and efficacy in
valid clinical trials. In this activity, the accessibility of the primary literature will be explained as
well as the definition of clinical study elements and how to separate and analyze good medical
information from the bad.
The TV as huckster
Although the Internet has captured most of the attention these days, TV is still the media king,
especially when it comes to hawking products. According to the United States Department of
Labor’s Bureau of Labor Statistics, the average American ages 15 years and up watch TV 2.83
hours a day. That’s more than time spent than playing sports, exercising, doing housework,
eating and drinking, volunteering and attending to phone calls and mail – combined. And
within those almost 3 hours, there is a chockablock of advertisements thrown at us: if you
figure 30 commercials per hour, that is about 90-100 ads per 24-hour intervals. That does not
even factor in to what people are exposed in radio, magazines and newspapers [Media Matters,
2007]. Many of these promotions are health-related.
Being the astute professional that you are, you may notice the difference between products
that have been proven to work, that is, they have been approved by the United States Food and
Drug Administration (FDA) and products that simply declare that they work. The manufacturers
who insist their products do the trick usually obtain testimonials from elated, ecstatic people
for whom that product exponentially changed their lives for the better and why it is better (e.g.,
lost weight, increased muscle mass, sloughed off cellulite).
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However, ads for FDA-approved drugs go by a different philosophy, principally because the FDA
tells them so. For example, the indications for a drug do not have to be stated. You can see an
ad for an allergy medication and the indication is implied – for example, a girl running through a
field replete with pollen-producing plants and not sneezing her head off. Other ads can state
the indication – such as erectile dysfunction for men or painful sexual intercourse for women.
But the ads are light on the facts and heavy on the emotion. Side effects are trivialized and
rapidly spewed out. And there is also a good chance any health care professional who promotes
a drug is being compensated for it. Although last year, GlaxoSmithKline announced they would
not be doling out honoraria for such endorsements [PBS, 2013].
Bottom line: The patient wants to know if the product is worth buying. As pharmacists, we do
not know everything but we can have the tools to gain knowledge.
What are clinical studies and why are they important to pharmacists?
Generally, clinical studies are designed to add to medical knowledge related to the treatment,
diagnosis, and prevention of diseases or conditions. Some common reasons for conducting
clinical studies are shown in Table 2. Knowing how to locate clinical studies and draw your own
conclusions about whether or not a product is of value to the patient can bring a new
dimension to your knowledge as a pharmacist, whether you work in a community setting or an
institutional arena.
You want to be in pictures?
Consider anti-aging preparations. One of your patients, Mrs. Jones, asks you about a skin cream
she saw on TV. Although topical creams and other anti-aging products purport to reduce the
appearance of aging and skin wrinkling, no critical analysis has been published in the scientific
literature of their effectiveness. A meta-analysis refers to a method that focuses on contrasting
and combining results from different clinical studies, in the expectation of identifying patterns
among study results, sources of disagreement among those results, or other interesting
relationships that may come to light in the context of multiple studies [Greenland, 2008]. In
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2010, a meta-analysis was performed to critically evaluate the evidence for the effectiveness or
efficacy of botanical treatments in reducing skin aging and wrinkling [Hunt, 2010]. Of 36
potentially relevant studies, 11 trials of botanical extracts for reducing skin wrinkling and the
appearance of aging met all the inclusion criteria. No trials were identified that were funded by
anti-aging and cosmetic organizations, cosmetic companies or professional bodies. A significant
reduction in skin wrinkling was noted for date kernel extract, cork extract, soy extract,
Rosaceae and peony extract. No significant reduction was noted for green tea, Vitaphenol® (a
combination of green and white teas, mangosteen and pomegranate extract) or maca root. All
trials were of poor methodological quality. Adverse effects were frequently not reported.
Conclusion: some weak evidence exists to suggest that several botanical extracts may be
effective in reducing the appearance of skin aging but no evidence was revealed to assert this
effect enduring. According to the authors of this meta-analysis, independent replications with
larger, more diverse samples, longer treatment durations and more rigorous study designs are
required to validate these preliminary findings. Therefore, as a pharmacist you can quickly
review the meta-analysis abstract and advise the patients from a cost-standpoint (“The $65
cream may work no better than the $5 cream.”). Or you can delve into the article itself and find
out which botanical cream may work better than another.
Dissecting a clinical study
As opposed to a pre-clinical study which tests molecules on animals, a clinical study involves
research using human subjects – also called participants – that is intended to add to our body of
medical knowledge. ClinicalTrials.gov is a registry of clinical trials. It is run by the United
States National Library of Medicine at the National Institutes of Health, and is the largest clinical
trials database, currently holding registrations from over 130,000 trials from more than 170
countries in the world. According to clinicaltrials.gov, two chief types of clinical studies exist:
clinical (also called interventional) trials and observational studies.
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Clinical Trials
In a clinical trial, participants receive specific interventions according to the research plan or
protocol created by the investigators. These interventions may be medical products, such as
drugs or devices; procedures; or modifications in participants' behavior, such as whether
exercise or diet can improve an individual’s condition. Clinical trials may compare a new
medical approach to a standard one that is already available or to a placebo that contains no
active ingredients or to no intervention. Some clinical trials compare existing interventions.
When a new product or approach is being studied, whether it will be helpful, harmful, or no
different than available alternatives is generally not yet known. Thus, the investigators attempt
to determine the safety and efficacy of the intervention by measuring certain outcomes as
demonstrated by the participants. For example, investigators may give a drug or treatment to
participants who have hypertension to observe whether their serum glucose levels decrease.
Clinical trials used in drug development are sometimes described by phase. These phases are
defined by the Food and Drug Administration (FDA) and are presented in Table 3.
Observational Studies
In an observational study, investigators assess health outcomes in groups of participants
according to a protocol or research plan. Participants may receive interventions, which can
include medical products, such as drugs or devices, or procedures as part of their routine
medical care. However, participants are not assigned to specific interventions by the
investigator, as they would be in a clinical trial. For example, investigators may observe a group
of older adults to learn more about the effects of different lifestyles on cardiac health.
The elements of a clinical study
A clinical study contains the following 7 elements:
Abstract
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An abstract is a concise summary of the full text of a research paper, typically 200 to 250 words
but can be shorter or longer. An abstract contains the background for the study, the purpose of
the study, the procedures followed such as how study volunteers were selected, and
observational and analytic methods used. Abstracts must also contain the study’s main findings,
the conclusions drawn from the data and any other important aspects of the study. Reading the
abstract is the quickest way to see if the information which you are seeking is within the body
of the published paper.
Introduction and literature review
The introduction section of a clinical study contains the rationale for the study and puts it in
context. As it is technically a backgrounder, it should contain the objective of the study and the
researchers’ hypothesis. Unlike a newspaper article which starts off with the most important
and most sensationalistic information first (e.g., Three car pileup leaves Route 81 backed up for
15 miles), a clinical study starts off slow and easy. If it is about the common cold, for instance,
the opening paragraphs will discuss the history of the disease, epidemiology, symptoms, and
any other information to set the stage for the study that follows. It will also explain the
knowledge gaps that the study that will become the reason why this study is being done (e.g.,
to date, no vaccine has ever been successfully formulated that can prevent the common cold).
Materials and methods
The material and methods section explains how the study was set up, that is, how the study
was designed. The methods section also describes the sample size, provides a statistical
analysis of the data, explains whether the study was randomized, placebo-controlled and
blinded (usually double-blinded, that is, neither the patient nor the investigators know which
treatment is being given to which participant) and inclusion criteria (e.g., all participants must
be ages 25 to 60) as well as the exclusion criteria (e.g., participants should not be pregnant,
allergic to latex, or come from the West Coast). In addition, this section will tell who supplied
the materials being tested, for example, from where did the study drug come. A statistical
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analysis will also be explained in this section so that there is a record of how the data was
collected and interpreted from a mathematical standpoint. Figure 1 illustrates the 4 phases that
investigators go through in a randomized study to ensure that all participants are treated in the
same way. How many people are enrolled? Of these, how many are randomized? The next
hurdle is who is eligible to receive treatment (intervention allocation) and then who actually
received the pill or procedure which was the purpose of the study. Then participants are
followed-up. Patients who prematurely discontinued the treatment, or who dropped out from
the study for whatever reason are considered “lost to follow-up”. Finally, the data harvested
from the study is analyzed with respect to the remaining participants. This can be the most
mind-numbing section of any paper but it must be included to prove statistic validity. This part
is required in any clinical study that is published.
Results
The results section contains all the findings of a study. This includes patient characteristics (e.g.,
350 adults ranging in age from 22 to 58.5 years) of those completed the study. Then, all of the
clinical data is presented using text, graphs, and tables. Safety data are also reported here,
including the incidence of adverse reactions and what they were. This section is not
editorialized in any way, that is, no conclusions can be drawn in this section. Just the facts.
Discussion and conclusions
The discussion and conclusions section puts the study in perspective. This section should
include the implication the research results may have on future treatment of the subject health
condition or disease. Any study limitations or weaknesses should be included, such as whether
bias or confounding may have influenced the results.
References
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This is a listing of where all specific information that was cited in the paper, including other
clinical studies, statistics, and epidemiology. For example, if the statement reads “over 30
million people suffered from a cold in New York between 2011 and 2014,’ that statement needs
to be referenced. The purpose of this section is to give the reader an easy way to look at other
studies that pertain to the original one.
Acknowledgement of funding and conflict of interest statement
Authors must disclose financial conflicts that could potentially influence how they describe or
present the research results. If an investigator works for the company that is researching the
drug in question, then it must be stated here.
Clinical studies are expensive
Depending on the therapy, bringing a single drug to market can cost between $500 million to
$2 billion [Adams, 2006]. With a combination of high late-stage failure rates and the exorbitant
cost of drug trials, the number of new molecular entities being approved by the FDA has
bottom out at historically low levels, plummeting from 53 in 1996 to just 19 in 2009 [Holland,
2013]. If the cost of drug trials is not contained, expect to see fewer new drugs and a
disproportionally greater number of generics on pharmacy shelves as your career continues.
How to do a simple literature search
Thanks to the Internet, doing an online literature search is simple. The most valuable tool for
conducting a literature search is to use PubMed. PubMed.gov is a free search engine accessing
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primarily the MEDLINE database of references and abstracts on life sciences and biomedical
topics. The United States National Library of Medicine (NLM) at the National Institutes of
Health (NIH) maintains the databases that the latest published information can be swiftly
retrieved.
Perhaps you would like to find out about polio. You would type the word “polio” into the search
box and hit the enter key. You will see that over 23,000 links pop up. That’s too many for
anyone’s schedule. Therefore you have to refine your search. What is it about polio you want to
know? Type in “polio vaccine” and hit the enter key. We are down to 7,200 links – still too
many. But if you put in “polio vaccine efficacy united states,” you get 29 returns [Figure 2]. This
is a manageable amount and you can quickly scroll through the list and find the articles you
want. The entries are listed in chronological order and display the title, authors, and a link to
the abstract [Figure 3]. Click on one of the articles and an abstract of approximately 250 words
can be seen. Although some publishing companies may charge you to see the entire article, an
ever-increasing amount will let you open the article – often as a PDF file – for free.
More informational websites of high quality information can be found at other sites managed
by NIH. The following websites from the National Institutes of Health (NIH) and the Food and
Drug Administration (FDA) provide information about clinical studies, drug development, and
other health care issues: [clinicaltrials.gov, 2014].

NIH Clinical Research Trials and You
The NIH Clinical Research Trials and You website provides general information on participating
in clinical research with a focus on NIH-funded research.

MedlinePlus® Clinical Trials Information
MedlinePlus is a web-based health information service of the National Library of Medicine. It
explains health topics using language that is easy to understand. Visit the clinical trials page or
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the interactive tutorial on clinical trials (both pages available in Spanish) to learn more about
clinical research and find answers to common questions.

Children and Clinical Studies
The National Heart, Lung, and Blood Institute provides information about pediatric studies on
its Children and Clinical Studies page.

Clinical Trials and Drug Development
The Food and Drug Administration (FDA) is responsible for ensuring the safety and effectiveness
of drugs, vaccines, and other medical products. Read more about clinical trials and the drug
development process on FDA's website, fda.gov.
What constitutes a poorly designed study?
Let’s take the case of a mythical product called Nervoid. Nervoid consists of 3 different
ingredients: sodium complexinate, y-jinga root, and Beatle extract. The manufacturer touts the
product as good for sleep, weight loss, and raising testosterone levels. The manufacturer of
Nervoid cites a clinical study which is posted on their website. Briefly analyzing the study
involves the following elements:
Element 1: Was the clinical study conducted on the product, per se, or does the marketer of the
product merely cite other clinical studies on the ingredients in their product? If so, does the
product actually incorporate at least the minimal dosage level that a consensus of qualified
clinical studies proved efficacious? If you look at the ingredients list on the labels of many
products, there can literally be a dozen or more components which imply that few, if any, are at
clinically validated dosage levels. For example, let’s say that a recent study cited in PubMed
shows that y-jinga root has some benefit in restoring hair loss. However, the dosage used in
that study was 50 mcg, whereas the amount of y-jinga root in Nervoid contains only 15 mcg. So
strike one on the hair restoration claim. Sodium complexinate is at a higher dose that other
cited studies and interacts with warfarin and digoxin (which no warnings on the label). Strike
two! Beatle extract has only been tested in mice, not humans. Strike 3!
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Element 2: Was the study actually published? Depends. Some studies are internal so they are
not going to be published in the medical literature. This is not an ideal way to go because
verifying how the study was done is not possible. Pharmaceuticals are subject to rigorous
requirements set by the FDA. And, in fact, not many make it all the way to the final approval
process. Failures in phase 2 studies can be limited if the trial is well implemented.
Unfortunately, this is not the norm. The rate of failure in pivotal studies is substantial, standing
at about 45% [Kola, 2004]. In certain key areas, such as oncology, and with more novel
compounds, the failure rate has been considerably higher. For example, among
biopharmaceuticals that entered clinical trials in oncology throughout the 1990’s, the success
rate was a very low 13% [Pavlou , 2004]. More recent estimates by the FDA have lowered this
figure to approximately 8% [FDA, 2010b]. If one looks at all agents developed for oncology
applications in the same time frame, only 5% of those that entered clinical development ever
reached approval; approximately 60% of those that had apparently successful phase 2
programs failed in phase 3 studies [Kola, 2004]. For certain CNS applications, especially
neuroprotection in ischemic stroke or head trauma, the attrition rate is probably the
uppermost of any field [Retizos, 2010]. Fifty-plus molecular agents have been tested in
numerous clinical trials but none was proven clinically beneficial [Kidwell, 2001; Ginsberg,
2008]. The industry seems to be falling below the numbers required for replacement of
commercially successful compounds required to maintain revenues. The rarity of new drugs
and biologics is fueling a number of mergers and acquisitions in the industry, which is failing to
provide adequate solutions in many devastating diseases [Retzios, 2010].
The FDA classifies nutritional products, such as vitamins and muscle-building in two ways:
supplements and regulated food products. How the manufacturer wants to classify a product is
at the pleasure of the manufacturer. Supplements are not subject to FDA regulations so
athletes should be advised to avoid them. The only reason not to submit a product for FDA
evaluation is poor quality or harmful ingredients. Using the example of protein beverages, a
product may contain potentially albeit debatably harmful chemicals such as acesulfame
potassium and/or sucralose – both artificial sweeteners – or products that contain poor quality
12
protein. Very likely, that manufacturer does not want an actual, thorough evaluation done on
their nutrient levels and protein sources. So, they define them as foods which absolve them
from a whole slew of testing. Because the ingredients used in Nervoid’s are considered food
additives, it is termed a food.
Element 3: Did the study test a statistically significant sample size (e.g. 75-100 subjects) and
employ guidelines and ethics recommendations set up by the US Department of Health,
Education, and Welfare (DHEW) for conducting a randomized, double-blind, and placebocontrolled trial? [Table 4] In the case of Nervoid, only 30 people participated in the study. More
is always better but this number is too low to make any statistically significant conclusions that
can be extrapolated to, perhaps, millions of customers.
Element 4: Did the study use clinically acceptable instruments for the objective measurement
of a broad range of sleep, weight, and testosterone functions? We do not know because the
design of the study was not revealed. Instead, the client used advertising claims such as
“Clinically proven to stop hair loss, to lose weight and to raise testosterone levels.” We also do
not know if the study protocol was approved by an independent review board (e.g. Institutional
Review Board – IRB), or whether it was conducted by an internationally recognized research
university or Clinical Research Organization (CRO)?
Conclusions
When it comes to buying unregulated health products that promise too-good-to-be-true
results, let the buyer beware. The FDA has strict standards in terms of pharmaceutical
advertising. However, when it comes to supplements, health products and even some food
items that are not regulated by the FDA, they can be blatantly advertised on TV and through
other media, while retail shelves groan under the weight of products making unfettered and
bogus claims. The pharmacist can be a great help in directing patients toward products that
have been proven to work. And by having the ability to recognize and navigate the primary
literature, we can offer customers, who trust us implicitly, a higher and safer level of service.
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Table 1 – Primary, secondary and tertiary literature sources [UMaryland, 2014]
Categories of scientific
Definition
Examples
Comparisons
literature
Primary literature
Original materials that have
Journal articles published in
The diary of Louis
not been filtered through
peer-reviewed publications;
Pasteur
interpretation or evaluation
Photographs;
and on which other research is
Proceedings of meetings,
based; usually the first formal
conferences and symposia;
appearance of results in
Survey research (e.g., market
physical, print or electronic
surveys, public opinion polls);
format and present original
Some websites (.gov, .edu, .org)
thinking, report a discovery, or
share new information.
Secondary literature
Tertiary literature
Accounts written after the fact
Biographies;
A biography about
with the benefit of hindsight;
Commentaries, criticisms;
Louis Pasteur’s life
interpretations and
Dictionaries;
evaluations of primary
Review articles about a disease,
sources; are not evidence, but
a drug, or a drug class;
rather commentary on and
Meta-analyses
discussion of evidence.
Scientific monographs
Sources that consist of
Almanacs;
A textbook about
information which is a
Encyclopedias;
pasteurization
distillation and collection of
Fact books;
primary and secondary
Manuals;
sources.
Textbooks
Table 2 – Reasons for conducting a clinical study [clinicaltrials.gov, 2014]

To evaluate one or more interventions – such as a drug, medical device, an approach to
surgery or radiation therapy – for the purpose of treating a disease, syndrome, or condition

To find methods for preventing the initial development or recurrence of a disease or
condition. These can include medicines, vaccines, or lifestyle changes, such as losing weight.
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
To assess one or more interventions aimed at identifying or diagnosing a particular
disease or condition

To examine methods for identifying a condition or risk factors for that condition

To explore and to measure ways to improve the comfort and quality of life of people
with a chronic illness through supportive care
Table 3 – Clinical study phases [FDA, 2010a; Friedman, 2010]
Phase
Definition
Phase 0
An exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic
goals. Examples include screening studies and microdose studies, the latter of which observes the behavior of
drugs in humans through the administration of doses so low (sub-therapeutic) they are unlikely to produce
whole-body effects, but high enough to allow the cellular response to be studied.
Phase 1
A study that is typically conducted with healthy volunteers with the emphasis on safety. The object is to
reveal the molecule’s most frequent and serious adverse events as well as how the drug is metabolized and
excreted, as would be the case in pharmacokinetic studies. The number of subjects typically ranges from 20
to 80 [FDA, 2014].
Phase 2
A study that harvests preliminary data on efficacy in a certain disease or condition. For example, participants
receiving the drug may be compared with similar participants receiving a different treatment, usually a
placebo or a different drug. Safety continues to be evaluated, and short-term adverse events are
studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300 [FDA,
2014].
Phase 3
A study that gathers more information about safety and effectiveness by studying different populations and
different dosages and by using the drug in combination with other drugs. Phase 3 trials are the most
expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical
conditions. However, the data obtained via the study results is the information submitted to the FDA to see if
that agency approves the drug for market. The number of subjects usually ranges from several hundred to
about 3,000 people [FDA, 2014].
Phase 4
A study that is conducted after the FDA approves the marketing of a drug and the agent is released into the
general population. The purpose of phase 4 research is to examine the long-term effects and safety of a drug
over an extended time period for a larger group of people. Phase 4 clinical trials often test the drug’s effect
on certain types of people, such as pregnant women, or to test the drugs’ interaction with other medications
patients are taking. Harmful effects discovered by Phase 4 trials may result in a drug being no longer sold, or
restricted to certain uses: recent examples include cervistatin (Baycol), troglitazone (Rezulin) and rofecoxib
(Vioxx).
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Table 4 – Ethical requirements for conducting a placebo-controlled clinical study [National Commission,
1978]
Definable conditions exist that should be addressed before placebo-controlled trials are
permitted to proceed. The assessment of these clinical conditions is grounded in the ethical
requirements outlined in DHEW’s Belmont Report. For the approval of placebo controls in
phase 2, 3, and 4 trials, the following questions should be considered:

Do participants have a disease or condition for which treatment is available, normally
prescribed, and of known efficacy?

Will lack of treatment likely result in progression of the disease or condition or the
infliction of pain or suffering during the trial?

If the disease or condition progresses, is this likely to be reversible?

If the disease process is irreversible, how great is the burden of this progression, and
how likely is existing treatment to resolve or reduce this burden?

Is there substantial evidence that the experimental treatment is of therapeutic benefit?
Figure 1- Flowchart of the 4 phases – enrollment, intervention allocation, follow-up, and data
analysis – of a parallel randomized trial of 2 groups, modified from the CONSORT (Consolidated
Standards of Reporting Trials) 2010 Statement [Schulz, 2010]
16
17
Figure 2 – An example of the results of a literature search on PubMed
18
Figure 3 – An example of a clinical study abstract from PubMed
19
References
Adams CP, Brantner VV. Estimating the cost of new drug development: Is it really $802
million? Health Affairs. 2006;25: 420–8.
Bureau of Labor Statistics. US Department of Labor. American Time Use Survey Summary –
2012 results; 2013. Available at: http://www.bls.gov/news.release/atus.nr0.htm Accessed
June 2, 2014.
Clinicaltrials.gov. Learn About Clinical Studies; 2012. Available at:
http://clinicaltrials.gov/ct2/about-studies/learn Accessed June 2, 2014.
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 4th ed. New York:
Springer Publishing Co.; 2010.
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ACTIVITY TEST
1. According to the United States Department of Labor’s Bureau of Labor Statistics, the average
American ages 15 years and up watches TV:
A. 2 or 3 hours a day
B. Under 2 hours a day
C. Approximately 4 hours a day
D. Approximately 5-1/2 hours a day
2. What is an example of a primary literature source?
A. A review article about asthma medications
B. An original journal article about a treatment for bipolar disease
C. A criticism of the methods by which a phase 3 study was designed
D. The 6 o’clock news
3. What is not an example of a secondary literature source?
A. The Farmer’s Almanac
B. A monograph about a new cholesterol-lowering agent
C. A commentary on the state of Big Pharma
D. Dorland’s Medical Dictionary
4. In which clinical drug development stage were Vioxx and Baycol removed from the market?
A. Phase 0
B. Phase 1
C. Phase 3
D. Phase 4
5. Which clinical trials are the most expensive, time consuming and difficult to design and
conduct?
A. Phase 4
B. Phase 3
C. Phase 2
D. Phase 1
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6. What is not true about the economics of clinically testing a new drug entity?
A. Being a single drug to market can exceed $1 billion
B. Late-stage failure rates during the latter stages of clinical testing can be diminishing
C. The number of new drugs being approved by the FDA is declining
D. All of the above
7. Which is a registry of clinical trials?
A. ClinicalTrials.org
B. ClinicalTrials.edu
C. ClinicalTrials.gov
D. ClinicalTrials.com
8. What is not a good reason to conduct a clinical study?
A. To evaluate whether or not a new molecular entity can control hyperglycemia better than a
particular sulfonylurea
B. To determine whether 30 minutes of exercise a day can lower weight more significantly than 15
minutes of the same exercise a day
C. To assess whether testosterone levels in men can predict the emergence of prostate cancer
D. None of the above
9. In the flowchart of the 4 phases of a parallel randomized trial of 2 groups, which phase is
done last?
A. Data analysis
B. Enrollment
C. Follow-up
D. Intervention allocation
10. Which of the following websites from NIH and FDA provides general information on
participating in clinical research with a focus on NIH-funded research?
A. Children and Clinical Studies
B. MedlinePlus® Clinical Trials Information
C. NIH Clinical Research Trials and You
D. Clinical Trials and Drug Development
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11. What would be a statistically significant sample size for a clinical study?
A. 10-25 participants
B. 30-50 participants
C. 55-70 participants
D. 75-100 participants
12. For the approval of placebo controls in phase 2, 3, and 4 trials, which of the following
questions should be considered?
A. Do participants have a disease or condition for which treatment is available, normally prescribed,
and of known efficacy?
B. If the disease or condition progresses, is this likely to be reversible?
C. Does substantial evidence exist to show that the experimental treatment is of therapeutic benefit?
D. All of the above
13. Which element of a clinical study explains how the study was designed?
A. The Introduction and Literature Review
B. The Methods and Materials section
C. The Results section
D. The Discussion section
14. Which element of a clinical study contains the safety data?
A. The Introduction and Literature Review
B. The Methods and Materials section
C. The Results section
D. The Discussion section
15. Which statement seen in a clinical study does not necessarily need to be referenced?
A. Marfan syndrome is an autosomal dominant connective tissue disorder with skeletal involvement.
B. The estimated prevalence of Marfan syndrome is about 1 per 10,000 persons.
C. Marfan syndrome has been found to be caused by mutations in the FBN1 gene.
D. TGF-β has been shown in preclinical studies to positively regulate osteoblast proliferation and
differentiation in vitro.
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16. In what study phase would a drug’s pharmacokinetics be assessed?
A. Phase 1
B. Phase 2
C. Phase 3
D. Phase 4
17. Participants in a clinical trial receive specific interventions according to the research plan or
protocol created by _____________.
A. The FDA
B. NIH
C. The drug manufacturer
D. The study investigators
18. How does an observational study differ from a clinical study?
A. Participants are not assigned to a specific intervention
B. Participants must be of the same age group
C. The observational study may compare a new medical approach to one already available.
D. In an observational study, a drug may be given to participants who have diabetes and observe
whether their blood pressure increases.
19. Which of the following are regulated by the FDA?
A. Penicillin
B. Gingko biloba
C. Noxzema™
D. A and B
20. Reading a study’s __________ is the quickest way to see if the information which you are
seeking is in the published paper.
A. Discussion
B. Methods and materials
C. Abstract
D. Results
Please submit your final responses on freeCE.com. Thank you.
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