Fundamentals of Clinical Trials

 A clinical trial is a prospective study

assessing the effect and value of
intervention(s) vs. control in human
subjects
 Each clinical trial has a PRIMARY question

(outcome)
 There may be multiple SECONDARY
outcomes
 Trials are not powered to definitely answer most

questions about secondary outcomes…interpret with

caution
Time (In Years) To Develop A New
Drug (Average) Pre-Clinical Testing
To Approval 1960s-1990s (US FDA)
Pre-clinical Clinical Approval
Phase Phase Phase
1960s 3.6 2.8 2.4

1970s 4.6 4.4 2.1

1980s 4.7 5.7 2.8

1990s 4.7 6.6 1.9

Pitfalls Of The Current Model Of Drug
Discovery & Development.
- High and unaffordable costs of R&D and
consequently of new drugs.
- Too many products with identical
pharmacological profile and mechanism – the
milligram battle.
- Low therapeutic rationale and advance for new
drugs.
- Many products especially biotech products
developed through technology push rather than
medical demand pull.
Can We Make Regulatory Submissions
More Crisp And Meaningful
No. of Words In Documents

Pythagoras Theorem 24

Archimedes Principle 67

The Ten Commandments 179

American Declaration of 300

Independence
European Legislation on when
24,942
and where one can smoke
Average IND Submission to FDA 800,000
 At The Same Time Regulations in New
Drugs Research Are Needed To:
- To ensure safety and efficacy of New Drugs
by an independent authority
- To ensure that uniform and well-laid out
standards apply to all products
- To ensure that products are continuously
monitored, post-marketing
- To review safety and efficacy standards
based on new knowledge
- To recommend appropriate amendments to
Drugs and Cosmetics Act
FDA REGULATIONS MOSTLY A REACTIVE RESPONSE

1906 History of FDA, USA, concerned only with

purity.

1936 Elixir Sulfanilamide 10% solution in 70%

Diethylene Glycol implicated in 105 deaths.
1938 Federal Food, Drug & Cosmetic Act passed
concerned with safety, not efficacy – NDA to
be approved.
1961 Thalidomide disaster in Europe. .
1962 Kefauver-Harris Amendment passed regarding
extensive safety and efficacy studies – IND
mandatory.
1987 Format of IND changed.
 Criticisms & Negative Perceptions On
Clinical Trials
 Trial objectives skewed in favor of potential
positive outcomes.
 Cutting out tests likely to end in negative
results.
 Manipulation of Subject inclusion &
exclusion criteria.
 Outright fraud in selection of investigators
with vested interests.
 Suppression of publication of negative
results.
To Eliminate Or Minimize These Negatives,
Clinical Trials Need To Be Conducted Under
Internationally Accepted Good Clinical
Practice (GCP) Guidelines.

 GCP protects patients/subjects.

 GCP ensures that clinical trials produce accurate,
credible data by:
- defining standards
- defining responsibilities
 Good Clinical Practice
1962
1961 Drug Amendments Act 1963
Thalidomide IND Procedure

ORIGINS

1977 1964
Proposed FDA Regulations covering Declaration of Helsinki
obligations of Sponsors, Monitors
and Clinical Investigators
 The Emergence Of ICH
Guidelines

ICH was evolved to negotiate common

standards for the regulation of pharmaceutical
products in Europe, Japan and U.S.A.
According to its Mission Statement –
ICH exists “to provide a forum for a
constructive dialogue between the regulatory
authorities and the pharma industry on the real
and perceived differences in the technical
requirements for product registration”.
 ICH -International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human
Use (Objectives)
- Eliminate redundant & duplicative technical
development.
- Expedite global development.
- Expedite availability of new medicines.
- Maintaining safeguards on quality, safety &
efficacy.
 ICH
Some key areas of interest :
 Safety reporting/Adverse Events
(definitions and timings)
 New standards/templates (e.g.,
protocol, investigator’s brochure)
 Essential documents
Clinical Research An important Component Of
The Regulatory System Has The Following
Components

-Candidate Drug
-Trial Sponsor
- CRO/Monitor
- Investigators & Trial Centers
- Trial Subjects : Healthy Volunteers &
Patients
- Biostatisticians
The Investigator’s Obligations
are spread over three phases.

• Prior to Initiation of the trial

• During The Trial

3) Post Trial
 Prior To The Trials
- The investigator should be excited about the
study for its scientific merit rather than other
considerations.
- Should ensure that confidentiality should be
maintained.
- Should have sufficient time allocated to involve in
the trials
- Should be familiar with the product and well
acquainted all pre-clinical data & IND dossier.
- Ensure that there are adequate resources
available & allocated.
- Should discuss the Protocol & details of trials
with Sponsor/Monitor.
- Finalize local clearances, IEC, IRB etc as per the
ICH guidelines, Informed Consent Forms .
 During The Clinical Studies
- Investigator should prepare a File containing all documents
related to the Trial which should be kept in a secure area
accessible to only him & his staff.
- Patient identification codes & details should be preserved at
least for 15 years and should be destroyed only with prior
permission from the sponsor.
- General medical Care should be provided to all subjects by the
investigator or family physician.
- Ensure strict adherence to randomization, unblinding etc as per
the protocol.
-- Safety & adverse reaction reports to be regularly obtained and
action taken as per protocol to cause no or least damage to
subjects. (ICH 4.11)
-- Ensure proper completion/validation of the Case record Forms..
- Assess causality in terms of ‘not related, unlikely, possible,
probable and most probable’, send reports and take corrective
action.
 INVESTIGATOR SOPs
Objectives
Ensuring that the investigator understands the
responsibilities and obligations of the study.
Planning & conducting the study as per the approved
protocols and complying with ICH/GCP guidelines.
Ensuring that the safety & welfare of the subjects are
always the prime concern.
Proper and accurate collection , Documentation &
analysis of Data from the trials.
Cooperate in inspections, monitoring and auditing of
the study by third parties.
 Investigators To Be Familiar With Documents Used By
- Ethics Committee.
-GCP Guideline same
-Investigator Brochure and safety Information.
-Trial Protocol.
-Consent Forms & Trial Information Sheets
-Subject Recruitment Procedures.
-Information on payment & remuneration to subjects.
-Any Amendments To The Protocols Or SOPs..
-Any other document required by IEC/IRB.

See ICH Guidelines 3.1.2.

 Nature Of Regulatory Inspections
2) Study related Inspections
3) Investigator Related Inspections
- Based on the pivotal nature of the study
- Sponsor’s Difficulties in getting some Reports.
- Violation of trial protocol.
- Work involved turns out to be outside
competence of the investigator .
- Results at variance with those of other
investigators.
 Inspection Reporting Systems
• No lapse.
• Requires corrective action for remediable
lapses.
• Warning letter if corrective action not taken
or delayed, with copies to sponsor
&reviewing IRB.
• Inviting for possible hearings.
• Disqualification when the Investigator has
deliberately violated the Agency’s regulatory
standards or submitted false information.
 Clinical Trials Deficiencies* (1999)
Apart From Deliberate Fraud, Clinical Trials fail due to
following categories of deficiencies
Protocols - 28%
Records & Documentation - 20%
Adverse Drug Reaction Reporting - 15%
Informed Consent - 10%
Drug Accounting - 10%

*Data From U.S.FDA.

 FIDDES CASE- FRAUD AT ITS
WORST
From early 1990s Dr. Fiddes, President
of a California based CRO had
conducted over 200 Clinical Trials for
47 companies. Engaged in extensive
fraudulent and falsified data, he was
sentenced and jailed in Federal Prison
for 15 months, a penalty of
$ 800000 imposed in 1998 and was
disqualified as a clinical investigator in
1999.
 Glaxo Paxil Case-Emergence Of
Transparency In Clinical Trials
✬ In the lawsuit against GSK, New York
Attorney General Eliot Spitzer asserted that
a novel fraud of suppression of information
was committed in the promotion of Paxil for
use as an anti-depressant.
In August 2004, Glaxo started posting the
full details of Clinical trials in their Website,
creating a Clinical register and started
inclusion of Safety & Efficacy data, off-label
drug use issues etc in Medical Information
Letters to Physicians... GSK also paid a fine
of $ 2.5 million.
 Profile of Regulatory Agencies: More
applicable to Developing Countries
- Need to balance the interests of the consumers as well
as the industry.
- Under-staffed and over-burdened: working on shoestring
budgets.
- No independent database to arrive at timely and scientific
judgements.
-Vulnerable to pressures from politicians and consumer
activists.
--No control on recruitment of Clinical Centers &
Investigators.
- Dependency on ‘Experts’ who have little stake in the
impact of their judgements on consumers or producers.
- Not equipped physically or technically to ensure
compliance with GCP/ICH Guidelines
 Fundamentals of Clinical Trials
The study population must be defined in
advance, with clear rationale and
eligibility criteria
A control group must always be used
against which the new intervention can
be compared
Randomization is the most reliable way
to assign participants to the treatment
groups
 Fundamentals of Clinical Trials
 A double blind design is the best way
to avoid bias during collection of data
If not possible, single blind and other
methods should be utilized
 Calculation of sample size should be

sufficient to provide adequate power

and levels of statistical significance
 Fundamentals of Clinical Trials
 Relevant BASELINE data should be
acquired before initiation of
intervention
 All efforts should be made to collect

accurate and consistent data

 Need plan for assessment, analysis
and reporting of adverse effects (AEs)
and serious adverse events (SAEs)
 Evidence Based Medicine: Levels
of Evidence
 Class I
1. Randomized double-blind, placebo-controlled trials
2. Meta-analyses of such RDBPC trials
 Class II

• Observational trials (case-control studies or concurrent

control studies)
 Class III

• All other controlled trials (including well-defined natural

history controls or patients serving as own controls) in a
representative population, where outcome assessment
is independent of patient treatment.
 Class IV:

• Evidence from uncontrolled studies, case series, case

reports, or expert opinion.
 Fundamentals of Clinical Trials
 FDA requires evidence of SAFETY and
EFFICACY to consider approving medications
for prescription use.
 The process by which medications come to
market goes through:
preclinical development
dose finding
then safety trials
exploratory efficacy/safety trials
larger scale trials to determine the size and
consistency of clinical effects, and develop more
safety data
 Drug Development Process
 Discovery
(2 - 10 years)

 Pre-clinical Testing
Laboratory and animal testing
 Phase 1- 20-80 healthy volunteers used to
determine safety and dosage
 Phase 2 - 100-300 patient volunteers used to
look for efficacy (POC) and side effects
 Phase 3 - 3,000-5,000 patient volunteers used
to monitor adverse reactions to long-term use
 FDA Review/Approval
 Diagnostic Test Studies
 How well does a test
identify people with the disease?
exclude people without the disease?
 Compare test results on people with
the disease with test results on
people without the disease.
 Need to know who has the disease.
 Diagnostic Test Studies
 Two designs
 Prospective or cohort design, or cross-
sectional design: take a sample of subject
eligible for the test, test them all and get
true diagnosis on them all.
 Retrospective or case-control design: take
a sample with true diagnosis established
as positive and another sample of
controls. We may have negative diagnosis
established on controls and we may not.
 Who has the disease?
True diagnosis.
 We can never be absolutely sure that the
‘true’ diagnosis is correct.
 We decide to accept one method as ‘true’:
call this the gold standard or reference
standard.
 Often more invasive than the test, e.g.
histopathology compared to ultrasound
image.
 It is always possible that the reference
standard is wrong for some subjects.
 Statistics of diagnostic test
studies
 Sensitivity
 Specificity
 Receiver operating characteristic curve
(ROC curve)
 Likelihood ratio (LR) for positive test
 Likelihood ratio (LR) for negative test
 Odds ratio (OR)
 Positive predictive value (PPV)
 Negative predictive value (NPV)
 Statistics of diagnostic test
studies
 Example: diabetic eye tests (cross-
sectional)
test = direct opthalmoscopy
reference standard = slit lamp
stereoscopic biomicroscopy
 Single sample of subjects all received
reference standard test.
 Statistics of diagnostic test
studies
 Sensitivity = proportion of reference
positive cases who are positive on
the test = proportion of true cases
that the test finds.
 Specificity = proportion of reference
negative cases who are negative on
the test = proportion of true non-
cases that the test finds.
 Example: eye disease in
diabetics

 45 reference standard positive cases

of whom 40 were positive on the
test, 275 reference standard
negative noncases of whom 237
were negative on the test.
 Sensitivity = 40/45 = 0.89 = 89%.

 Specificity = 237/275 = 0.86 = 86%.

 Statistics of diagnostic test
studies
 Positivepredictive value (PPV) =
proportion of test positives who are
reference positive.
 Negative predictive value (NPV) =
proportion of test negatives who are
reference negative.
 Example: eye disease in
diabetics
 78 test positives of whom 40 were
positive on the reference standard,
242 test negatives of whom 237
were negative on the reference
standard.
 PPV = 40/78 = 51%.

 NPV = 237/242 = 98%.

 .

Reading medical
articles critically
 Getting Ready

Choose a few good peer-reviewed journal articles

 Relevant to biomedical informatics
 Interesting for you & audience
 Important result or approach

Send choices to instructor for feedback

(2 weeks before your presentation)
 Choose one article
 Read critically
 Take notes while reading
 Reread even more critically
 Skim related articles or web information
 Creating the Content

 Introduce yourself
 Why did you choose this paper?
 How does it relate to your interests?
 Summarize article (briefly!)
 Provide context
 Critique, question, react
 Conclude
 Summarize Article
 Assume audience read the paper
 Do not assume audience understood it

 Provide context

When?
Where?
Why?
 State authors’ take home messages

 Focus on interesting/controversial issues

 Provide Context
 Research author and related work
 Look up author’s webpage
 Email author specific
questions/clarifications
 Compare & Contrast
 Earlier work (follow citations)
 Conflicting work (by others)
 Alternative visions for same niche
 Later work (follow citation index)
 Critique, Question, React
 Objectively
Did the author(s) support their point?
Was their support valid?
 Subjectively
How does it relate to your own
experiences?
Why did you find this paper interesting or
important?
What do you think the impact of this
paper is?
 Conclude
 Restate author’s take-home message
 State your own take-home message

 Provide a personal perspective

 Be provocative
 Summary
 Choose a good article
 Introduce yourself

 Summarize article

 Provide context

 Critique, question, react

 Conclude
 .

Types of medical
studies.
The evidence pyramid
.
.
.
.
 Observational Studies
 Cohort
– Question answered: “what will happen?”
– Prospective/forward
– e.g. Framingham study of cardiovascular
disease: Started in 1948, 6000 citizens
participated, followed for 20 years (study in
1970 by Gordon and Kannel)
– Possible uses:
 Typical cohort study
 Outcome assessment (patient outcomes:
economic, functional, satisfaction, QOL, ..)
 Historical Cohort studies/AKA Retrospective cohort:
Relies on prospective records collected (If
accurate) – still forward in time in the past
Cohort Studies
 Cohort studies: marching
towards outcomes

Lancet 2002; 359: 341-45

The defining characteristic of all cohort studies is that they track people forward in
time from exposure to outcome. Data collection may be prospective or
retrospective. Ex. Contraceptives and DVT.
.
 Observational Studies
 Case-Control
– Retrospective
– Question answered: “What happened?”
– Matching needed for controls
– Might be difficult to differentiate from
Case Series (Both are after the fact)
 Ask if the goal was to describe a
phenomenon, if description is the goal 
Case Series
Case Control Studies
 Case-control Studies: research in
reverse

Example: association between smoking and lung cancer.

People with lung cancer are enrolled to form the case group, and people without lung cancer
are identified as controls.
Researchers then look back in time to ascertain each person's exposure status (smoking history),
(retrospective design). Investigators compare the frequency of smoking exposure in the case group
with that in the control group, and calculate a measure of association.
 Observational Studies
 Case Series
– What are they?
 Author describes some interesting or intriguing
observations that occurred to a small number of
patients
– Characteristics:
 The simplest design
 Descriptive
 Lead to hypotheses subsequently investigated by
other types (Case-Control, Cross-Sectional or
Cohort study)
 Generally over short period of time
 Generally no controls
Case Series & Case Reports
Both Cohort and Case-Control studies
are called

“Longitudinal Studies”

Notion of time
 Observational Studies

Case Series Case-Control Cohort Cross Sectional

Longitudinal Studies
 Experimental Studies
 AKA Clinical Trials (Involve
humans)
 Easier to identify (usually explicitly
stated in the abstract)
 Two main categories of clinical
trials:
1. Controlled trials
2. Uncontrolled trials
.
 Experimental Studies
Controlled Trials
 Trials with independent  Trials with self controls
concurrent controls – Subject to bias
– Double or single blind (Hawthorne effect)
– Best is randomized – Can do crossover study
assignment (with washout period in
– Same point in time between)
– These include:  Trials with external control
 RCT: – Uses the results of another
– The epitome of all investigator’s research as
research designs a comparison
– Provides the strongest – Historical controls can also
evidence of concluding
causation be used: for disease with
– Best insurance that no cures yet
results are due to the
intervention
 Nonrandomized trials:
– Assignment not
randomized
– Opened to biases
.
Randomized Controlled Studies
The Double Blind Method
 Experimental Studies
Uncontrolled trials
 Investigator’s experience with the
new drug or procedure is described
but not formally compared with
another one
 More likely to be used for
interventions that are procedures
rather than drug
 Experimental Studies

Controlled trials Uncontrolled trials

Self controls Independent External controls

concurrent
controls

RCT Non-randomized
.
.
.
Systematic Reviews &Meta-
analyses
.
Study Pyramid
Best

Worst
 Classification of types of clinical research

Lancet 2002; 359: 57-61

 Temporal direction of study
designs

Lancet 2002; 359: 57-61

 Clinical Trials
 Advantages:

– RCT is the gold standard or reference

 Disadvantages:

– Expensive
– Long duration
 Cohort Studies
 Advantages:

– Design of choice for studying cause of a

disease, course, risk factors
 Disadvantages:

– Cannot be used to prove causation

– Long studies can be costly
– Vulnerable to patient attrition, migration
 Case-Control Studies
 Advantages:
– Quickest
– Least expensive
– Good for rare diseases and diseases that take
long time
– Good for investigation of a preliminary
hypothesis
– Time factor research
 Disadvantages:
– Large biases
– Difficult to find matching controls
 Cross Sectional Studies
 Advantages:

– Best for:
 Determining status quo of a disease
 Prevalence of disease

 Evaluation of diagnostic procedures

– Relatively quick and inexpensive

 Disadvantages:

– Provide only a snapshot in time

 Case Series
 Advantages:

– Easy to write
– May be extremely useful to
investigators looking for causes of
the observation
 Disadvantages:

– Subject to many biases in patient

selection
– Should be viewed as hypothesis
generating, not conclusive
 EXPERIMENT 1
A researcher assembles two groups
of study participants with Lyme
Disease. She administers the
antibiotic doxycycline to one group
and amoxicillin to the other. The
researcher then measures which has
more of a beneficial effect
 EXPERIMENT 2
A researcher identifies two groups of
elderly immobilized patients in a
nursing home. One group of patients
is repositioned every two hours. The
other group is repositioned every 1.5
hours. The researcher measures
whether the incidence of bed sores is
lower in the group repositioned every
1.5 hours than the group
repositioned every 2 hours
 EXPERIMENT 3
A researcher develops a counseling
program designed to increase
medication compliance in AIDS
patients. The researcher delivers the
program to one group of patients but
not another, then studies whether
the group that underwent the
counseling program adhered to their
medication better than the group
that did not
What do all three experiments
have in common?

?
 .

 In each case the researcher actively

interfered with one group of study
subjects and then compared the
outcome with a similar group of
subject that did not receive the same
intervention. Experiments in which
researchers interfere with their study
subjects are known as clinical
investigations. All examples above
pertain to humans, but many clinical
investigations are done using animal
subjects, particularly for new or risky
interventions
 EXPERIMENT 1
 A researcher identifies a group of
patients who were incorrectly
diagnosed with Lyme Disease, then
records whether the patients
experienced adverse effects from the
antibiotics they were prescribed for
treatment of Lyme
 EXPERIMENT 2
 A researcher identifies a group of
elderly immobilized patients in a
nursing home. The researcher follows
the patients for 6 months and records
the administration of any topical
(skin) agent. At the end of the study
period, the researcher conducts an
analysis to determine whether certain
topical regimens related to reduced
incidence of bed sores
 EXPERIMENT 3
 A researcher identifies a group of
individuals with AIDS who have low
medication compliance. The
researcher administers a
questionnaire to the patients to
determine what factors relate to their
poor compliance
What do all three experiments have
in common?

? .
 .

 Ineach case the researcher does not

actively manipulate or intervene with
patients; rather, the researcher
merely observes the effect of one or
more factors on an outcome. It is
easy to see why observational
studies received their moniker
 .

Article
Types
 ORIGINAL RESEARCH
 Original Articles are scientific reports of
the results of original clinical research. The
text is limited to 2700 words, with an
abstract, a maximum of 5 tables and
figures (total), and up to 40 references.
 Special Articles are scientific reports of
original research in such areas as
economic policy, ethics, law, and health
care delivery. The text is limited to 2700
words, with an abstract, a maximum of 5
tables and figures (total), and up to 40
references
 CLINICAL CASES
 Brief Reports usually describe one to three patients or a
single family. The text is limited to 2000 words, a
maximum of 3 tables and figures (total), and up to 25
references. They begin with a brief summary of no more
than 100 words.

 Clinical Problem-Solving manuscripts consider the step-

by-step process of clinical decision making. Information
about a patient is presented to an expert clinician or
clinicians in stages (indicated by boldface type in the
manuscript) to simulate the way such information emerges
in clinical practice. The clinician responds (in regular type)
as new information is presented, sharing his or her
reasoning with the reader. The text should not exceed 2500
words, and there should be no more than 20 references.
 REVIEW ARTICLES
 Review articles are usually solicited
by the editors. All review articles
undergo the same peer-review and
editorial process as original research
reports.
 Clinical Practice articles
 Are evidence-based reviews of topics
relevant to practicing physicians, both
primary care providers and specialists.
Articles in this series should include the
following sections: the clinical problem,
strategies and evidence, areas of
uncertainty, guidelines from professional
societies, and the authors' conclusions and
recommendations. The text is limited to
2500 words and a small number of figures
and tables. These articles do not include
an abstract.
Clinical Therapeutics articles
 Are evidence-based reviews of topics relevant to
practicing physicians. The series focuses on
clinically oriented information about specific forms
of therapy, including drugs, devices, and
procedures. Each article in the series begins with
a clinical vignette describing a patient with a
specified condition for whom the treatment under
discussion has been recommended. This vignette
is followed by a definition of the clinical problem,
a description of the path physiology and how the
therapy works, clinical evidence, clinical use
(including costs), adverse effects, areas of
uncertainty, guidelines, and recommendations.
The text is limited to 2500 words. These articles
do not include an abstract.
 Current Concepts articles
 Focus on clinical topics, including
those in specialty areas but of wide
interest. The text is limited to 2400
words, with a maximum of 4 figures
and tables (total), and up to 50
references. These articles do not
include an abstract.
 Drug Therapy articles
 Detailthe pharmacology and use of
specific drugs or classes of drugs, or
the various drugs used to treat
particular diseases. The text is
limited to 4000 words, with a
maximum of 6 figures and tables
(total), and up to 120 references.
These articles do not include an
abstract.
 Mechanisms of Disease articles
 Discuss the cellular and molecular
mechanisms of diseases or
categories of diseases. The text is
limited to 3500 words, with a
maximum of 6 figures and tables
(total), and up to 100 references.
These articles do not include an
abstract.
 Medical Progress articles
 Provide comprehensive, scholarly
overviews of important clinical subjects,
with the principal (but not exclusive) focus
on developments during the past five
years. Each article details how the
perception of a disease, disease category,
diagnostic approach, or therapeutic
intervention has evolved in recent years.
The text is limited to 3500 words, with a
maximum of 6 tables and figures (total),
and up to 100 references. These articles
do not include an abstract.
 OTHER SUBMISSIONS

.
 Editorials
 Usually provide commentary and
analysis concerning an article in the
issue of the Journal in which they
appear. They may include 1 figure or
table. They are nearly always
solicited, although unsolicited
editorials may occasionally be
considered. Editorials are limited to
1000 words, with up to 15 references
 Perspective articles
 Cover a wide variety of topics of
current interest in health care,
medicine, and the intersection
between medicine and society.
Perspective articles are limited to
1000 to 1200 words and usually
include one figure. There is a
maximum of 5 references
 Sounding Board articles
 Are opinion essays. They are similar
to editorials but are not tied to a
particular article. They often present
opinions on health policy issues and
are normally unsolicited. The text is
limited to 2000 words.
 Clinical Implications of Basic
Research articles
 Discuss single papers from preclinical
journals. The purpose is to explain
the findings and comment on their
possible clinical applications in fewer
than 750 words. There may be 1
figure and up to 4 references.
 Special Reports
 Aremiscellaneous articles of special
interest to the medical community.
They are limited to 2700 words.
 Letters to the Editor
 Provide a forum for readers to
comment about articles recently
published in the Journal, and they
are a place to publish concise
articles, such as reports of novel
cases