History is important! ..Why??

Because it teaches us of mistakes made in the past in order to ensure

that it isnt repeated in the present or in the future!
THE EARLIEST CLINICAL RESEARCH
Medical practice and clinical research are grounded in the beginnings of civilization
Documents from early Judeo-Christian and eastern civilizations provide examples of the origin of clinical
research
Hippocrates teachings (460370 bc) remained dominant and unchallenged until the time of Galen of
Pergamum (ca. 130200 ad), the physician to the Roman Emperor Marcus Aurelius
Galen was one of the first individuals to utilize animal studies to understand human disease.
In the Middle Ages, improvements in medicine became evident, and the infrastructure for clinical
research began to develop
By the 1100s and 1200s, hospitals were being built in England, Scotland, France, and Germany.
Documentation through case records is an essential feature of clinical research.
Pre-Renaissance medicine of the 14th and 15th centuries saw the birth of Consilia or medical-case
books, consisting of clinical records from the practice of well-known physicians
The 18th century brought extraordinary advances in the biological sciences and medicine.
Modern clinical trials can be recognized in the 1700s.
Scurvy was a major health problem for the British Navy. William Harvey earlier had recommended
lemons to treat scurvy but argued that the therapeutic effect was a result of the acid in the fruit.
James Lind, a native of Scotland and a Royal Navy surgeon, conducted a clinical trial in 1747 to assess
this hypothesis comparing three therapies for scurvy.
12 sailors with scurvy were divided in 6 groups of 2 - All given identical diets
The various groups supplemented with
vinegar, dilute sulfuric acid, cider, seawater, a nutmeg, garlic, and horseradish mixture, and with two
oranges and one lemon daily.
Sulfuric acid, vinegar, seawater, cider, and other remedy had no benefit.
2 sailors receiving citrus fruit avoided scurvy.
This early clinical study formed the basis for successfully avoiding scurvy with citrus fruit.
This study is often referred to as the first controlled clinical trial
Franz Mesmer - Mesmers magnetic fluid induced hypnosis
In 1784, a commission of inquiry was appointed by King Louis XVI of France to investigate medical
claims of mesmerism.

 The commission, headed had as a goal to assess whether the reported effects of this new healing
method were due to real force or due to illness of the mind.
Among the many tests performed, blindfolded people were told that they were either receiving or not
receiving magnetism when in fact, at times, the reverse was happening.
The results showed that study subjects felt effects of magnetism only when they were told they
received magnetism and felt no effects when they were not told, whether or not they were receiving
the treatment.
This was the beginning of the use of blinded studies in clinical research.
The 18th century also provided the first legal example that physicians must obtain informed consent
from patients before a procedure.
In an English lawsuit, Slater v. Baker & Stapleton, two surgeons were found liable for disuniting a
partially healed fracture without the patients consent
Court ruled that patients consent was essential before carrying out such procedures and operations
During the course of the 19th Century, larger and more organized clinical trials became increasingly
typical in medicine.
In 1863, Sir William Gull and his colleague Sutton used a placebo treatment.
They wanted to study the importance of placebo in assessing the natural history of the course of a
disease and the possibility of a spontaneous cure.
They treated 44 rheumatic fever patients with mint water.
They demonstrated that too much importance was being attached to the use of medicines and that the
use of medicines was questionable where there was a natural tendency to get better with no
treatment.
In the early 1900s, digitalis was a popular treatment for pneumonia.
In 1930, English physician John Wyckoff studied all the cases for treatment of pneumonia for the
previous 20 years.
He wrote, The analysis of the hospital records of previous years with the study of digitalis in untreated
and treated groups does not constitute a properly controlled series.
Dr. Wycoff refined the alternate control method, using four groups of classifications:
Class 1: no serum, no digitalis
Class B: serum only
Class C: digitalis only
Class D: both serum and digitalis.
He found that the death rate was about 25% higher among digitalis-treated patients than among
untreated patients.
This landmark study stopped the use of digitalis for pneumonia

 The first use of randomization was in 1923, by Fisher

Randomization was first used in clinical trials in 1924, in a study by Dr. Amberson of sanocrysin in the
treatment of pulmonary tuberculosis in Northville, Michigan.
Sanocrysin contained gold, which was thought to be helpful in treating tuberculosis.
Dr. Amberson divided 24 patients into 2 groups and assigned treatment based on a flip of a coin.
Dr. Amberson also used blinding to help prevent staff from knowing which patients received treatment
and minimize bias in the outcome of the study.
The Lancet and British Medical Journal were the first to use the term clinical trials in 1931, in a report
of the Medical Research Councils Therapeutic Trials Committee.
Until 1948, most randomization involved flipping a coin. A study of streptomycin in the treatment of
tuberculosis that year used random numbers sampling to allocate the treatment and control groups.

CR Ethics A Historical Perspective

Determination of what is right and wrong
Sulfanilamide Tragedy
Experiments in Nazi Germany
Thalidomide Tragedy
Tuskegee Syphilis Study
Milgram's Study
Sulfanilamide Tragedy In 1937, S. E. Massengill Co., a pharmaceutical manufacturer, created
a preparation of sulfanilamide using diethylene glycol (DEG)as a solvent, and called the
preparation "Elixir Sulfanilamide".
DEG is poisonous to humans, but Harold Watkins, the company's chief pharmacist and chemist,
was not aware of this (although it was known at the time).
The company chemist merely added raspberry flavoring to the sulfa drug which he had
dissolved in DEG and the company marketed the product. Although animal testing should have
been routine in most drug company operations, Massengill performed none and there were no
regulations requiring premarket safety testing of new drugs.
The company started selling and distributing the medication in September 1937. By October
11, at least 100 deaths were blamed on the medication.
Outcome- Food, Drug, and Cosmetic Act preclinical testing mandatory
Nazi Experiments Conducted between 1939 1945
German scientists conduct research on concentration camp prisoners.
The range of the testing was broad and specialized.

 The two major groups of experiments were meant to serve two purposes: first to refine the
master race and second to determine the cause of defects.
Experiments concerning high altitude and the effect of cold - an obvious relation to
aeronautical and naval combat and rescue problems.
Apart from this experiments were also carried out in children- twins children were put in hot
water and their tissue samples were examined after they passed out from the heat- no
anesthesia.
Outcome- Nuremberg Code voluntary participation, respect, beneficence
Thalidomide tragedy
In the late 1950s, thalidomide was approved as a sedative in Europe; it was not approved in
the United States by the FDA.
The drug was prescribed to control sleep and nausea throughout pregnancy, but it was soon
found that taking this drug during pregnancy caused severe deformities in the fetus phocomelia
Many patients did not know they were taking a drug that was not approved for use by the FDA,
nor did they give informed consent.
Some 12,000 babies were born with severe deformities due to thalidomide.
U.S. Senate hearings followed and in 1962 the so-called "Kefauver Amendments" to the Food,
Drug and Cosmetic Act were passed into law to ensure drug efficacy and greater drug safety.
For the first time, drug manufacturers were required to prove to FDA the effectiveness of their
products before marketing them.
Tuskegee syphilis study
Prior to availability of penicillin, experiment to follow the natural history of syphilis in African
American males near Tuskegee AL (1932)
Participants given free medical exams and meals, and burial insurance
Physicians told participants being treated for bad blood
Participants were denied available treatment for syphilis
In 1972, The New York Times published articles exposing the ethical atrocities
The study was only supposed to last about six months but the researchers were getting good
data and decided to continue it.
Outcome- Belmont Report respect, beneficence, justice
Milgram's experiment

 The Milgram's experiment was a series of social psychology experiments conducted by Yale
University psychologist Stanley Milgram
Experiment measured the willingness of study participants to obey an authority figure who
instructed them to perform acts that conflicted with their personal conscience.
The experiments began in July 1961, three months after the start of the trial of Nazi war
criminal Adolf Eichmann in Jerusalem.
The experimenter (E) orders the teacher (T), the subject of the experiment, to give what the
latter believes are painful electric shocks to a learner (L), who is actually an actor.
The subject believes that for each wrong answer, the learner was receiving actual electric
shocks, though in reality there were no such punishments.
Being separated from the subject, the actor set up a tape recorder integrated with the electroshock generator, which played pre-recorded sounds for each shock level
65% administered the final shock level (450 volt)
Only one participant steadfastly refused to administer shocks before the 300-volt level

CODING
The process of grouping or classifying reported terms like medications, adverse events,
medical history, diagnoses, disease conditions with reference to known standard terms
An English Dictionary has a list of words
List of possibilities or standard terms is a dictionary or thesaurus
CDM Dictionaries have listings of Diagnoses/Diseases, Drugs etc., either pre-listed or can
incorporate newer terms (Autocoders)
Coding Dictionaries can be updated regularly to include newer terms, which is a tedious
process

If

Coding Fails.
Discrepancies arise if the terms do not get coded
These discrepancies should be managed i.e., appropriate action taken by Data Management
Feedback can be given by the Thesaurus Management Group, about appropriate action to be
taken
Based on proper feedback, edits or updates of the stored data should be made in the database
Structure of Dictionaries
Different dictionaries follow different structures based on the classification levels and depth of
the classification
A simple structure for a dictionary usually includes a Preferred Term (for a matched verbatim
term) and a Code
Text term is always known as the Preferred Term
A code is Numeric in nature, but not a number always
A code can be a text, usually a version of the preferred term

Understanding the Need for Coding

Consider a Clinical Trial for Safety and efficacy evaluation for Headache for a investigational
pain reliever
Statisticians would be interested in analyzing the frequency of taking the OTC pain reliever
before, during, or after the investigational drug was taken
Also, number of attacks of headache (adverse event) is analyzed
The patient might take several OTC drugs which may have the same active ingredient.
Hence, if these medications are not coded for standard terms, this data will significantly
affect the Safety & Efficacy Data

Need for Coding terms in CDM

Consider an example for adverse event

Example: Vomiting versus Mild Vomiting
Both events resemble, but the verbatim differs and hence do not have an exact match with
the dictionary term

Differences in analysis will arise if same code is not assigned to each of these adverse
events.

Challenges While Recording of Adverse Events/diagnosis/diseases

Mis-spelling of certain terms

Numbers and text instead of standard medical terms
Recording phrases or sentences instead of a standard term
More than one/multiple adverse events recorded together
Using certain symbols example: Fever & rashes
Listing Surgical Procedures as events

Coding Dictionaries

WHOART, COSTART and MedDRA are used for coding of adverse events
WHODD is used for coding of concomitant medication
ICD9CM and MedDRA are used for coding of medical history
Inventory of Coding Dictionaries
V:MedLib/Inventory/MedLib Dictionary Inventory
Each coding dictionary is stored under its own directory under V:MedLib
Under the directory of the dictionary is the source, and the version
e.g. WHODD2000Q2 was supplied by Bayer (source) and is stored as follows
V:MedLib/WHODD/Bayer/WHODD2000Q2

Coding Dictionaries Structure

Each dictionary has it own unique structure

Each coding dictionary has a hierarchical structure

Dictionary Maintenance/Updates

Maintenance of dictionaries presents multiple challenges

New versions/updates have influence on already coded terms
Coding groups should decide well in advance how to handle version changes
Changes have an impact on adverse events/drugs which already coded
Dictionary Change Control

Selected dictionary and version should be documented for future reference

Coding dictionary securely maintained
If modifications are made, it should be clearly stated - so as not to mislead reviewers
Changes made to dictionary entries should be included in audit trial

WAYS IN WHICH WE CAN USE DICTIONARY

Dictionary Version Control

Dictionaries may be available in an electronic or printed format and multiple versions
released or published
These versions for a given project, time period or sets of data clearly documented
Evaluation of extent of changes between versions
Impact on previously coded terms
Criteria for implementing the latest version and recording

Selection of a Dictionary-Things to Keep in Mind

The needs of all users that process, analyze, and report coded data
Regulatory agencies who eventually review the information

Auto-coders/Auto-encoders

Most modern/advanced coding dictionaries heavily depend on auto-coders

Broadly may be classified into two types:
Simple (use exact-match algorithms) auto-coders
Sophisticated (use multi-step algorithms) auto-coders
Algorithms are logical step-by-step instructions written for coding

Autoencoding

Once data from the case report form has been entered and verified, the Data Manager
begins an electronic autoencoding process which compares the text of the investigator
term in the clinical trial database to the text strings stored in the dictionary databases.
When an exact match occurs, the code from the term in the dictionary database is
automatically entered into the clinical trial database. The term is considered
autoencoded.
Auto-encoding is highly recommended to executing a dictionary against AEs.
There are auto-encoding programs available to assist with the programming aspect.
Training of the monitors and site personnel to cultivate an understanding of the coding
process should facilitate capture of AE data in a format that can be auto-encoded.
Training should include guidelines such as the following:
Avoid use of adjectives as initial words (e.g., weeping wound may be coded to crying
or faint rash may be coded to syncope)
Avoid use of symbols and abbreviations in the AE text field (symbols may be interpreted
by different individuals differently)
Avoid inclusion of severity (e.g., severe headache in the AE text box inhibits autoencoding; severity should be recorded in the severity box, not the AE text box)
Ensure AE text has clinical meaning (e.g., bouncing off the walls and feeling weird are
difficult to interpret)
Ensure AE text has clear meaning (e.g., cold feeling may be interpreted as chills or flu
symptoms).
Advantages of Auto-coders

Re-evaluation of previously coded terms taken care

Consistency in coding
Capable of handling large numbers of entries
Coding Algorithm (set of instructions) ease handling of mis-spellings, synonyms, word
variations etc.
What Happens When A Term Doesnt Autoencode?
Three potential dispensations can be assigned:
Accepted: the term is added to the central dictionaries and will be available for
autoencoding the next time that exact term exists in a database.
Accepted as a Misspelled Term: the term is added to the central dictionaries with a flag of
M indicating it is an unambiguous misspelled term. These terms will autoencode.
Rejected: as is, term cannot be accepted into the central dictionaries. More information is
needed.

Hard-coding

Hard-coding or coding outside the clinical database, is generally a dangerous practice. For
coding AEs, hard-coding is sometimes used to introduce medical judgment that the standard
dictionary does not offer. When events such as strange feeling are reported and no additional
information from the site is available, the medical monitor for the study may have insight that
assists with the codification of the event, which can be inserted into the AE analysis file through
hard-coding.
Any use of hard-coding requires careful documentation.
Lumping and Splitting
Among coders, there are lumpers and splitters, and there is no universally agreed method of
handling AE text that includes more than one event. Tingling in hands and arms is regarded by
some as a single event and by others as two events. There are consequences to decisions to
lump or split.
When two events are reported in the same text field (e.g., indigestion and diarrhea), if
splitting is done by the data management staff rather than the site, inconsistencies within
the database may result.
Often, when the data manager splits the AE text into two (or more) events, the associated
items are duplicated (or replicated). If, for example, there is medication that is given for
treatment of the AE, and the concomitant medications page of the CRF shows as the reason
for use one event, (e.g., indigestion), the splitting induces an AE with treatment given for
which no treatment is recorded.

 CLASSIFICATION OF DICTIONARIES
MedDRA:
ICH-M 1
Medical Dictionary for Regulatory Activities (MedDRA) is a new international medical terminology
designed to support the classification, retrieval, presentation, and communication of medical
information throughout the medical product regulatory cycle.
MedDRA was developed under the auspices of the International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for Human Use ( ICH).
MedDRA is used in the US, European Union, and Japan. Its use is currently mandated in Europe
and Japan for safety reporting.
ICH-M 1
MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international
medical terminology used by regulatory authorities and the regulated biopharmaceutical
industry throughout the entire regulatory process, from pre-marketing to post-marketing
activities.
ICH-M 1
It is the adverse event classification dictionary endorsed ICH. Its goal is to provide a
comprehensive and specific terminology to help standardize, facilitate and simplify regulatory
processes.
Why MedDRA?
MedDRA is used to report adverse event data from clinical trials, as well as in pre marketing,
post-marketing and pharmacovigilance.
It includes terminology for symptoms, signs, diseases and diagnoses. In addition, it contains the
names of investigations (e.g. Liver function analyses, metabolism tests), sites (e.g. application
site reactions, implant site reactions and injection site reactions), therapeutic indications,
surgical and medical procedures and medical, social and family history terms.
Why MedDRA?
Increased specificity

Ex: In COSTART the verbatim Hypoglycemia and Decreased glucose are linked to the same
Body system;
however, in MedDRA, both are coded to different system organ classes (SOCs).
ICH-M 1
The MedDRA Maintenance and Support Services Organization ( MSSO) holds a contract with the
International Federation of Pharmaceutical Manufacturers Associations ( IFPMA) to maintain and
support the implementation of the terminology.
The MSSO updates MedDRA from subscriber change requests to add a new medical concept that
is yet to be in MedDRA or to change an existing concept. The decisions are made by
international medical officers on how to map the terminology within the grouping categories
according to a general consensus based on language considerations internationally.
ICH-M 1
The MSSO releases updated MedDRA versions twice a year - in March and September.
The March release is the main annual release and contains LLT and PT changes, and changes at
the HLT level and above.
The September release typically contains changes only at the LLT and PT level.
The March 2010 Version 12.1 release is the current version.
FDA has been using MedDRA since 1997 and has committed to keeping current on MedDRA.

System Organ Class (SOC)

1. High-Level Group Terms (HLGT)

2. High-Level Terms(HLT)
3. Preferred Terms(PT)
4. Lower-Level Terms(LLT)