Clinical data management

Clinical Trails, GCP
&
Management
Ajay Murali
MSc Biotechnology

Clinical Data Management (What ?)
●
Definition
– Clinical Data Management (CDM) assure collection, Integration and availability of data at appropriate
quality and cost all the while supporting the conduct, management and analysis of studies across the
spectrum of clinical research
Goal – Validity of the study by scientifically documented data
International Organizations
Association of clinical data management (ACDM)
Society for clinical data management (SCDM)
French data management organization (FDM)
Clinical trial --> Data --> Assess for safety and Efficacy

Clinical Data Management (Who does it ?)
Role of CD Manager
– Decide on ways and tools to use for data collection, storage, documented consistant with CT protocol
– Once data collected a QA is done (whether all data collected,Validated, documented, complete and
consistent)
– Ensure secure and robust data tansfer/documentation from other data providers keeping consistency
and update that on the CRF timely
– At the end of CT, CD manager ensures the completeness, validity and consitency of data and
management protocols anhe declare data to be complete( Database Lock/ Database freeze)
Different Job profile in CDM -clinical researcher, clinical research associate, clinical
research coordinator

Clinical Data Management (How it’s done)
Data Management Plan
Describes the activities to be conducted in the course of processing data
●
SOPs to be followed
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Clinical data management system to be used
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Description of data sources
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Data tranfer formats and process
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Quality control process to be applied
SOP – Standard Operating Protocols
Describe how the CDM is to be conducted in compliance with laws and guidelines (ICH-GCP; National
guidelines)
The QA team job to ensure that study meets the SOP regulations
SOP assures efficiency, quality, uniformity and decreases mistakes

●
Case report form
The data collected for Clinical trial
Either paper based(CDM personals fill - single/double entry) or electronic (investigator fills)
The report design should fully satisfy the purpose of CT protocol and Statistical analysis further
An edit check programs prompts the personals enter valid answers as it would bring up error(“Query”)
message if found any discrepency in same fields of the duplicate CRF
The data on the CRF is feed into a relational database
Computerized Sytem validation – Checks if the PC system used in processing and management gives
intended performance and reproducible data
CDISC – Clinical data interchange standard consortium – Forms the global data standards to be used in CT,
describe parameters such as the name, length and format of each data field (variable) in the relational
database.

Steps
Data Entry – Into the eCRF or paper CRF – Such that in 2 phases by two independent individual, Lowers
the statistical error
●
Types of data -CT data, Central laboratory data, External data, Patient recorded data – CDM
manager takes care of acquisition and proper reconsilation of it in CRF and then its validation
Data Validated
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Validation rule
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User acceptance testing
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This process is automated and should sent a “querry” if discrepency is found and CD manager can
ask for clarification from the investigator --
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Commonly called “edit check” or “validation check”
●
Programmed using SQL/Python/SAS/ C#
Data finalizations and extraction ---> Sent to a statistician for analysis

Clinical data management systems
Tools for clinical trial data management, It ensures human errors are at the minimum by employing
multiple modes of varification
Typographic errors fixing
Logical errors (approve/disapprove if a condition is met)
Coding of data – Adverse event terms and medication names
●
Dictionary for adverse event – MedDRA, WHOART
●
Dictionary for medication --COSTART and WHO Drug Dictionary
These may suport IVRS facility for data collection
Perceptive Informatics, Medidata RAVE, Castor EDC,Forte Research Systems' OnCore eClinical, Aetiol EDC
[Jade Global Solutions {JGS}] and IBM Watson Health's IBM Clinical Development – Web Based for eCRF
XNAT LORIS, and EEGBase include support for imaging, electrophysiology, and other data modalities less
suitable to eCRFs

Clinical Trials
Clinal trials establishes the safety and efficacy of a new drug/ medication or established
drug for a disease/ new disease
ICH-GCP Intenational council for hormonization – Good clinical Practises (E6v2)
History
– 1906 – US Food and drug Act – labelling
– 1937 - Elixir Sulfanamide disaster
– 1938 - Food, Drug and Cosmetics Act
– 1947 – Nazi physician trials
– 1948 – Nuremberg code

Clinical Trials
●
Nurenberg Code
– Avoidence of unnecessary phy and mental injury
– Bannig of lethal and disable procedure
– Degree of risk should never exceed benefit
– Proper preparation and proper facilities to prevent injury and death
– Performance of experimentd only by scientifically qualified persons
– Participant may freely end the experimentation
– Experiment must stop if proven dangerous
●
1957 – Thalimide tragedy
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1962 - Kefavver-Hurris Amendentment

Clinical Trials
●
1964 – Helsinki Declaration
Conerstone document – On proper conduct of clinical trials @ International level
– Many ammendments have been made 1964- 2013
– World medical association
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1932- 1972 – Tuskegee Syphillis study
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1979 – Belmont report
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1996 – ICH – GCP
– European -US -Japan – WHO- Nordic countries
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Ethical guidelines for biomedical research in human subject ICMR 2001
●
GCP Guidelines, CDSCO, New Delhi 2001

https://pubrica.com/academy/2019/08/21/on-biostatistics-and-clinical-trials/
Stages of Clinical trial

ICH - GCP
Internationally accepted standard for conduct of clinical research by authorities of individual
countries
Contains lots of guidelines which are categorized of which one is ‘E’ - Efficacy
GCP comes under E6 which has undergone two revision R1(@1996) and R2 (@2016)
The ICH -GCP guideline contains 8 sections
– 1.Glossary, 2. The principle of ICH-GCP, 3. Institutional review board/Indipendent ethics committee,
4.Investigator, 5. Sponser, 6 Clinical trial protocol and protocol ammendments,7. Investigator brochure
8.Essential documents for the conduct of clinical trial
These documents describe duties, guidelines, principles, ethics and other details each parties
whomsoever/whatsoever involved should do and adhere to at all time during the tenure of clinical trial
https://ichgcp.net/

Principle of ICH -GCP
●
Glossary – Section -One – Contain definition of important terms in clinical research
●
The Section two of ICH-GCP(E6R2) describe 13 principles
1.Clinical trials should be conducted in accordance with the ethical principle that have their origin in the
decalration of helsinki, and that are consistant with GCP and applies regulatory requirement
2. Before a trial is initiated foreseable risk and inconveniances should be weighted against the
anticipated benefit for the individual trial subject and society. A trial should be initiated and continued
only if the benefits justify risks
3. The rights, safety and well-being of the trial subject are the most important considerations and
should prevail over interest of science and society
4. The available clinical and non-clinical information on an iinvestigational product should be adequate
to support thr proposed clinical trial
5.Clinical trials should be scientifically sound and described in a clear and detailed protocol

6.A trial should be conducted in compliance with the protocol that has received prior institutional
review board/ Independent ethics committee approval
7.The medical care given to, a medical decision made on behalf of the subject should always be the
responsibility of a qualified physician or when appropriate of a qualified dentist
8. Each Individual involved in conducting a trail should be qualified by education, training and
experiance to perform his or her respective roles
9. Freely given informed consent should be obtained from every subject prior to clinical trial
participation
10. All cli. Trail info should be recorded, handled and stored in a that allows its accurate respository,
interpretation and varification. This principle applies to all records referenced in this guidelines,
irrespective of the type of media used
11.The confidentiality of record that could identify subjects should be protected, respecting the privacy
and confidentiality rule in accordance with applicable regulatory requirement

12. Investigational products should be manufactored, handled and stored in accordance with
applicable good manufacturing practise GMP. They should be used in accordance with approved
protocols
13. Systems with procedures that assures the quality of every aspects of the trial should be
implemented. Aspects of the trial that are essential for the emsure the subject protection and
reliability of trial results should be the focus of such system.
IRB/IEC
Sponser
Investigator
Players of
cli.
research

Investigational review board and their role
Section 3 of ICH-GCP describes of IRB/IEC
This section includes the
– Responsibility (3.1),
– Composition, Functions and Operations (3.2),
– Procedure (3.3)
– Records (3.4)
Composed of medical/ non-medical personnals (atleast 5 memebers, 1 non-scientific personals, external
expert with no right to vote)
Ensures that right, safety and well-being of the subject is retained
Review and approve suitability of investigator, facility, met and methods used in obtaining and
documenting informed consent, other necessary documetation like SOPs, monitory compensation for
subject, qualification of the investigator and its on committe members, investigator brochure, available
safety information
Ensures the ethical and principle guldelines are followed before and during clinical trial and also ensure
no sort of bias in subject selection or procedure deviating from SOPs is entertained

Investigational review board and their role
Uphold the principles like social, scientific, fair subject selection, favourable risk to benefit ratio,
Independent review, informed consent, and respect for enrolled subject is given
The legal status, composition, function, operation and regulatory requirement pertaining to IEC may
differ among countries, but should always be in accordance with GCP
The IRB itself shall follow SOPs and comply with GCP regulation, maintain detailed records or activity in
meeting, ask professional recommendation from the investigator then come to a unbiased result.

Investigator
●
Section 4 of ICH-GCP contains 14 subsection detailing extensive guideline to be followed
at each of these events
– 1.Investigators qualification and agreements
Proper certificates and paperworks are to submitted that ensure the qualification both at
academic training and experience to carry out the procedure
Should be knowlegable in GCP protocols and all the techniques that are to be executed in this
clinical trial
Permit monitoring, auditing and inspection and also delegation of duties to staff
– 2 Adequate resources
●
Training the staff and acquisition of resources for timely conduction of CT
– 3.medical care of the trail subjects
●
Investigator is responsible for any medical decision
●
Care during and after CT is mandatory

Investigator
– 5. communication with IRB/IEC
Detailed reports, Informed consents, subject selection, SOPs, norms for CRF and any update on each
of these and other important document should be submitted before and during trial for review
before the IRB
– 6.compliance with protocol
The sponser IRB and other regulatory body agreed and documented protocol should be adhered to
Administrative changes may be okay otherwise any change made in order to advert Adverse events
needs to be properly documented and presented before the board
– 7. Investigational product
Use in accordance with the SOPs and stored as mentioned in regulatory priniciple
Charge of use/storage/ data acuqisition at the trial site
– 8. Randomization procedure and unblinding
Proper documetation should be provided on the conduct of the trials, if in any event the
condition(randomized, blinded) are not met it shall be duly reported in detail to the higher ups

Investigator
– 9.Informed consent and trial subjects
It should be written in atmost laymen perspective, such that it shalln’t cause any level of confusion or
coercion to the subject
Should comply with GCP and other regulatory guidelines
– 10 records and reports
●
Ensure accuracy, completeness, legibility and timeliness of data to sponsor in CRF
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Progress report to IRB
●
Any correction to important documents to be signed and dated and are to maintained to a lengthier tenure
– 11 progress report
The summary of status of CT is to be presented before IRB or sopnser whenever asked or in a timely fashion
– 12.Safety reporting
SAE are to reported before IRB and Sponser timely, So should the AE and laborotary abnormalities

Investigator
– 13. Premature termination or suspension of a trial
if CT stops abruplty then Investigator should inform
– Inform subject and follow up on the therapy
– Inform the regulatory autorities/Sponser/IRB with explanation
– 14.final report by the investigator
The final outcome shall be given out as a summary to the IRB/Sponser/Institution

Section 5 -Sponser
●
An individual, company, institution, or organization which takes responsibility for the
initiation, mangement, and/or financing of a clinical trial
Quality assurance and Control - 5.1
– QC and QA is done in order to validate SOPs are proceeded in compliance with GCP
– Securing agreement from all sites of monitoring, auditing and inspection
– QC of data handling
– Payment agreement
5.2 – CRO -->Contract research Organization
A person or organzation contracted by the sponser given the responsibility to carry out the duties of
the sponser

Section 5 -Sponser
●
Sponser’s responsibility
– Trial design, management, data handling, recording, storage and investigator selection, allocation of
responsibility
– Financing of the CT, audit, Non compliance, Multicentric trials
– Submission to Regulatory autority
– Confirmation of review by IRB
– Information on investigational product
– Manufacturing, labelling, packaging & coding, supply and handling of product
– Safety evaluations and adverse drug reaction reporting, Premature termination of CT
– Monitoring
●
Overseeing the progress of the CT and ensuring its conducted accoring to SOPs,GCP and other
applicable regulatory requirement

Clinical trial - Section6- protocol ammendment
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Protocol - A complete, well designed and structure documentation describing all aspect of
the study
1. General Information
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Contact name adresses
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Contact medical expert, Investigator, Institute , laboratory, department contact
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Name and title of authorized signatory
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Protocol Title, Identifyig number & date, Ammendment
2.Objective and justification
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Aim, objective, phase of study
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Name and description of inv product
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Summary of clin and non- clin study , risk and benfit
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Description of route of administration, dosage
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Statement of GCP compliance

Clinical trial and protocol ammendment
– 3. Trial design
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Primary and secondary endpoint
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Randomized/comparator/blinded/open, placebo controlled
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Blinding techniques (double/single blind)
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Randomization(methods and procedure)
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Diagram if design procedure and stages
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Medication permitted and non-permitted during study
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Packing/ labeling Duration of subject participationa and sequence of all study periods including
follow ups
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Proposed date of initiation of study
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Dicontinuition criteria of subjects
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Procedure for monitoring compliance
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Instruction on suspending or terminating the study

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5 Selcetion and withdrawal of subjects
– Inclusion / exclusion criteria dependent -->
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Subject withdrawal criteria and procedure
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Specify exclusion criteria
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Information of the subject to be recorded (age, gender, ethnic group, prognostic factors,
diagnostic criteria)
6. Assesment of efficacy
– Efficacy parameters are specified and how they are to be measured and recorded
– Time and periodicity of recording
– Description of special analysis/test (PK, Clinical , lab, radiology)
– Specification of safety parameters
– Procedure for reporting ADR

●
7. Statistics
Statistcal method used are to be described
– Significance level, power
– Timing of interim analysis, if any
– Details of enrollment plan
– Procedure for reporting if any deviation from original statistical plan
– Selection of subjects to be included in final analysis
8. Direct Access to source data/document
The sponser should ensure that the investigator. Institute will permit trial-related monitoring, auditing,
IRB/IEC reviewand regulatory inspections providing direct access to source data/ document

●
9 -Protocol -QA and QC
– Checks that ensures the protocol is in compliance with GCP and other regulatory requirements
– Suggest Instruction if any defiance of protocol had took place
– Basically are steps and procedure for evaluation and monitoring the study
10.Ethical Consideration
Describes how patients/volunteers would be informed
11. Data handling and record keeping
– Procedure for handling and processing records of effects and adverse events
– Handling of products
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Sytematic labeling with specifications to be focused on, storage and handling measure

●
14 -Finance and Insurance
– Budget, financial aspects
– Source of economic support
– Subject payment
– Reimbursment to team members
– Insurance details of the study subject

Investigators Brochure
A collective clinical and nonclinical documentation about the investigational product.
It facilitate the choice of rationale for and its compliance with many feature like dose, dose
frequency, methods of administration and safety in the protocol
IB should be presented in a concise, simple, objective, balanced, and non-promotional form
1. General cosnideration IB should include
– Title
– Confidentiality Statement
2. Content of the investigator Brochure
– Table of content
– Summary
Summary of significant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical
development

– Introduction
●
Generic, Trade name, Active ingredient, Pharmacological class, Rationale for CT, Proposed
prophylatic effect
– Physical, Chemical, and Pharmaceutical Properties and Formulation
●
Summary relevant physical, chemical, and pharmaceutical properties
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Formulation used and rationale
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Storage and handling
– Non-clinical Studies
●
Summary of of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and
investigational product metabolism studies
●
Address the methodology used, result and discussion on the therapeutic and side effects of IP
– Effects in human
●
Pharmacokinetics and Product Metabolism in Humans.

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Safety and Efficacy
●
Marketing Experience
Summary of data and Guidance for Investigator

Essential documents for clinical trials
●
Investigator Brochure
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Signed Protocol And Amendments, If Any, And Sample Case Report Form (crf)
●
Information Given To Trial Subject
– Informed Consent Form and any updates if any
– Any Other Written Information
– Advertisement For Subject Recruitment and Compensation documentation
●
Financial Aspects Of The Trial
●
Insurance Statement
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Signed Agreement Between Involved Parties
– Investigator, CRO, Sponser, regulatory authorities,IRB
●
Dated, Documented Approval/Favourable Opinion Of Institutional Review Board (irb) /independent Ethics Committee (iec) Of The
Following:
●
Institutional Review Board/Independent Ethics Committee Composition
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Regulatory Authority(Ies) Authorisation/Approval/Notification Of Protocol
●
Credential of the Investigators
●
Normal Values of Lab/Technical procedure of test
●
Certification, Accredation, Established QC,Other Validation
– Sample label Attachment to the investigational product
Instruction for handling the investigational product
– Shipping records
– Certificate of analysis for IP
– Master randomization list
– Procedure for blinded test
– Pretrial monitoring report
– Trial initiation monitoring report
These Document needs to varified by the regulatory authorities and
during the CT, Dated & validated documents by IRB are to be kept and if
any modification then documents for that shall also be presented

Indian GCP
●
Indian GCP is developed by Central drugs standard control organization (CDSCO) and endorsed
by Drug technical advisary board (DTAB), with consideration of international ICH-GCP regulation
●
Consist of 8 Section
– Definition
– Pre-requisite
– Responsibilities
– Records and data Quality Assurance
– Statistics
– Special Concerns
– Appendices
1940 – Drugs and cosmetics Act
2006 – Ammendment – Shedule Y( Contains 11 appendices)
Regulation and guidelines for import/ manufacture/sale or clinical trial of new drug
122A, 122B,122D,122DA,122DAA and 122E -Rules for following

References
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https://en.wikipedia.org/wiki/Clinical_data_management_system
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https://en.wikipedia.org/wiki/Clinical_research
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https://www.slideshare.net/rajdoct80/ichgcp-and-their-diffirences-to-indian-clinical-trial-guidelines?qid=1f0365b9-6ff2-4ae4-9ed4-
1173132df338&v=&b=&from_search=3
●
https://www.slideshare.net/Pradeepben84/clinical-trials-terminology?qid=29870a7b-2488-49ee-a044-9b4e6478af8d&v=&b=&from_search=1
●
https://ichgcp.net/
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https://www.cmch-vellore.edu/SITES/research/Files/Good%20Clinical%20Practices%20For%20Clinical%20Research%20In%20India.pdf#:~:text=Good
%20Clinical%20Practices%20For%20Clinical%20Research%20In%20India,designing%2C%20conducting%20and%20recording%20trials%20that%20involve
%20the

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