The document provides details on clinical trial protocols, investigator's brochures, and case report forms (CRFs). It discusses the key elements that should be included in clinical trial protocols like background information, objectives, trial design, selection and withdrawal of subjects, treatment, efficacy and safety assessments, and statistics. It also describes the purpose and contents of investigator's brochures and CRFs which are important documents used in clinical trials to capture subject data and report trial results. CRFs help ensure accurate collection, analysis and reporting of trial data.

1. CLINICAL TRIAL PROTOCOL,
INVESTIGATOR'S BROCHURE,CASE
REPORT FORM(ELECTRONIC CASE
REPORT FORM)
SUBMITTED BY
AKSHAY S
1st YEAR M PHARM
PHARMCOLOGY DEPARTMENT

2. CLINICAL TRIAL PROTOCOL AND PROTOCOL
AMENDMENT
• The contents of a trial protocol should generally include the following
topics. However, site specific information may be provided on
separate protocol page, or addressed in a separate agreement, and
some of the information listed below may be contained in other
protocol referenced documents, such as an Investigator’s Brochure.

3. General Information
• Protocol title, protocol identifying number, and date. Any amendment
should also bear the amendment number and date.
• Name and address of the sponsor and monitor.
• Name and title of the person authorized to sign the protocol and the
protocol amendment for the sponsor.
• Name, title, address, and telephone number of the sponsor's medical
expert for the trial.
• Name and title of the investigator who is responsible for conducting the
trial, and the address and telephone number of the trial site.
• Name, title, address, and telephone number of the qualified physician who
is responsible for all trial-site related medical decisions.

4. Background Information
• Name and description of the investigational product.
• A summary of findings from nonclinical studies that potentially have clinical
significance and from clinical trials that are relevant to the trial.
• Summary of the known and potential risks and benefits, if any, to human
subjects.
• Description of and justification for the route of administration, dosage,
dosage regimen, and treatment period.
• A statement that the trial will be conducted in compliance with the
protocol, GCP and the applicable regulatory requirement.
• Description of the population to be studied.
• References to literature and data that are relevant to the trial, and that
provide background for the trial.

5. Trial Objectives and Purpose
• A detailed description of the objectives and the purpose of the trial.
Trial Design
• The scientific integrity of the trial and the credibility of the data from the
trial depend substantially on the trial design. A description of the trial
design, should include:
• A specific statement of the primary endpoints and the secondary
endpoints, if any, to be measured during the trial.
• A description of the type/design of trial to be conducted (e.g., double-
blind, placebocontrolled, parallel design) and a schematic diagram of trial
design, procedures and stages.
• A description of the measures taken to minimize/avoid bias, including: (a)
Randomization. (b) Blinding.

6. • A description of the trial treatment and the dosage and dosage regimen of
the investigational product. Also include a description of the dosage form,
packaging, and labelling of the investigational product.
• The expected duration of subject participation, and a description of the
sequence and duration of all trial periods, including follow-up, if any.
• A description of the "stopping rules" or "discontinuation criteria" for
individual subjects, parts of trial and entire trial
• Accountability procedures for the investigational product, including the
placebo and comparator, if any.
• Maintenance of trial treatment randomization codes and procedures for
breaking codes.
• The identification of any data to be recorded directly on the CRFs (i.e., no
prior written or electronic record of data), and to be considered to be
source data.

7. Selection and Withdrawal of Subjects
• Subject inclusion criteria.
• Subject exclusion criteria.
• Subject withdrawal criteria (i.e., terminating investigational product
treatment/trial treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/ investigational
product treatment.
(b) The type and timing of the data to be collected for withdrawn subjects.
(c) Whether and how subjects are to be replaced.
(d) The follow-up for subjects withdrawn from investigational product
treatment/trial treatment.

8. Treatment of Subjects
• The treatment to be administered, including the name of all the
product, the dose, the dosing schedule, the route/mode of
administration, and the treatment period, including the follow-up
period for subjects for each investigational product treatment/trial
treatment group/arm of the trial.
• Medication/treatment permitted (including rescue medication) and
not permitted before and/or during the trial.
• Procedures for monitoring subject compliance.

9. Assessment of Efficacy
• Specification of the efficacy parameters.
• Methods and timing for assessing, recording, and analysing of efficacy
parameters.
Assessment of Safety
• Specification of safety parameters.
• The methods and timing for assessing, recording, and analysing safety
parameters.
• Procedures for eliciting reports of and for recording and reporting adverse
event and intercurrent illnesses.
• The type and duration of the follow-up of subjects after adverse events.

10. Statistics
• A description of the statistical methods to be employed, including timing of
any planned interim analysis.
• The number of subjects planned to be enrolled. In multicentre trials, the
numbers of enrolled subjects projected for each trial site should be
specified. Reason for choice of sample size, including reflections on (or
calculations of) the power of the trial and clinical justification.
• The level of significance to be used.
• Criteria for the termination of the trial.
• Procedure for accounting for missing, unused, and spurious data.
• Procedures for reporting any deviation from the original statistical plan.
• The selection of subjects to be included in the analyses.

11. Direct Access to Source Data/Documents
• The sponsor should ensure that it is specified in the protocol or other
written agreement that the investigator(s)/institution(s) will permit
trial-related monitoring, audits, IRB/IEC review, and regulatory
inspection(s), providing direct access to source data/documents.
Quality Control and Quality Assurance
Ethics
• Description of ethical considerations relating to the trial.

12. Data Handling and Record Keeping
Financing and Insurance
• Financing and insurance if not addressed in a separate agreement.
Publication Policy
• Publication policy, if not addressed in a separate agreement.

13. INVESTIGATORS BROCHURE(IB)

14. INVESTIGATORS BROCHURE(IB)
• The Investigator's Brochure (IB) is a compilation of the clinical and
nonclinical data on the investigational product(s) that are relevant to
the study of the product(s) in human subjects.
• The information should be presented in a concise, simple, objective,
balanced, and non-promotional form that enables a clinician, or
potential investigator, to understand it and make his/her own
unbiased risk-benefit assessment of the appropriateness of the
proposed trial.

15. • The type and extent of information available will vary in each.
• Investigational product is marketed, an extensive IB may not be
necessary.
• If a marketed product is being studied for a new use , an IB specific to
that new use should be prepared.
• Reviewed at least annually and revised as necessary in compliance
with a sponsor's written procedures.
• More frequent revision may be appropriate depending on the stage
of development and the generation of relevant new information.

16. • In accordance with GCP, relevant new information may be so
important that it should be communicated to the investigators, and
possibly to the (IRBs)/(IECs) and/or regulatory authorities before it is
included in a revised IB.
• sponsor is responsible for ensuring that an up-to-date IB is made
available to the investigator(s).
• investigators are responsible for providing the up-to-date IB to the
responsible IRBs/IECs.

17. General Considerations
TITLE PAGE:
• Provide the sponsor's name
• The identity of each investigational product and the release date.
edition number, and a reference to the number and date of the edition
it supersedes, be provided.

18. CONFIDENTIALITY STATEMENT
A statement instructing the investigator/recipients to treat the IB as a
confidential document for the sole information and use of the
investigator's team and the IRB/IEC.

20. Contents of the Investigator’s Brochure
• Table of contents
• Summary
• Introduction
• Physical, Chemical, and Pharmaceutical Properties and Formulation
• Nonclinical Studies
Introduction
(a) Nonclinical Pharmacology.
(b) Pharmacokinetics and Product Metabolism in Animals.
(c) Toxicology.
• Effects in Humans
Introduction
(a) Pharmacokinetics and Product Metabolism in Humans
(b) Safety and efficacy
(c) Marketing experience.
• Summary of Data and Guidance for the Investigator

21. TABLE OF CONTENTS

23. SUMMARY:
•A brief summary should be given,
•Highlighting the significant physical, chemical,
pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information
available that is relevant to the stage of clinical
development of the investigational product.

25. INTRODUCTION
A brief introductory statement chemical name of the investigational
product(s), pharmacological class, all active ingredients, and the
anticipated prophylactic, therapeutic, or diagnostic indication(s).
Provide the general approach to be followed in evaluating the
investigational product.

27. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL
PROPERTIES AND FORMULATION:
• A brief summary should be given of the relevant physical, chemical, and
pharmaceutical properties.
• To permit appropriate safety measures to be taken in the course of the trial,
a description of the formulation to be used, including excipients.
• Instructions for the storage and handling of the dosage form should also be
given.
• Any structural similarities to other known compounds should be mentioned.

29. NONCLINICAL STUDIES
• The results of all relevant nonclinical pharmacology, toxicology,
pharmacokinetic, and investigational product metabolism studies
methodology used, the results, and a discussion of the relevance of the
findings to the investigated therapeutic and the possible unfavourable and
unintended effects in human.
• Species tested
• Number and sex of animals in each group
• Unit dose
• Dose interval
• Route of administration
• Duration of dosing
• Information on systemic distribution

30. (a) NONCLINICAL PHARMACOLOGY:
• Summary of the pharmacological aspects of the investigational
product and, where appropriate, its significant metabolites studied in
animals.
• incorporate studies that assess potential therapeutic activity - efficacy
models, receptor binding & specificity and those that assess safety -
special studies to assess pharmacological actions other than the
intended therapeutic effect.

32. (b) PHARMACOKINETICS AND PRODUCT METABOLISM IN ANIMALS:
• Summary of the pharmacokinetics and biological transformation and
disposition of the investigational product.
• Discuss analytical method used for interpretation of kinetic data.
• Address their relationship to the pharmacological and toxicological findings
in animal species.

34. (c) TOXICOLOGY:
• A summary of the toxicological effects found in relevant studies;
single/multiple dose, carcinogenicity, mutagenicity, reprotoxicity, special
studies(irritancy, sensitization).
• Results of toxicity studies including following information:
o nature & frequency of toxic effects.
oSeverity or intensity of toxic effects.
oDuration of effects.
oReversibility of effects.

36. EFFECTS IN HUMANS:
• Discussion of the known effects of the investigational products in humans
should be provided.
• A summary of each completed clinical trial should be provided.
(a) PHARMACOKINETICS AND PRODUCT METABOLISM IN HUMANS
• A summary of information on the pharmacokinetics including;
 Pharmacokinetics
 Bioavailability of the investigational product.
 Population subgroups
 Interactions
 Other pharmacokinetic data

37. (b) SAFETY AND EFFICACY:
• A summary on safety, pharmacodynamics, efficacy, and dose response that were
obtained from preceding trials in subjects.
• The implications of this information should be discussed.
• Tabular summaries of adverse drug reactions would be useful.
• Important differences in adverse drug reaction patterns/incidences across
indications or subgroups should be discussed.
• Description of the possible risks and adverse drug reactions to be anticipated on
the basis of prior experiences and their precautions.

39. (c) MARKETING EXPERIENCE:
• IB should identify countries where the investigational product has been marketed
or approved.
• Any significant information arising from the marketed use should be summarized.
• identify all the countries where the investigational product did not receive
approval/registration for marketing or was withdrawn from marketing/registration.

40. SUMMARY OF DATA AND GUIDANCE FOR THE
INVESTIGATOR
• Overall discussion of the nonclinical and clinical data.
• Summarize the information from various sources on different aspects of
the investigational product(s), wherever possible.
• Provided with the most informative interpretation of the available data and
with an assessment of the implications of the information for future clinical
trials.
• Where appropriate, the published reports on related products should be
discussed.

42. CONCLUSION
• Provide the investigator with a clear understanding of the possible
risks and adverse reactions.
• This understanding should be based on the available physical,
chemical, pharmaceutical, pharmacological, toxicological, and clinical
information on the investigational product.
• Guidance should also be provided to the clinical investigator on the
recognition and treatment of possible overdose and adverse drug
reactions that is based on previous human experience and on the
pharmacology of the investigational product.

43. CASE REPORT FORM

44. INTRODUCTION
▪ The case report form [CRF] is a tool used to collect all data from each
participating subject or patient in a clinical trial.
▪ The International Conference on Harmonization [ICH] guidelines for GCP
define the CRF as : a printed ,optical or electronic document designed to
record all of the protocol-required information to be reported to the
sponsor on each trial subjects.
▪ This is important for the clinical trial team because the analysis and
reporting of the trial outcome is largely based on the completeness and
accuracy of data recorded from each patient recruited in the trial

45. PURPOSE OF CRF
▪ CRF are based on study protocol.
▪ To answer the hypothesis formulated in the study protocol.
▪ To provide relevant safety data related to the drug.
▪ To ensure precise collection , analysis and reporting of data.
▪ The investigator is responsible for ensuring a ligible and accurate CRF that is
completed in a timely manner , although data may be recorded by other
research staff members.
▪ The sponsor usually develops or outsources CRF development , to collect
the specific data they need to test their hypothesis and find answer to their
research questions.

46. TYPES OF CRF
▪ 2 types of CRF:
o Traditional paper CRF
o Improvised electronic CRF [eCRF]
❑Paper CRF
▪ Paper CRF is the traditional way of data capture and a better option if
studies are small or vary in design .
▪ Drawback : designing a paper CRF is a tedious job that could result in data
errors and wrong conclusion, requiring meticulous attention to minimize
duplication of CRF page.

47. ❑Electronic CRF
▪ eCRF are considered if studies are large with similar designs.
▪ In the current global scenario, eCRF are preferred over paper CRFs as they are less
time consuming .
▪ Also the use of eCRF makes it easy to collect and harmonize data from multicenter
studies.
▪ It is designed in such a way that data entry can be done with zero/minimal errors.
▪ Moreover regulatory authorities are readily accepting submissions in which
validated electronic data capture [EDC] systems are used.
▪ While designing an eCRF , repetitive data such as protocol ID, site code, subject
ID, and patient initials will be generated by the system automatically from the first
page to all others, thus ensuring no duplication of CRF page.

48. ❖Advantage of eCRF over paper CRF
⮚Consistency and accuracy of data
▪ By eliminating the possibility of errors during manual transcription or miscoding.
▪ It is possible to correct or add items during the study without having re-edit the
entire observation notebook.
▪ The data can be verified through queries. A query is an electronic request send to
the investigating team to confirm or alert them to any inconsistencies or potential
data entry errors.
⮚Data monitoring and score calculation
▪ Monitoring and remote follow up is ensured.
▪ Automatic notifications send directly by the eCRF in case of adverse events, allow
clinical research team to track data more easily and regularly .
▪ Scores are also calculated automatically, removing bias in investigator’s
calculation and misinterpretations

49. ⮚Data security
▪ Only authorized person can collect and manage the data.
▪ All entries and modifications are tracked, ensuring traceability.
▪ It is possible to know who changed what and when.
▪ Regular and permanent data backup, unlike paper CRF which can be lost or
altered.
⮚Significant time saving
▪ Data are captured in real time as the eCRF study progresses, whereas they
are captured at the end of the patient follow up period on paper CRF .
▪ Once recorded in the eCRF ,the data are easier to manage and intermediate
analysis are simplified because they are already in the database.

50. CONTENT
▪ All CRFs should include the following data:
Study title and number
Investigators name
Study subject/patient ID [number and initials]
Inclusion/exclusion criteria
Demographic data
Detailed description of dosage regimens of investigational drug
The patients medical history and the result of the physical examination by the
doctor.
Efficacy and safety parameters.
Adverse events
Conclusion on subjects health
Investigators signature and date

51. ▪ Inclusion and exclusion criteria : features a patient needs to fulfill to get
enrolled into the study
▪ Demographics : the patients personnel information in an anonymized way
▪ Efficacy and safety parameters : measurements that show the effect of the
medicine and potential side effect of the medicine

52. STANDARD CASE REPORT FORM DESIGN
▪ Primary objective of CRF designing is to gather complete and accurate data
by avoiding duplication and facilitating transcription of data from source
documents onto the CRF.
▪ Always minimum amount of data needed to answer the study hypothesis
should be collected avoiding collection of elaborate, unimportant
information.
▪ Capturing the same data in more than one place [duplication] on the CRF
should be avoided.
▪ Placing too many details on the same page, makes the CRF look cluttered
and makes data entry difficult, which eventually leads to increase in data
discrepancies.
▪ Moreover it should capture legible, consistent, and valid data, thereby
reducing query generation.

53. ❑Formatting CRF
▪ The units of all measurements should be specified in the CRF to maintain
uniformity.
▪ Appropriate boxes should be provided to avoid confusion .
▪ The CRF entries should be neatly written preferably in block letters to avoid
errors.
▪ Use consistent formats, font size and font style throughout the CRF booklet.
▪ Using the option ‘circling of answers should be limited as its hard to
interpret.
▪ Provide bold and italic instructions.
▪ Use standard data format throughout the CRF.

54. ❑Formatting questionary
▪ Use simple and non-technical language .
▪ Use examples wherever necessary.
▪ Minimize free text entry.
▪ Font size should be more than 1.0 to enable comfortable reading by the
aged

55. ❑Procedure for making correction in the CRF
▪ Errors identified in the CRF have to be dealt with the help of a query form
that is specific to the CRF of the particular study provided by the sponsor.
▪ Common errors : missing data, spelling error, blank mandatory comment
field, unacceptable terminology, missing investigators signature etc…
▪ Query can be generated by the CRA or data entry operator.
▪ The identified errors must be discussed by the CRA with the investigator
and CRC to obtain the explanation.
▪ The CRC must make the necessary corrections by striking a line through the
incorrect entry, entering the correct data with date and initials.
▪ The reason for the change has to be explained.
▪ The original entry should not be erased from the CRF as one must be able
to see the original incorrect value.

56. STANDARD CRF TEMPLATES
▪ A library of standard templates should be established and maintained by
the sponsor or pharmaceutical companies in order to maintain uniformity
in the CRF design and to save time.
▪ Most commonly used standard CRF templates are inclusion criteria ,
exclusion criteria, demography, medical history, AE , concomitant
medication.
▪ This should be developed in a way which can be customized as per protocol
requirements.
▪ These are also called safety modules.
▪ The modules which capture efficacy data are not unique. There design
varies from study to study depending on the protocol specifications

57. WELL DESIGNED VS POORLY DESIGNED CRF

58. ▪ Poor CRF design results in frequent database modification thus affecting
the study timelines.
▪ Collection of derived data again on the CRF should be avoided to minimize
calculation error.
✔Eg : age can be calculated using date of birth
BMI can be calculated using height and weight of the subject.
▪ In some places, answers are coded in order to simplify the data collection.
▪ When codes are used to obtain an answer for a question, consistency in
codes should be maintained throughout the CRF booklet.
✔Eg : if yes /no answers are coded as 1=yes and 2=no, the same order should
be practiced throughout the CRF.

60. ▪ It is advisable to use indicator questions wherever needed to avoid
assumptions about the data.
▪ Use indicator questions in connection to a set of other questions and the
response to the indicator question would decide on whether the associated
set of questions needs to be answered or not.
✔Eg: in an AE question group, an indicator question could be, Did any AE
occur after the last visit ?
✔If the response is YES , the remaining questions pertaining to the details of
the AE require response.
✔If the response is NO , the rest of the question group is not answered.

62. CONCLUSION
▪ CRF is a tool used to collect data from each participating subject or patient
in a clinical trial.
▪ Purpose is to answer hypothesis formulated on the study protocol.
▪ eCRF is more preferred over paper CRF.
▪ Primary objective of CRF designing is to gather complete and accurate data
by avoiding duplication and error.
▪ It can provide relevant safety data related to the drug.

63. REFERENCE
• Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice.
• NewDrugs-CTRules 2019.
• https://www.ucl.ac.uk › joint-research
• Shantala Bellary, Binny Krishnankutty et.al [2014] BASICS OF CASE RPORT
FORM DESIGNING IN CLINICAL RESEARCH perspectives in clinical research
5[4]:159-166
• Designing of clinical study documentation protocol and CRF: ICH guideline
E6

64. Thank
you