ICH-E6A - Protocols and IB

Question 1

What General Information should be included in the protocol or separate protocol pages?

Answer 1

6. 1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
7. 1.2 Name and address of the sponsor and monitor (if other than the sponsor).
8. 1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
9. 1.4 Name, title, address, and telephone number(s) of the sponsor’s medical expert (or dentist when appropriate) for the trial.
10. 1.5 Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
11. 1.6 Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
12. 1.7 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.

Question 2

What Background Information should be included in the protocol or separate protocol pages?

Answer 2

6. 2.1 Name and description of the investigational product(s).
7. 2.2 A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
8. 2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
9. 2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
10. 2.5 A statement that the trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
11. 2.6 Description of the population to be studied.
12. 2.7 References to literature and data that are relevant to the trial and that provide background for the trial.

Question 3

What should the trial object and purpose in the protocol describe?

Answer 3

A detailed description of the objectives and the purpose of the trial

Question 4

What TRIAL DESIGN Information should be included in the protocol or separate protocol pages?

Answer 4

6. 4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
7. 4.2 A description of the type/design of trial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures, and stages.
8. 4.3 A description of the measures taken to minimize/avoid bias, including:
   (a) Randomization
   (b) Blinding.
9. 4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
10. 4.5 The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
11. 4.6 A description of the “stopping rules” or “discontinuation criteria” for individual subjects, parts of trial, and entire trial
12. 4.7 Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
13. 4.8 Maintenance of trial treatment randomization codes and procedures for breaking codes.
14. 4.9 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.

Question 5

What Information about SELECTION and WITHDRAWAL OF SUBJECTS should be included in the protocol or separate protocol pages?

Answer 5

6. 5.1 Subject inclusion criteria.
7. 5.2 Subject exclusion criteria.
8. 5.3 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.

Question 6

What Information about TREATMENT OF SUBJECTS be included in the protocol or separate protocol pages?

Answer 6

6. 6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
7. 6.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
8. 6.3 Procedures for monitoring subject compliance

Question 7

What Information about ASSESSMENT OF EFFICACY should be included in the protocol or separate protocol pages?

Answer 7

6. 7.1 Specification of the efficacy parameters.

6. 7.2 Methods and timing for assessing, recording, and analyzing efficacy parameters.

Question 8

What Information about ASSESSMENT OF SAFETY should be included in the protocol or separate protocol pages?

Answer 8

6. 8.1 Specification of safety parameters
7. 8.2 The methods and timing for assessing, recording, and analyzing safety parameters.
8. 8.3 Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
9. 8.4 The type and duration of the follow-up of subjects after adverse events.

Question 9

What Information about STATISTICS should be included in the protocol or separate protocol pages?

Answer 9

6. 9.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
7. 9.2 The number of subjects planned to be enrolled. In multicenter 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.
8. 9.3 The level of significance to be used.
9. 9.4 Criteria for the termination of the trial.
10. 9.5 Procedure for accounting for missing, unused, and spurious data.
11. 9.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).

6.9.7 The selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).

Question 10

True or False?

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.

Answer 10

True

Question 11

Do you have to have a description of ethical considerations relating to the trial listed in the protocol?

Answer 11

Yes

Question 12

If not addressed in a separate agreement what must go into the protocol? Select all that apply

A. Financing and Insurance
B. Publication Policy
C. Animal Testing Information
D. All of the above

Answer 12

A & B

Question 13

Describe what the IB is?

Answer 13

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. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures

Question 14

Who should edit/write the IB?

Answer 14

A medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data.

Question 15

True or False:

The information in an IB 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

Answer 15

True

Question 16

True or False

If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared.

Answer 16

True

Question 17

How often should the IB be reviewed?

Answer 17

The IB should be 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.

Question 18

Who is responsible for keeping the IB up to date?

Answer 18

Sponsor

Question 19

In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the _________.

Answer 19

Commercial Manufacturer

Question 20

What top level things should be in the IB?

Answer 20

• Title Page & Confidentiality Statement
• Table of Contents
• Summary
• Introduction
• Physical, Chemical, and Pharmaceutical Properties and Formulation
• Nonclinical Studies
• Effects in Humans
• Summary of Data and Guidance for the Investigator

Question 21

In the IB you should include literature references where appropriate?

Answer 21

Yes

Question 22

Study this about the IB. It was bolded in ICH Guidelines about 7.3.7 section about Summary of Data and Guidance for the Investigator:
The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that are based on previous human experience and on the pharmacology of the investigational product.

Answer 22

Did ya read all of it?

Question 23

What is not on the title page of an IB?

A. Edition number of IB
B. Identity of each individual product and its release date
C. Sponsors name
D Sponsor contact infomation

Answer 23

D

Question 24

What should the summary of IB be like?

Answer 24

A brief summary (preferably not exceeding two pages) 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.

Question 25

What should be included in the INTRODUCTION of an IB?

A. Pharmacological class and expected position within class
B. All active ingredients
C. Chemical Name
D. Generic and Trades names when approved
E. Rationale for research
F. anticipated prophylactic, therapeutic, or diagnostic indication(s)
G. general approach to be followed in evaluating the investigational product

Answer 25

ALL OF THEM

Question 26

In the section of the IB about Physical, Chemical, and Pharmaceutical Properties and Formulation the following should be included:

A. Description of substance(s)
B. Brief Summary of relevant physical, chemical and pharmaceutical properties
C. Description of Formulations (include excipients)
D. Instructions for storage and handling of dosage
E Any structural similarities to other known compounds

Answer 26

ALL OF THEM

Question 27

The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the
relevance of the findings to the investigated therapeutic and the possible unfavorable and unintended effects in humans is in what part of the IB?

Answer 27

7.3.5 Nonclinical Studies

Question 28

What does Nonclinical pharmacology talk about in the IB when referencing nonclinical studies section?

Answer 28

A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).

Question 29

What does Pharmacokinetics and Product Metabolism in Animals talk about in the IB when referencing nonclinical studies section?

Answer 29

A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species.

Question 30

A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:
− Single dose
− Repeated dose
− Carcinogenicity
− Special studies (e.g., irritancy and sensitization)
− Reproductive toxicity
− Genotoxicity (mutagenicity)

Answer 30

Just study it. Referencing nonclinical studies section of ICH. Page P53

Question 31

In the IB when referencing EFFECTS IN HUMANS what should you include?

Answer 31

• Intro
• Pharmacokinetics and Product Metabolism in Humans
• Safety and Efficacy
• Marketing Experience

Question 32

The IB should identify countries where the investigational product has been ____________. Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration.

Answer 32

Marketed or approved.