Investigator’s brochures

and
Investigational medicinal products
dossier
Presented by:
Dignesh Khunt
Assistant Professor
Department of Pharmaceutics

Shree S K Patel College of Pharmaceutical

 Introduction
All marketed drugs and biologics are sold accompanied by:
1. package leaflet (European Union [EU])
2. package insert (Japan and the United States)
What this document content ?????
 product characteristics (active and inactive ingredients,
 chemical structure, formula, and pharmaceutical
properties), summarize all known
 nonclinical and clinical information, and provide guidance
for dosing and administration
But this leaflet and insert does not exist during pre-approval
stage

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 Introduction
Therefore need of document which guide to clinical
investigators ….
The “Investigator’s Brochure (IB)” is a multidisciplinary
document that summarises the main elements of an entire
development programme to date
What is primary purpose of this IB????
 it is primarily written to enable investigators conducting
clinical studies to assess the risks and benefits associated
with an investigational product

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 Introduction
When IB required????
 conducting the first clinical study in humans
However, it is a living document and will then need to be updated as the
development programme progresses and further information becomes
available.
ICH E6 specifies that an IB should be ‘reviewed at least annually and
revised as necessary’, and that ‘more frequent revision may be appropriate
depending on the stage of development and the generation of relevant new
information’.
By ‘relevant new information’ the guideline means information that
substantially influences what is known about the characteristics of the
investigational product, especially safety, to the extent that this needs to be
communicated to enable reassessment of the benefits and risks.
Alternatively, some sponsors issue an addendum to the IB when needing to
rapidly communicate ‘relevant new information’.
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Regulatory guidance on structure and
content
Section 7 of ICH E6 provides what is essentially a table of
contents that is almost always used unchanged. The highest
level sections are:
• Summary
• Introduction
• Physical, chemical, and pharmaceutical properties and formulation
• Non-clinical studies
• Effects in humans
• Summary of data and guidance for the investigator.
three fundamental areas:
Nonclinical: testing in animals
Clinical: testing in humans
Drug description and chemical or biologic characteristics: formulation, dosing, administration,
and storage information

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Sections of an IB

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Title page
The title page includes important information, primarily
related to administrative functions (Table 1).

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Table of contents, table of tables or
figures
 detailed and accurate table of contents, which should
include page numbers for sections as well as for tables and
figures, and a list and location of appendices.

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Table of contents, table of tables or
figures

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List of abbreviations
A list of abbreviations and definitions should be provided for
the purpose of defining abbreviations used in the document.

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Summary
All three content areas contained in the document:
◦ drug description and chemical or biologic characteristics,
◦ nonclinical testing, and
◦ clinical testing (if applicable; the first edition of an investigator’s
brochure often does not contain any results of human testing).
Not exceed two pages, unless the complexities of the product
require more space.
Written after all sections

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Introduction
A brief introductory statement includes the following information:
Product description: chemical and generic name, all active ingredients, the
pharmacological class
Any advantages the investigational product is expected to have in this class
Indication: the disease, syndrome, or diagnosis for which the product is
intended and the population for whom it is intended. The indication statement,
generally the result of cross-functional team consensus, requires that the writer
work with regulatory affairs to determine the status and exact wording.
Investigational plan: a very brief (one to two sentences) description of clinical
Development plans. Clinical development plans comprise the number and types
of clinical studies planned for the coming year. Care should be taken not to
elaborate excessively on this point, since it will likely change substantially over
the course of development.

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Physical, chemical, and pharmaceutical
properties and formulation
 Very brief (one to two pages) description of drug characteristics
 Sufficient to orient the investigator to fundamental aspects that help to
place the investigational product in a therapeutic class and assist in
predicting potential drug effects.
 The information used in this section is provided by manufacturing staff
(Table 2).

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Physical, chemical, and pharmaceutical
properties and formulation
 During the course of development, certain manufacturing and
testing characteristics or procedures are expected to change as
knowledge of the specific formulation improves. Although these
changes are anticipated as a fundamental aspect of drug
development, any change may potentially alter drug effects on
biologic systems. Because testing in animals intends to predict drug
effects in humans, use Nonclinical studies
of the same batch of drug product for both
nonclinical and clinical testing (which is assumed to have been
manufactured and tested under identical conditions using identical
materials) is optimal.
 Because it may not be possible to do such testing, any substantial
difference between the drug product used in nonclinical testing and
that to be used in clinical testing should be briefly described and
presented in a table.

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Physical, chemical, and pharmaceutical
properties and formulation
Table 3 presents an example of a change in formulation
table, but in reality the content of the tabular presentation
will vary widely from product to product.

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Nonclinical studies
 Atan early stage in development, nonclinical information generally forms
most of the argument for safe first use in humans.
 After initiation of clinical trials, and as human data become available for
inclusion in the investigator’s brochure, the relevancy of certain nonclinical
studies may diminish somewhat, and consequently these sections should be
culled to retain the size of the brochure (approximately 50 pages) as clinical
trial data are added and those sections expanded.
 Dividedinto three categories
 Pharmacology
 Pharmacokinetics and metabolism
 Toxicology
 As presented in Figure 1, this section comprises both integrated
text (discussion of more than one study) and text from a source
document (eg, an abstract discussing results of a single study).

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Nonclinical studies

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Nonclinical studies
Summarized nonclinical information may be structured using
an
 introduction with key messages,
 overview text,
 tabular summaries, and
 synopses from the individual study reports
Abstracts from publications may be used in place of a study
report synopsis.
Note that information in the introduction is the most
summarized in the nonclinical section, and that the level of
detail expands in complexity and volume in the source text.
This structure is appropriate for nonclinical programs that are
extensive, and include a large number of studies.

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Nonclinical studies
Organization of nonclinical information in the
investigator’s brochure as presented in Figure 1
distinguishes between the three nonclinical categories
(pharmacology, pharmacokinetics, and toxicology) and
provides a tabular summary and overview text
individually for each of these three categories in an effort
to organize a large amount of information.

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Nonclinical studies
 In a smaller program with fewer studies, it may be beneficial to
simplify organization and summarize all studies in one tabular
summary, and in one overview summary (Figure 2).

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Introduction in nonclinical section
The point of this section is to introduce the reviewer and
clinical trial staff to the investigational product and its
use for the proposed indication.
A few brief statements about the nonclinical program
(species tested, routes of administration, acute versus
chronic testing, doses), and a short bulleted list of key
messages that sharply focuses on a few of the most
relevant points help to orient the reader to the program.
Relevancy is based on communicating characteristics of
the drug or biologic that will allow a clinician to most
safely and effectively use the investigational product.

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Introduction in nonclinical section
 All three study categories (pharmacology, pharmacokinetics, and toxicology)
should be mentioned in the key messages, as shown in Table 4 for the fictional
drug xerimax, under development for an oncological indication.

 The first point (pharmacology) makes a statement about the effects of the drug
xerimax on tumor growth. This statement is therefore intended to support
efficacy (or in the case of oncology drugs, activity).
 The second key message (pharmacokinetics) states observed metabolic
characteristics.
 The third point (toxicology) describes safety considerations that may help to
predict adverse events in humans (also known as side effects).
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Overview in nonclinical section
 text that integrates information from several studies
 For the purposes of an investigator’s brochure, the overview sections for
pharmacology, pharmacokinetics, and toxicology should each be
approximately one to five pages (with the exception of a small
nonclinical program, in which the integrated overview of pharmacology,
pharmacokinetics, and toxicology is combined for a total of
approximately one to ten pages), and provide a synthesis of the most
relevant information (the term ‘relevant’ is not defined, but allows for
elimination of those studies that do not substantially contribute to an
understanding of the drug due to selection of a poor model, dosing or
procedural deficiencies, lack of data collection, etc)
 Tabular presentation may be beneficial to understanding drug
characteristics for the most important assessments in light of differences
in dosing, species used, study design, or outcomes assessed.
 the tabular presentation notes the differences between two studies with
respect to the study design (dose and frequency of dosing, time to
endpoint and neurological assessments), and results (% tumor growth
delay, time to endpoint, ie, growth of the tumors to aCollege
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of Pharmaceutical
Overview in nonclinical section

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Tabular summary in nonclinical section
all relevant nonclinical pharmacology, toxicology, and
pharmacokinetics, and investigational metabolism studies.
This presentation should provide an easy, quick, and
focused look at the entire nonclinical program to date.
Contents for a tabular summary will by necessity vary
somewhat from one program to the next, but species, the
number of animals studied (N), the dose and route of
administration, the number of doses, the model used, major
endpoints, and results of major endpoints should be
displayed. Each study occupies one row of the table (Table
6).

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Tabular summary in nonclinical section

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Synopses in nonclinical section
From an individual study report (or the abstract from a
publication) should be sufficiently brief and informative to
use for the investigator’s brochure
If request by investigatory then full report provide else no
need
nonclinical study spans the different study categories
(pharmacology, pharmacokinetics, toxicology)
the most relevant studies in the tabular summary

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Effects in humans
 The first version of any investigator’s brochure is unlikely to have
information on the effects of the investigational product in humans
when it is submitted with a Clinical Trial Application (CTA, Europe),
Clinical Trial Notification (CTN, Japan), or Investigational New Drug
Application (IND, United States), which represent the first request for
use in humans
 Clinical testing or marketing may have been initiated in another
country or may occurred in the past as part of a previous development
program, in which case this section should provide a summary of all
known information
 As time progresses and clinical trial data become available, this section
expands and nonclinical sections tend to shrink, except for
investigator’s brochures used in Japan.
 This section comprises both integrated text (discussion of more than
one study) and text from a source document (discussion of a single
study) (Figure 3)

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Effects in humans
 The structure for clinical information may be similar to that for
nonclinical information for a small nonclinical program, using an
introduction with key messages, overview text, tabular summaries, and
synopses from the individual study reports (or abstracts from
publications).

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Effects in humans
 Clinical data are generally categorized by study phase (Chapter 1,
Developing a Target), starting with phase 1, and continuing on to
phases 2, 3, and 4 rather than physiologic effect as in nonclinical
studies (pharmacology, pharmacokinetics, and toxicology).
 In general, many fewer human studies tend to be conducted compared
with nonclinical studies, so structure of this section tends to be simpler
and more similar to that for a small nonclinical program.

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Introduction to use in humans
A few brief statements about the populations tested in all clinical
studies to date (volunteers versus subjects with the disease, men and
women, disease characteristics or indications, age groups, etc), region
in which the testing was conducted, routes of administration (by
mouth, intravenously, subcutaneously, etc), doses (using quantity and
units), and a short bulleted list of key messages that focus on product
characteristics that are relevant to safe and effective clinical use should
be in the introduction.
 Keymessages in clinical trials are generally categorized as:
􀁵 Efficacy (or activity in oncology trials)
􀁵 Pharmacokinetics/pharmacodynamics
􀁵 Safety

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Introduction to use in humans
 In the example for the fictional drug xerimax (under development for
an oncological indication), bulleted points shown in Table 7 focus on
efficacy (the first two key messages), pharmacokinetics (the third key
message), and safety (the last two key messages) of both the
investigational product (xerimax) and an active control agent (trexon,
also fictional).

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Overview of human experience
 An overview is text that integrates information from several studies.
For the purposes of an investigator’s brochure, the overview clinical
section should be fewer than 10 pages and provide a synthesis of the
most clinically relevant information.
 Determination of clinical relevancy is done in collaboration with a
medical officer.
 Tabular presentation of important outcomes across all clinical studies
(or those considered to be most representative of the product’s
characteristics) may be beneficial.
 Again, tabular presentations should be modified to suite the product.
 Results of three individual phase 1 and phase 2 studies are presented in
Table 8, allowing comparison of the efficacy and safety observed in all
three studies and for results of pharmacokinetics from the phase 1
study.
 Finishing clinical study, submit marketing approval (an MAA in
Europe and Japan, and an NDA in the United States)
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Overview of human experience

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Tabular summary
 The tabular display in Table 8 presents a focused look at the most
important efficacy results from more than one study. This type of
display is meant to allow easy comparison and discussion of outcomes
(overall survival, for example) and should not be confused with a
tabular summary, which has a slightly different purpose (Table 9).

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Tabular summary
A tabular summary is a table containing one row each for all clinical
trials (unlike nonclinical studies for which only relevant studies may
be listed, all clinical trials in humans should be listed here).
 The purpose of a tabular summary is to provide an accounting of all
clinical trials conducted (the number of trials, the number of subjects,
the regions in which the trials were conducted, the progression from
one phase to the next, etc), as well as providing an easy, quick, and
very focused look at the entire clinical program to date. Contents for a
tabular summary will by necessity vary, but the number of subjects
studied (N), the dose and route of administration, the number of doses,
major disease characteristics, timing and results of major endpoints
should be displayed. Each study occupies one row of the table (Table
9).

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Synopses in clinical section
 A well-written synopsis from an individual study report (or the abstract
from a publication) should be informative enough to use for the
investigator’s brochure, but it may on occasion be overly long and
require additional summarization.
 Ifan investigator requires the full text of a study report, he or she may
request it from the sponsor, so there is no need to provide extensive
details in the investigator’s brochure. Unlike the descriptions of
nonclinical studies, information on all clinical studies should be
included.
 An example of a synopsis from a clinical study reportmay be found in
Appendix IX. (pg 200)

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Summary of data and guidance for the
investigator
 Theguidance on this section of the investigator’s brochure is relatively
nonspecific, but has been generally interpreted as a place to begin the
product’s labeling.
 The section should, therefore, be structured similarly to a European
Summary of Product Characteristics (SmPC) or a Japanese or United
States package insert.
 Thesethree documents are used frequently by clinical practitioners
because they constitute the primary means by which a drug company
conveys product information in Europe and the United States.
 Japanese package inserts tend to be brief, since Japanese marketing
representatives supply much of the information to practicing
physicians. The intent of this section is to place all known product
information into a package insert format, which is readily recognizable
and easily understood.

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Summary of data and guidance for the
investigator
 Use of a competing product’s labeling (or a product that has some
similarity such as indication or therapeutic class) is helpful in writing
this section of the investigator’s brochure. Clearly, not all the
information from another product’s labeling will be available for your
investigational product, but it is a starting point.
 Product labeling is easily available on the Internet. With few
exceptions, all of the information in this section (if it exists) is in other
sections of the brochure, but the information may require additional
summarization or categorization, based on the region in which the
information will be submitted.

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References
1 European Commission, Enterprise and Industry Directorate-General, A
Guideline on Summary of Product Characteristics, October 2005.
Revision 1.
2 Guidelines for Package Inserts for Prescription Drugs (Notification No.
606 of PAB dated April 25, 1997).
3 Guidelines for Package Inserts for Prescription Drugs (Notification No.
59 of the Safety Division, PAB dated April 25, 1997).
4 Guidelines for Precautions for Prescription Drugs (Notification No.
607 of PAB dated April 25, 1997).
5 Title 21 – Food and Drugs Chapter I – Food and Drug Administration
Department of Health and Human Services Subchapter C – Drugs:
General Part 201 Labeling, Subpart B Labeling requirements for
prescription drugs and/or insulin, Section 201.56 [71 FR 3986],
January 24, 2006.
6 ICH Harmonised Tripartite Guideline E6(R1) Guideline for Good
Clinical Practice: Consolidated Guidance, ICH June 1996,
http://www/ich.org (Accessed 27 February 2007).
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Education and Research, Ganpat University
Investigational medicinal products
dossier

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Introduction
What is IMPD?????
Before human clinical trials can be started in the European
Union (EU), the sponsor must request authorization to conduct
clinical trials through a submission called a Clinical Trial
Authorisation (CTA). This application includes a group of
scientific documents called an Investigational Medicinal
Products Dossier (IMPD).
 Type??

two types of IMPDs, a full IMPD and a simplified IMPD, based

on whether the product has been described previously in another
CTA or a marketing authorization application…

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Introduction
 Guidance on the structure and content of an IMPD is
provided by the European Commission (EC) in ENTR/F2/BL
D(2003) CT1 Revision 2, dated October 2005.
 The IMPD consists of a group of documents, with cross-
references to other documents, such as the investigator’s
brochure, the clinical protocol, or another IMPD.
 The IMPD has a general structure:
􀁵Quality (chemistry, manufacturing, and controls) data
􀁵Nonclinical pharmacology and toxicology data
􀁵Previous clinical trial and human experience data
􀁵Overall risk and benefit assessment

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