Investigational medicinal product dossier (IMPD) and Investigational brochure (IB) in Regulatory affairs

1. Investigational Medicinal Product
Dossier (IMPD) And Investigator
Brochure (IB)

2. CONTENTS
Dossiers
Goals of Dossier
Investigational medicinal product dossier (IMPD)
Objectives of IMPD
Data related to IMPD
Types of IMPD
IMPD in case of placebo
IMPD for marketed products
Introduction to Investigational Brochure (IB)
Table of content of IB

3. DOSSIERS:
» Actual meaning of “Dossier” is – a collection or file
of documents on some subjects, especially a file
containing detailed information about that topic.
E.g. Patient history file.
» Dossier ( or Registration Dossier ) of
pharmaceutical product is a document that
contains all technical data ( Administrative, Quality,
Clinical and Non-clinical data) of a pharmaceutical
product to be approved /registered/marketed in a
country.

4. DOSSIERS:
» Quality
» Efficacy
» Safety properties suitable for the
intended use
» Additional administrative
documents
» Sample of finished product or
related substances.
» Reagents necessary to perform
analysis of finished product.
» It is more commonly called
as:
» New Drug Application
(NDA) in the USA
» Marketing Authorization
Application (MAA) In
EU
» Or simply Registration
Dossier.
It consists of data proving that the drug has :

5. GOALS OF DOSSIER
» whether the drug is safe and effective in its
proposed use when used as directed, and do
the benefits of the drug outweigh the risk?
» Is the drug’s proposed labeling (Package
insert) appropriate and what it contains?
» Are the methods used in manufacturing the
drug and the controls used to maintain the
drug’s quality adequate to preserve drug’s
identity, strength, quality and purity.

6. INVESTIGATIONAL MEDICINAL PRODUCT
DOSSIER (IMPD)
» The Investigational Medicinal Product Dossier (IMPD)
is one of several pieces of Investigational Medicinal
Product related data, required whenever the
performance of a clinical trial is intended in one or
more European Union Member States.
» The IMPD includes summaries of information related
to the quality, manufacture and control of the
investigational Medicinal Product, data from non-
clinical studies and from its clinical use.

7. IMPD
» IMPDs are submitted as a part of clinical trial
application dossier, as the basis for the
approval of clinical trials by competent
regulatory authorities within the European
union.

8. Objectives of IMPD
» Clinical trails often to be designed as
multicentre studies, potentially involving
different member states.
» Aim of these guidelines to defines harmonized
requirement of documentation to be submitted
throughout the European community.

9. TYPES OF IMPDs
» The EU has provided for two types of IMPDs, “Full
IMPD” and a “Simplified IMPD”, based on whether
the product has been described previously in a
CTA or any other marketing authorization
application or not.
» Full IMPD is required when little or no information
about an IMP has been previously submitted to
competent authorities. When it is not possible to
cross-refer to data submitted by another sponsor
or when there is no MA in the community.

10. FULL IMPD
» It is required if no prior submission of any information
about the chemical or biological product is made to the
competent authority and in cases when information
cannot be cross referred.
» It also includes the summaries of information regarding
quality, manufacture and control parameters of IMP
along with non-clinical and clinical data including animal
pharmacology and toxicology studies, previous reports of
clinical trial and human experience with the product,
overall risk and benefit assessment.

11. SIMPLIFIED IMPD
» A simplified IMPD may be submitted if
information has been assessed previously as
part of a marketing authorization In any
Member State or a clinical trial to that
competent authority or when it is possible to
cross-refer to data In some other documents.

12. SIMPLIFIED IMPD
» The applicant has the possibility to refer to other documentation which may
be submitted alone or with a simplified IMPD:
1. Possibility to refer to the Investigational brochure (IB) for the preclinical and
clinical parts of the IMPD.
2. The applicant may submit the current vision of the SmPC (summery of
product characteristics) or document equivalent to the SmPC as the IMPD if
an IMP has a marketing authorization in any Member State or in an ICH
country.
The IMPD may have been submitted by the same applicant or by another
applicant, in these cases applicant are allowed to cross-refer to the previous
submission.
If submission was made by another applicant, a letter from that applicant
should be submitted authorizing the national competent authority to cross
refer that data.

13. CONTENTS OF SIMPLIFIED IMPD

14. DATA RELATED TO IMPD
» The IMPD can be replaced by other
documentation which may be submitted alone or
with simplified IMPD.
» It should be prefaced with a detailed table of
content and a glossary of terms.
» The information in the IMPD should be concise. It
should not be unnecessarily voluminous.
» It is preferable to present data In tabular form
accompanied by brief narrative highlighting the
main salient points.

15. SECTIONS OF IMPD
» IMPD is divided into four distinct sections:

16. A. QUALITY DATA
» Includes summaries of chemical,
pharmaceutical and biological data on quality of
any Investigational medicinal Product (IMP).
» Only those IMPs can be sent for clinical trial
whose manufacture complies with principles of
Good Manufacturing Practice.(GMP)

17. NOTE : In Exceptional cases, where impurities are not justified or when
unexpected impurities are detected, the certificate of analysis for test
product should be attached.
To document this requirement the applicant should provide the
following:
If the IMP is manufactured in the EU and does not have a marketing
authorization in the EU:
A copy of the manufacturing authorization.
If the IMP is not manufactured in the EU and does not have a
marketing authorization in the EU:
Certification of the Qualified Person that the manufacturing site work
in compliance with the GMP at least equivalent to EU GMP.
certification of the GMP status of any active biological substance.
copy of the importer’s authorization.

18. CTD Headings for Investigational medicinal product
“QUALITY DATA”
 Drug substance
 General Information.
 Nomenclature.
 Structure .
 General Properties.
 Manufacture:
 Manufacturers.
 Description of mfg
process and process
control.
 Control of critical step
and intermediates.
 Process validation &/or
Evaluation.
 Mfg process
development.
 Characterization
 Structure elucidation and
other characteristics
 Impurities
Control of Drug
substance:
 Specification
 Analytical Procedure
 Validation of Analytical
Procedure
 Batch analysis
 Justification of specification
Reference standard or
material
Container closure
system
Stability
Medicinal product:
 Description & Composition
of the medicinal product
Pharmaceutical
Development:
 Drug substance
 Excipients
 Medicinal Product
 Formulation Development
 Overages
 Physicochemical and
Biological Properties
 Components of the
Medicinal Product

19. CTD Headings for Investigational medicinal product
“QUALITY DATA”
Manufacturing Process
Development
Container and closure
system
Microbiological
attributes
Manufacture:
 Manufacturers.
 Batch formula
 Description of mfg
process and process
control.
 Control of critical step
and intermediates.
 Process validation &/or
Evaluation.
Control of excipients
 Specification
 Analytical procedure
 Validation of analyticall
procedure
 Justification of specification
 Excipients of human and
animal origin
 Novel excipients
Control of Medicinal
product:
 Specification
 Analytical Procedure
 Validation of Analytical
Procedure
 Batch analysis
 Characterization of
impurities
 Justification of
specification
Reference standard or
material
Stability
Appendices:
 Facilities and equipments
 Adventitious agents safety
evaluation
 Novel excipients
 Solvents for reconstitution
and diluents

20. B. Non-clinical Pharmacology and Toxicology
data
 It should provide summaries of non-clinical pharmacology and
toxicology data for any IMP to be used in the clinical trial or
justify why they have not.
 It should also provide a reference list of studies conducted and
appropriate literature references.
 The summaries of studies conducted should allow an
assessment of the adequacy of the study and whether the study
has been conducted according to an acceptable protocol.
 Sponsors should provide the non-clinical information in the
IMPD under the headings provided ahead:

21. CTD Headings for Investigational Medicinal Product for
“Non-clinical pharmacology and Toxicology data”
Pharmacodynamics
 Brief summary
 Primary
pharmacodynamics
 Secondary
pharmacodynamics
 Safety pharmacology
 P’codynamics
interactions
 Discussion and
conclusion
Pharmacokinetics
 Brief summary
 Methods of analysis
 Absorption
 Distribution
 Metabolism
 Excretion
 P’cokinetic drug
interactions
 Other P’cokinetic studies
 Discussion and
conclusion including
evaluation of
toxicokinetics.
Toxicology:
 Brief summary
 Single dose toxicity
 Repeat dose toxicity
 Genotoxicity
 In vitro
 In vivo
 Carcinogenicity
 Reproductive and
developmental toxicity
 Local tolerance
 Other toxicity studies
 Discussion and
conclusion.

22. C. Previous Clinical Trial and Human Experience Data
 It should provide summaries of all available data from previous
clinical trials and human experience with proposed IMP in this
section.
 All studies have been conducted in accordance with the
principles of GCP.
 This should be confirmed by sponsor in the statement of the
GCP status of all studies and where this is not the case, he
should provide an explanation or justification if available.
 Applications should take account of the general guidance on
clinical trials in the development of a medicinal product.

23. CTD Headings for Investigational Medicinal Product for
“Previous Clinical Trials and Human Experience Data”
Clinical pharmacology
 Brief summary
 Mechanism of primary action
 Secondary p’cological effects
 P'codynamic interactions
Clinical pharmacokinetics:
 Brief summary
 Absorption
 Distribution
 Metabolism
 Excretion
 P’cokinetics of active metabolite
 Plasma concentration-effect
relationship
 Dose and time dependence
 Special patient populations
 Interactions
Human exposure:
 Brief summary
 Overview of safety and efficacy
 Healthy subject studies
 Patient studies
 Previous human experience
Benefits and risk assessment

24. D. Overall Risk and Benefit Assessment
 It should provide a brief summary that analyses the non-clinical and
clinical data in relation to the potential risk and benefits of the
proposed trial.
 Should use the relevant pharmacology, toxicology and kinetic results
to indicate possible risks in human.
 Should identify any studies that were terminated permanently and
discuss the reasons.
 Should discuss safety margins in terms of relative systemic exposure
to the investigational medicinal product, preferably based on :
● AUC
● Cmax Data
 Rather than in terms of applied dose.

25. IMPD In Case of Placebo
If the Investigational Medicinal Product is a placebo, the information
requirements can be reduced in line with the requirements set out in
Table below:

26. IMPD for Marketed Products
 The sponsor may submit the current version of SmPC
( summary of product characteristics) as the IMPD, if the
IMP has a marketing authorization in any member state in the
EU and is being used in same form, for the same conditions
and with a dosing regimen covered by the SmPC.
 If the applicant is the marketing authorization holder and he
has submitted an application to vary the SmPC, which has not
yet been authorized, the nature of variation and the reason for
it should be explained in the covering letter.

27.  There are situations where the IMP to be used in the clinical
trial has a Marketing Authorization (MA) in the Member
States (MS) but the protocol allows that any brand of IMP
may be administered to the trial subjects. In those situations,
providing that the IMP is not modified, it is acceptable that
IMPs to be used are only used are only identified by the
active substance name as follows:
IMPD for Marketed Products

28.  Sponsor may wish to conduct a trial with an active substance that
is available in the community in a number of medicines with
Marketing Authorities and different trade names
 In some trials the sponsor may wish to allow investigator in the
same multicentre trial to administer different regimens of IMPs.
 In other trials the sponsor may wish to study the effect of a
number of medical treatment on specific illness without
specifying the IMPs t be used except that they have a Market
Authorization In the Member state concerned.
IMPD for Marketed Products

29. INVESTIGATION BROCHURE
Definition:
“It is a compilation of the clinical and non-clinical data
on the investigational products that are relevant to the
study of products in human subjects“

30.  To provide information to the investigator and others involved in trials
with the information to facilitate their understanding of the rational role
for, and their compliance with, many key features of protocol, such as
dose, dose frequency, dose interval, methods of administration and
safety monitoring procedures.
 Provide insight to support the clinical management for carryout clinical
trial study.
 The information should be presented in concise, simple, objective,
balanced, and non promotional form that enables a clinician, or a
potential investigator, to understand it and make his own unbiased risk-
benefit assessment of the appropriateness of the proposed trial.
 The IB should be reviewed at least annually and revised as necessary
in compliance with a sponsor’s written procedures.
PURPOSE OF INVESTIGATION BROCHURE (IB)

31. » Generally sponsor is responsible for up-to-date IB is made available
to the investigators and investigators are responsible for providing up-
to-date IB to the responsible IRBs/ IECs
» In case of an investigator sponsored trial, the sponsor-investigator
should determine whether the brochure is available from the
commercial personal.
» If investigational product is provided by the sponsor-investigator, then
he should provide the necessary information to the trial personal.
» In case where preparation of the formal IB is impractical, the sponsor-
investigator should provide, as substitute, an expanded background
information section in the trial protocol that contains the minimum
current information described in this guideline.
PURPOSE OF INVESTIGATION BROCHURE (IB)

32. It should include:
 Title page:
 Sponsor name
 The identity of each investigational product (i.e. research number, chemical or
approved generic name & trade name)
 The release date, reference number, date of edition.
 Confidential statement-
sponsor may wish to include a statement instructing the investigator/
recipients to treat the IB as confidential document for sole information and use
of investigator’s team and IRB/IEC
 Table of contents
 Summary – Not exceeding 2 pages, Highlighting the Physical, Chemical,
Pharmaceutical, Pharmacological, Toxicological, Pharmacokinetic, Metabolic
and Clinical information available as per IP.
CONTENT OF INVESTIGATION BROCHURE (IB)

33.  Introduction
 Chemical name
 Active ingredients
 Pharmacological class
 Anticipated- therapeutic / diagnostic indications
 Description of IP- storage and handling, structural similarity of any other
compound.
 Non-clinical studies – it may include following information
 Species tested
 Number of sex in each group
 Unit dose (mg/kg)
 Dose interval
 Route of administration
 Duration of dosing
CONTENT OF INVESTIGATION BROCHURE (IB)

34.  Effects in human
 Pharmacokinetic and product metabolism in human
 Safety and efficacy
 Marketing experience
 Summary of data and guidance for the investigator-
It contains non-clinical and clinical data of IP.
 Thus IB provide the investigator a clear understanding of –
 The possible risks
 Adverse reactions
 Observation and precautions needed for clinical trials.
CONTENT OF INVESTIGATION BROCHURE (IB)

35. APENDIX OF GENERAL CONSIDERATION OF IB
1. TITLE PAGE
2. SPONSOR’S NAME
3. Product:
4. Research number:
5. Names : chemical, generic (if approved)
6. Trade names (if legally permissible and desired by the sponsor)
7. INVESTIGATOR’S BROCHURE
8. Edition number:
9. Release Date:
10. Replaces Previous Edition Number:
11. Date:

36. MAIN CONTENTS OF THE INVESTIGATOR’S BROCHURE
 Confidentiality statement (optional)
 Signature page (optional)
1. Table of contents
2. Summary
3. Introduction
4. Physical, chemical and pharmaceutical properties
5. Non-clinical studies
 Non-clinical pharmacology
 Pharmacokinetics and product metabolism in animals
 Toxicology
6. Effects in humans
 Pharmacokinetics and product metabolism in animals
 Safety and efficacy
 Marketing experience
7. Summary of data and guidance for investigator.

38. REFERANCES:
Guideline on the requirements for the chemical and
pharmaceutical quality documentation concerning investigational
medicinal products in clinical trials EMA/CHMP/QWP/545525/2017
http://www.imp-dossier.eu/imdp_guidance/
https://www.fda.gov/drugs/investigational-new-drug-ind-
application/ind-applications-clinical-investigations-regulatory-and-
administrative-components
http://www.niche.org.uk/asset/insider-insight/Insider-
Investigator-Brochure.pdf