Investigation of medicinal
Submitted by: Submitted to:
SADAF SALEEM DR. SANJULA BABOOTA
M.Pharm (Pharmaceutics) Dept. of Pharmaceutics
SPER, JAMIA HAMDARD
• Goals of dossier
• Drug approval process in EU
• CTA and IMPD
• Investigational medicinal products dossier(IMPD)
• Objectives of IMPD
• Data related to IMPD
• Types of IMPD
• IMPD in case of placebo
• IMPD for marketed products
The word “Dossier” has its meaning as – a collection or file of
documents on some subject, especially a file containing detailed
information about that topic.
Dossier(or registration dossier) of a pharmaceutical product is a
document that contains all technical data(administrative, quality,
clinical and non clinical) of a pharmaceutical product to be
approved/registered/marketed in a country.
It is a document that has to be submitted as a requirement
of a drug approval/market authorisation process and to obtain
worldwide licensing approval of a drug by diverse health authorities.
They are the vehicle in a country through which drug sponsors
formally propose, that the Regulatory Agencies approve a new
pharmaceutical for sale and marketing.
It consists of data proving that the drug has:
Safety properties suitable for the
intended use It is more commonly called as:
-New Drug Application (NDA)
Additional administrative documents in the USA
Samples of finished product or related -Marketing Authorization
substances Application (MAA) in EU
-or simply Registration
Reagents necessary to perform analyzes Dossier.
of finished product.
GOALS OF DOSSIER
The goals of the dossiers are to provide enough information to permit
regulatory agencies reviewers to establish the following:
• Is the drug safe and effective in its proposed use when used as
directed, and do the benefits of the drug outweigh the risks?
• Is the drug’s proposed labelling (package insert) appropriate
and what it contain?
• Are the methods used in manufacturing the drug and the
controls used to maintain the drug’s quality adequate to
preserve the drug’s identity, strength, quality, and purity?
DRUG APPROVAL PROCESS IN EUROPEAN UNION
There are two regulatory steps to go through before the
drug is approved to be marketed in the EU.
The two steps are:
Clinical trial application(CTA)-in order to obtain permission to
conduct clinical trials.
Marketing authorization application(MAA)-in order to obtain
permission to market the product.
Clinical trial applications are approved at the member
state level and Marketing authorization applications are
approved at both the member state and the centralized
A qualified person has to certify that the investigational
medicinal product(IMP) is being developed according to
CTA AND 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 Application (CTA).
• This application includes a group of scientific documents
called an Investigational Medicinal Products Dossier
INVESTIGATIONAL MEDICINAL PRODUCT
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.
IMPDs are submitted as a part of clinical trial application
dossier, as the basis for the approval of clinical trials by
competant regulatory authorities within the European
They are equivalent to the investigational new drug
application(INDA) in the united states.
OBJECTIVES OF IMPD
Since clinical trials are designed as multi
centered studies, potentially involving
different member states, it is the aim of
this guideline to define harmonized
requirements of the documentation to
be submitted throughout the European
DATA RELATED TO IMPD
• The IMPD can be replaced by other documentation which
may be submitted alone or with a simplified IMPD.
• It should be prefaced with a detailed table of contents
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
IMPD is divided in four distinct sections.
The IMPD provides information on the following:
Quality (chemistry, manufacturing, and controls) data
Nonclinical pharmacology and toxicology data
Previous clinical trial and human experience data
Overall risk and benefit assessment
1) Quality data
− Includes summaries of chemical, pharmaceutical and
biological data on quality of any IMP.
− Only those IMPs can be sent for a clinical trial whose
manufacture complies with the principles of Good
To document this requirement the applicant should
provide the following:
• If the IMP is manufactured in the EU and does not have a
marketing authorisation in the EU:
− A copy of the manufacturing authorisation
• If the IMP is not manufactured in the EU and does not
have a marketing authorisation in the EU,
− Certification of the Qualified Person that the
manufacturing site work in compliance with GMP
at least equivalent to EU GMP
− Certification of the GMP status of any active
− Copy of the importer’s authorisation
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.
Common Technical Document Headings for: Investigational
Medicinal Product “Quality Data”
DRUG SUBSTANCE − Elucidation of Structure and Other MEDICINAL PRODUCT
− General Information: characteristics Description and Composition of the
− Nomenclature − Impurities medicinal Product:
− General Properties Control of Drug Substance: Pharmaceutical Development:
− Specification − Components of the Medicinal Product
Manufacture: − Analytical Procedures − Drug Substance
− Manufacturers − Validation of Analytical Procedures − Excipients
− Description of Manufacturing Process − Batch Analyses
and Process Controls − Justification of specification − Medicinal Product
− Control of Materials − Formulation Development
− Controls of Critical Steps and Reference Standards or Materials − overages
Intermediates − Physicochemical and Biological
− Process Validation and/or Evaluation Container Closure System: properties
− Manufacturing Process Development
Manufacturing Process Development − Specifications: Container Closure System:
− Analytical Procedures
Container Closure System − Validation of Analytical Procedures Stability:
− Justification of Specification
Microbiological Attributes − Excipients of Human or Animal Origin APPENDICES
− Compatibility − Novel Excipients − Facilities and Equipment:
−Adventitious Agents Safety Evaluation:
Manufacture: Control of Medicinal Product: − Novel Excipients:
− Manufacturers − Specifications − Solvents for Reconstitution and
− Batch Formula − Analytical Procedures diluents:
− Description of Manufacturing Process − Validation of Analytical Procedures
and Process Controls batch Analyses
− Controls of Critical Steps and − Characterisation of Impurities
Intermediates − Justification of Specifications
− Process Validation and/or Evaluation
Reference Standards or Materials:
Control of Excipients:
2) Non-clinical pharmacology and toxicology data
− 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.
− Should also provide a reference list of studies
conducted and appropriate literature references.
− The summaries of the studies conducted should allow
an assessment of the adequacy of the study and
whether the study has been conducted according to an
− Sponsors should provide the nonclinical information in
the IMPD under the following headings:
Common Technical Document Headings for:
Investigational Medicinal Product for “Non-clinical
pharmacology and toxicology data”
Pharmacodynamics: − Excretion − Carcinogenicity *
− Brief summary − Pharmacokinetic Drug − Reproductive and −
− Primary Pharmacodynamics interactions −Developmental Toxicity *
− Secondary Pharmacodynamics − Other Pharmacokinetic Studies − Local Tolerance
− Safety Pharmacology − Discussion and conclusions − Other Toxicity Studies
−Pharmacodynamic interactions including evaluation of − Discussion and Conclusions.
− Discussion and conclusion toxicokinetics
− Brief Summary − Brief Summary
− Methods of analysis − Single Dose Toxicity
− Repeat-Dose Toxicity*
− Absorption − Genotoxicity:
− Distribution − In vitro
− Metabolism − In vivo *
3) Previous clinical trial and human experience data
− Should provide summaries of all available data from
previous clinical trials and human experience with the
proposed IMP in this section.
− All studies should have been conducted in accordance
with the principles of GCP.
− This should be confirmed by the sponsor in a statement of
the GCP status of all studies and where this is not the
case, he should provide an explanation or justification if
− Applicants should take account of the general guidance
on clinical trials in the development of a medicinal
Common Technical Document Headings for:
Investigational Medicinal Product for
“Previous clinical trials and human experience
Clinical pharmacology − Dose and time-dependencies
− Brief summary − Special patient populations
− Mechanism of primary action − Interactions
− Secondary pharmacological effects
− Pharmacodynamic interactions Human exposure
− Brief summary
Clinical pharmacokinetics − Overview of Safety and Efficacy
− Brief summary − Healthy subject studies
− Absorption − Patient studies
− Distribution − Previous human experience
− Pharmacokinetics of active metabolites Benefits and risks assessment
− Plasma concentration-effect relationship
4) Overall risk and benefit assessment
− Should provide a brief summary that analyses the non
clinical and clinical data in relation to the potential risks
and benefits of the proposed trial.
− Should use the relevant pharmacology, toxicology and
kinetic results to indicate possible risks in humans.
− Should identify any studies that were terminated
prematurely and discuss the reasons.
− Should discuss safety margins in terms of relative
systemic exposure to the investigational medicinal
product, preferably based on:
– Cmax data
rather than in terms of applied dose.
TYPES OF IMPDs
The EU has provided for two types of IMPDs, a “full IMPD”
and a “simplified IMPD”, based on whether the product has
been described previously in a CTA or any marketing
authorization application or not.
When applying for a clinical trial authorisation:
A full IMPD is required when little or no information about
an IMP has been previously submitted to competent
when it is not possible to cross-refer to data submitted by
another sponsor or when there is no MA in the community.
A simplified IMPD may be submitted if information has
been assessed previously as part of a Marketing
Authorisation in any MS or a clinical trial to that competent
authority or when it is possible to cross-refer to data in
some other documents.
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 include the summaries of information regarding quality,
manufacture and control parameters of the IMP along with non-
clinical and clinical data including animal pharmacology and
toxicology studies, previous reports of clinical trial and human
experiences with the product, overall risk and benefit assessment.
It may be submitted if information related to the IMP has
been assessed previously as part of a marketing
authorisation (MA) or as part of a clinical trial application.
The applicant has the possibility to refer to other
documentation which may be submitted alone or with a
► Possibility to refer to the IB for the preclinical and clinical parts of
− The applicant may cross-refer to the IB for the preclinical and
clinical parts of the IMPD.
SUMMARY OF PRODUCT CHARACTERISTICS
► Possibility to refer to the SmPC in another clinical trials application
− The applicant may submit the current version of the
SmPC (documents equivalent to the SmPC) as the IMPD if an IMP
has a marketing authorisation in any Member State or in an ICH
− The IMPD may have been submitted previously by the
same applicant or by another applicant, in these cases
applicants are allowed to cross- refer to the previous
− If the submission was made by another applicant, a
letter from that applicant should be submitted authorising
the national competent authority to cross refer to that data.
IMPD in cases of placebo
If the IMP is a placebo, the information requirements can be reduced in line
IMPD for Marketed products
• The sponsor may submit the current version of the SmPC as the
IMPD, if an IMP has a marketing authorisation in any Member State
in the EU and is being used in the same form, for the same
indications and with a dosing regimen covered by the SmPC.
• If the applicant is the marketing authorisation holder and he has
submitted an application to vary the SmPC, which has not yet been
authorised, the nature of the variation and the reason for it should
be explained in the covering letter.
• There are situations where the IMP to be used in the CT has a MA in
the MS but the protocol allows that any brand of the 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
identified by the active substance name as follows:
a) A sponsor may wish to conduct a trial with an active substance
that is available in the Community in a number of medicines with
MAs and different trade names.
b) In some trials the sponsor may wish to allow
investigators in the same multicentre trial to administer
different regimens of IMPs.
c) In other trials the sponsor may wish to study the effect
of a number of medical treatments on a specific illness
without specifying the IMPs to be used except that they
have a MA in the MS concerned.
• In order to obtain the permission of conducting clinical trials in the
EU or the countries that follow European directives, the
manufacturer needs to obtain a clinical trial authorization(CTA). The
IMPD is submitted in order to obtain the CTA. It contains all the
technical data about the investigational product that ensures that
the clinical trial would be conducted in compliance with the GCP,
and the information would further be used during the conduct of
• IMPD consists of the summaries of information related to the
chemistry, manufacture and quality control of the investigational
medicinal product, data from non-clinical (animal) studies and from
its clinical use.