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Non clinical drug development (Investigational Medicinal Product, IMPD) By Prajakta Sawant)
1. Presented By:
Ms. Prajakta Sawant
M.Pharm First Year (Roll No. 5)
(Dept. of Pharmaceutics)
Sub: Regulatory Affairs
Alard College Of Pharmacy, Pune.
Under the Guidance of:
Dr. Nalanda Borkar
Head of Department
(Dept. of Pharmaceutics)
Sub: Regulatory Affairs
Alard College Of Pharmacy, Pune.
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2. Phase 1: Discovery and Development.
Phase 2: Preclinical / Non-clinical Research.
Phase 3: Clinical Research.
Phase 4: FDA Review.
Phase 5: FDA Post-Market Safety Monitoring.
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3. The non-clinical development of a medicine
is complex and regulatory-driven.
The non-clinical development phase primarily
aims to
◦ identify which candidate compound has the
greatest probability of success
◦ assess its safety, and
◦ build a solid scientific foundation before transition
to the clinical development phase, i.e. Phase I
(first-in-human).
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4. During the non-clinical development phase:
◦ the intellectual property rights of the
candidate compound are registered
(patented), and
◦ availability of the medicinal product for
clinical trials is prepared
▸synthesis and production of an appropriate amount
of medicine for pre-clinical and clinical testing
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5. Once a lead molecule (candidate compound) is
identified, non-clinical development begins.
Non-clinical studies seek to answer the following
questions:
◦ Does it work? (Efficacy assessment)
◦ How can it be delivered and how does the body react?
(ADME profiling)
◦ Is it safe? (Toxicology/safety, pharmacology assessment)
◦ Is the manufacturing process viable and controllable?
(CMC activities)
Non-clinical development studies and activities
continue throughout the life-cycle of the
product.
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6. • To facilitate the conduct of clinical trials in the
member States of the European Union, especially
multi-centre clinical trials carried out in more than
one member State, it is necessary to have a
common understanding of the definition of an
Investigational Medicinal Product (IMP).
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7. The definition of an “investigational medicinal product” (IMP)
is linked to;
(a) the definition of a “medicinal product” i.e. Any substance or
combination of substances presented as having properties for
treating or preventing disease in human beings,
(b) the intended use of a medicinal product and
(c) the definition of a “clinical trial” i.e. Studies conducted to
evaluate the effectiveness and safety of medications or
medical devices by monitoring their effects on large groups
of people.
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8. The definition of an “Investigational Medicinal
Product” (IMP) is provided in Directive
2001/20/EC, Article 2 (d), as follows:
‘A pharmaceutical form of an active
substance or placebo being tested or used as
a reference in a clinical trial, including
products already with a marketing
authorization but used or assembled
(formulated or packaged) in a way different
from the authorized form, or when used for an
unauthorized indication, or when used to gain
further information about the authorized form.’
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9. Therefore, to classify a "medicinal product" as an "investigational
medicinal product" a sponsor must consider both its intended use
and the objectives of the study. For example, if it is to be used as
the test substance or reference substance (active comparator or
placebo) in a study, then it would meet the first criteria of an IMP.
Also, Medicinal products with a marketing authorization (MA) are
classified as IMPs. On this basis, provided that the requirement(s)
are met, reference products used as comparators should be
considered as IMPs.
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10. However, if the study is not intended to discover or verify:
(a) its clinical, pharmacological and/or other pharmacodynamic
effects or
(b) to identify any adverse reactions associated with its use or
(c) to study its absorption, distribution, metabolism and excretion;
with the objective of ascertaining its safety or efficacy,
then it would fail the second test. It would therefore not be
classified as an IMP.
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11. IMP Example : Organ function PET (positron
emission tomography) radiopharmaceuticals are
administered to a clinical trial population to
measure the function of a certain organ before
and after the subject has been given
an IMP whose effects in this organ are the primary
end-point of the clinical trial.
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12. Investigational Medical product Dossier (IMPD) is the basis for
approval of clinical trials by the competent authorities in the
EU (European Union).
The Clinical Trial Directive came in force, harmonizing the
laws, regulations and administrative provisions of the
Member states relating to the implementation of GCP (Good
Clinical Practice) in the conduct of clinical trials on medicinal
products for human use.
The directive introduced a harmonized procedure for the
authorization to perform a clinical study in any one of the EU
Member States.
In addition, it defines the documentation to be submitted to
the Ethics Committee as well as the Investigational Medicinal
Product Dossier (IMPD) to be submitted to the competent
authority for approval.
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13. The Investigational Medicinal Product Dossier (IMPD) is one of
several pieces of Investigational Medicinal Product (IMP) related
data required whenever the performance of a clinical trial is intended
in one or more European Union Member States.
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 Authorization (CTA).
This application includes a group of scientific documents called an
Investigational Medicinal Products Dossier (IMPD).
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14. ⇨ Dossier
“a collection of documents about a particular
person, event or subject”
E.g. Patient’s medical record
M.Pharm academic dossier
⇨ Medicinal product dossier
“File containing detailed records about a
particular drug product”
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15. 60 days for reviewing 60 days for reviewing
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Investigational Medicinal
Product Dossier
Ethical Committee National Agency
Approval Notification
Clinical Trial
16. The IMPD includes summaries of information related to the quality,
manufacture and control of the any Investigational Medicinal
Product (IMP) including reference product and placebo, data from
non-clinical studies and from its clinical use.
An overall risk-benefit assessment, critical analyses of the non-
clinical and clinical data in relation to the potential risks and benefits
of the proposed study have to be part of the IMPD.
In certain situations, e.g. where the Investigational Medicinal Product
has already been authorized as a medicinal product in one of the EU
Member States or where clinical studies with the IMP have already
been approved by a Member State, a simplified IMPD will be
sufficient.
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17. Guideline addresses the documentation on the chemical and
pharmaceutical quality of IMPs containing chemically defined active
substances, synthetic peptides, herbal substances, herbal preparations
and chemically defined radio-active/radio-labelled substances to be
submitted to the competent authority for approval prior to beginning
a clinical trial in humans.
It includes the requirements for IMPs to be tested in Phase I, Phase II
and Phase III studies as well as the requirements for modified and
unmodified comparator products and IMPs to be tested in generic
bioequivalence studies (and placebo products).
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18. 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 another CTA or a marketing authorization application.
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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19. The guidance allows for the IMPD’s content to be adapted to the
existing level of knowledge and the product’s phase of development.
When applying for a clinical trial authorization, a 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 and/or when there
is no MA in the Community.
However, there are situations where a simplified IMPD will be
sufficient. A simplified IMPD may be submitted if information has
been assessed previously as part of a Marketing Authorization in any
MS or a clinical trial to that competent authority.
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21. A. Basic Data on Clinical Study
• Cover letter, protocol, clinical trial summary
• Content of medicinal product
• Sponsor/applicant’s information
• Duration of the trial & intended use ( therapeutic, prophylactic, diagnostic )
• Number and type of patients
B. Clinical Objectives
• Description of therapy & background ( rationale, mortality of the disease treated )
• Mode of gene transfer ( in vivo / ex vivo )
• Type of treatment ( immunotherapy, gene expression modification, suicide
genes…..)
• Use of viral vectors, origin of target cells, patient’s dosing/treatment schedule,
bio-distribution
C. Vector Description
• Therapeutic gene, regulatory sequences, packaging signals
• Plasmid backbone, map of vector
• Packaging cell line ( experimental details )
• Vector tropism
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22. D. Manufacturing, Supply and Import
• GMP facility description
• Description of manufacturing process and process controls
• Evaluation of Safety (adventitious agents, RCV testing), Cell banking,
compliance with regulations
• Import License
E. Pre-clinical Data & Risk Assessment
• Pre-clinical safety evaluation (animal models)
• Absence of replication-competent & any other viruses, DNA & protein
contaminants, pyrogens, etc…
F. Patient & Informed Consent
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25. The IMP dossier required will depend on
many factors including:
Risk aspects
Nature of the product
State of development
Patient population
Nature and severity of the illness
Type and duration of the clinical trial itself
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