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IP Dept, CP, UPM FS 2013-2014

Department of Industrial Pharmacy


College of Pharmacy
UP Manila

PHARMACEUTICAL PRODUCT
DEVELOPMENT PROCESS
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IP Dept, CP, UPM FS 2013-2014

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IP Dept, CP, UPM FS 2013-2014

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IP Dept, CP, UPM FS 2013-2014

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IP Dept, CP, UPM FS 2013-2014

INNOVATION.ORG VIDEO

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IP Dept, CP, UPM FS 2013-2014

PHARMACEUTICAL PRODUCT
DEVELOPMENT
Research activities directed to the creation of a
new compound used as an active
pharmaceutical ingredient (API) for a new
product

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IP Dept, CP, UPM FS 2013-2014

PHARMACEUTICAL PRODUCT
DEVELOPMENT
 New approaches and new methods
 Application of acceptable scientific
principles
o Organization
o Verification

o Production

o Marketing

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IP Dept, CP, UPM FS 2013-2014

PHARMACEUTICAL PRODUCT
DEVELOPMENT
 Combination of several disciplines and
techniques
 Formulate, improve and innovate products
o Sustain clinical claims
o Address conditions of interest
 Multidisciplinary approach
 Basic science during the preformulation stage
 Applied science during the formulation stage

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IP Dept, CP, UPM FS 2013-2014
SOURCES OF IDEAS FOR
PHARMACEUTICAL PRODUCT
DEVELOPMENT
 Laboratory  Literature survey
 Natural products  Market research
 Existing chemical
 Study patent
library
 Statistical study
 Chemical synthesis
 Biotechnology
 Budget and
/Gene therapy procurement
 Accident /
considerations
serendipity  Formulation study

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IP Dept, CP, UPM FS 2013-2014

NEW DRUG

1. new or noble discovery


2. new use or application of known drugs or
chemicals
3. isolation of active principles
4. synthesis of existing biologicals / botanicals
5. synergistic combination of known drugs
6. modification of existing drugs
 patent avoidance (me-too)
 improved therapeutic index

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IP Dept, CP, UPM FS 2013-2014

NEW DRUG

7. new excipients that improve the


properties/quality of active ingredient/s
8. new dosage form that allows new route of
administration
 improved profile
 marketing advantage

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IP Dept, CP, UPM FS 2013-2014

DRUG DISCOVERY

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IP Dept, CP, UPM FS 2013-2014

THE DRUG DEVELOPMENT PROCESS

10-15 years to develop one new medicine

understand human disease at the molecular level


(genomics, proteomics and computational power)
for every 5,000-10,000 compounds in the R&D
pipeline, only one receives approval

$800 million to $1 billion (includes cost of failures)


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Distribution of Cost in
New Drug Development
Lead
Compound
Selection
Clinical 7% Discovery/
Research
Screening
38%
28%

Preclinical
Research
27%

FS 2013-2014 IP Dept, CP, UPM 15


IP Dept, CP, UPM FS 2013-2014

PHARMACEUTICAL PRODUCT
DEVELOPMENT PROCESS (PIPELINE)

I N
N D
D A

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IP Dept, CP, UPM FS 2013-2014

PRE-DISCOVERY
(ALSO PRE-PROJECT)

Understanding Target Target


the Disease Identification Validation
(basis for treatment)
choosing a testing the target
altered genes molecule to target and confirming its
encoded proteins role in the disease
protein-protein
interaction
changes in
specific tissues
effects on the
entire patient

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IP Dept, CP, UPM FS 2013-2014

DRUG DISCOVERY
 Finding a promising molecule (a lead compound) that
could become a drug
 Nature
 De novo: computer modeling to predict what type of
molecule may work
 High-throughput Screening: robotics and
computational power
 Biotechnology: genetically engineer living systems to
produce disease-fighting biological molecules
 3-5 years

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IP Dept, CP, UPM FS 2013-2014

DE NOVO
LEAD COMPOUND SELECTION
 Random Screening
Uses existing library of chemical agents
 Combinatorial Chemistry and Screening
 Semi-automated methods for preparation of large series
of synthetic analogues, often as mixtures
 Targeted Synthesis
 Focuses on a particular step in a disease process for
drug intervention
 Drug Modeling
 Uses computers to modify a compounds chemical
structure to enhance its potential activity

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IP Dept, CP, UPM FS 2013-2014

DRUG DISCOVERY
 Early Safety Tests
 Performing initial tests on promising compounds
 Pharmacological profile

 Lead Optimization
 Altering the structure of lead candidates to
improve properties
 Drug assay development
 Chemical synthesis scale-up

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IP Dept, CP, UPM FS 2013-2014

PRECLINICAL TESTING
 Performing lab and animal testing
 to determine if the candidate drug (and its metabolite/s)
is safe enough for human testing
 in vitro and in vivo tests
 In vitro: test tubes and beakers
 in vivo: living cell cultures and animal models
 how the drug works
 Safety profile
 Scale up
 enough quantities of the drug for clinical trials

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IP Dept, CP, UPM FS 2013-2014

PRECLINICAL TESTING

 Includes:
 Subacute, acute, subchronic, chronic toxicity
 Cytotoxicity, genotoxicity, carcinogenicity,
reproductive toxicology, receptor binding
 ADME in animal models
o Human Biomaterials
 Environmentally acceptable by-product
 Genomic and proteomic data for MOA

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IP Dept, CP, UPM FS 2013-2014

PRECLINICAL MANUFACTURING
RESEARCH

To generate Chemistry, Manufacturing


and Control (CMC) data
 Purification technology  Scale up the production
 Analysis and of the prototype dosage
physicochemical form
characterization  Transfer to a
 Formulation technology manufacturing plant
 Labeling and packaging  Validation of the
 Device development for manufacturing process
biopharmaceuticals  Strict regulatory
requirements

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IP Dept, CP, UPM FS 2013-2014

INVESTIGATIONAL NEW DRUG (IND)


APPLICATION
 filing IND with the FDA before clinical
testing can begin
 ensuring safety for clinical trial volunteers
 Institutional Review Board

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IP Dept, CP, UPM FS 2013-2014

INVESTIGATIONAL NEW DRUG


(IND) APPLICATION

Notice of Claimed Investigational Exemption for


a New Drug
To determine whether the drug is sufficiently
safe for clinical trials
 Animal Pharmacology and Toxicology Studies
 Manufacturing Information
 Clinical Protocols and Investigator Information
Center for Drug Evaluation and Research
(CDER)

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IP Dept, CP, UPM FS 2013-2014

INVESTIGATIONAL NEW DRUG


(IND) APPLICATION

Requests permission to begin human trials


 Regulatory green light for testing in people
 Review Clock = 30 days
 Clinical Hold
o Unacceptable risk to patients
o Insufficient or no data to determine the risk
Odds: 1 in 3

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IP Dept, CP, UPM FS 2013-2014

TYPES OF IND APPLICATION


 Commercial
 Single Investigator or Researcher
 one physician, at one study site
 testing new dosing regimens of an approved drug
 Emergency/Compassionate Use
 patients with an incurable disease who do not meet the enrollment
criteria for an ongoing treatment protocol but may derive some
benefit from the drug
 special circumstances, eg antidote development where exposure to
toxic substance is required and is thus considered unethical

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IP Dept, CP, UPM FS 2013-2014

CLINICAL TRIALS
 Testing in humans to determine if the drug is
safe and effective
 Most critical and demanding stage

 Institutional Review Boards (IRB)


 To ensure rights and welfare of clinical trial participants
 International guidelines on ethics, GCP
 9 years average

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IP Dept, CP, UPM FS 2013-2014

CLINICAL TRIALS
Phase 1

Phase 2

Phase 3
Healthy Patients Patients
Volunteers 200-300 2000-3000
30-50 Efficacy Efficacy
Safety Safety Safety
(short- (long-
term) term)

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IP Dept, CP, UPM FS 2013-2014

CLINICAL TRIALS
TECHNICAL DEVELOPMENT
Phases I and II
Final manufacturing method of the candidate drug and the
drug product
 Specifications, analytical control methods, delivery
system
Phase III
 Final product is used
 Scale-Up to Commercial Batch

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IP Dept, CP, UPM FS 2013-2014

PHASE 0

 Microdosing
 allows researchers to test a small drug dose
in fewer human volunteers
 to
quickly weed out drug candidates that are
metabolically or biologically ineffective

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IP Dept, CP, UPM FS 2013-2014

PHASE I
Safety
Ideal dosage range (max tolerable dose)
 Single dose to multiple escalating doses
Pharmacokinetic and pharmacodynamic properties
 Pharmacogenetics
0.5 - 1 year

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IP Dept, CP, UPM FS 2013-2014

PHASE II
 Efficacy
 Range of efficacious doses
 Double-blind controlled studies
 1-2 years

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IP Dept, CP, UPM FS 2013-2014

PHASE II
Phase IIa and IIb Trials
Maybe combined with Phase I
Phase IIa
understanding the safety of a potential drug
getting an early read on efficacy and dosage in a small group of
patients
Phase IIb
For designing a rigorous and focused Phase III trial

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IP Dept, CP, UPM FS 2013-2014

PHASE III
Safety and efficacy
Side effects especially with long-term use
 Clinical pharmacology studies
 Interaction with other pharmaceuticals
 Kinetics in renal or liver impaired patients
 Food interaction
 Comparable studies with existing pharmaceuticals
for the given indication
 To establish superiority as regards efficacy
 2-3 years

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IP Dept, CP, UPM FS 2013-2014

PHASE III
Phase IIIa
 Broad and representative patient population

 Phase IIIb
 Specific subpopulation of the given patient
population
o Comparative studies against specific
treatment modalities
 Health economics arguments

 Special studies in children and the elderly

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IP Dept, CP, UPM FS 2013-2014

EXPEDITED/ COMPRESSED
PHASES II AND III

For life-threatening and severely debilitating


disease
Conditions with no current treatment
1 - 3 years

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IP Dept, CP, UPM FS 2013-2014

ORPHAN DRUG
 product that treats a rare disease affecting fewer
than 200,000 Americans
 FDAs Office of Orphan Products Development
 Intended for the diagnosis, prevention or
treatment of life-threatening or chronically
debilitating condition affecting no more than five
in 10,000 persons in European Union
 European Medicines Agency

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IP Dept, CP, UPM FS 2013-2014

ORPHAN DRUG
 Incentives:
 marketing exclusivity
 fee reductions

 tax exemption during clinical trials

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IP Dept, CP, UPM FS 2013-2014

NEW DRUG APPLICATION (NDA)

 Contains highly organized and complete


presentation of all pre-clinical and
clinical data
 Average pages of data = 120,000 (300
binders with 500 pages each)
 Computer-assisted new drug applications
(CANDA) (10 CD-ROMS)
 Average: 2.6 years

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IP Dept, CP, UPM FS 2013-2014

NDA REVIEW AND APPROVAL


Sponsor reviews FDA determines No Refuse-to-File
data and submits fileability of NDA
(RTF)
NDA 45-Day Meeting

FDA reviews NDA


Yes Advisory
CDER
Committee
180-Day Review
No Action reviews NDA
Clock

FDA issues
Approvable Not Approvable
Action Letter

Approved
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IP Dept, CP, UPM FS 2013-2014

NDA FILING CLASSIFICATIONS


 Type S  Type 2
 Standard review  Derivative of active moiety
 Other treatments are approved in the US
currently available  Type 3
 Type P  New formulation of an
 Priority review approved drug
 Therapeutic gain  Type 4
 New mechanism of action  New combination of drugs

 Type 1  Type 5
 New drugs not available in  New manufacturer
the US market  single designation (P or S) or
multiple designation (1P, 3S, 3
and 5)

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IP Dept, CP, UPM FS 2013-2014

NEW ACTION LETTERS


 complete Agency actions (for performance goal and review
clock purposes) in response to the application or
supplement review process
 complete Agency review of applications or supplements and stop the review
clock.
 Complete Response Letter
 Summarize all of the deficiencies remaining, and
 Where appropriate, describe actions necessary to place the
application/supplement in a condition for approval.
 Approval Letter
 Following completion of all aspects of the review process, including testing
of submitted product lots, pre-licensing inspection and evaluation of final
printed labeling or a suitable alternative, an approval letter will constitute the
final action.

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IP Dept, CP, UPM FS 2013-2014

POST-MARKETING SURVEILLANCE
Phase IV Clinical Studies
Impact on particular patient subgroups
Clearer clinical benefits or safety
 Rare adverse reactions
 Increases in known reactions
 risk factors or pre-existing conditions that may promote
reaction
Pursue life cycle management activities
 New medical indications
 New production methods
 New facilities
Pharmacovigilance

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IP Dept, CP, UPM FS 2013-2014

PHARMACOVIGILANCE

 identification and evaluation of safety signals

Adverse events

Potential risk factors

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IP Dept, CP, UPM FS 2013-2014

The clever man will tell you what he


knows; he may even try to explain it to
you. The wise man encourages you to
discover it for yourself, even though he
knows it inside out.
R Evans (1980), quoted in Action Research, Principles and Practice,McNiff, 1988, 52

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