New Drug Development

UNIT 2

Text – “Pharmaceutical Dosage Forms

and Drug Delivery Systems” section 1,
chapter 2 pg 26-28 for introduction and
schematic flow diagram
New Drug Development
 New Drug (definition): see Section 1
chapter 2 pg 35 – “FDA’s definition of
a new drug” and considerations for
“old” drugs
 Any molecule not recognized as being
safe and effective in the conditions
recommended for its use by experts
who are qualified to judge this based
on their scientific training and
experience
New Drug Development

 Proposed new dosage form does not

need to contain a NCE to be
considered “new”
 A change in formulation or method of
manufacture of an existing drug will
cause drug to be treated as “new” –
why?
 Two “old” drugs formulated together
are considered “new” – why?
New Drug Development

 A new indication, dosage regimen,

route of administration or new dosage
type of an established drug will cause
it to be reconsidered as a “new” drug
New Drug Development

 Must be approved by TPD, FDA

 Applies to domestic or imported drugs
 Company must show that product is
safe and effective – scientific evidence
 Must also show that production,
manufacture, packaging and labelling
is properly controlled and validated
New Drug Development

 Drug approval process can be very

lengthy – 6-12 years
 Pros and cons?
 Low success rate – about one out of
every 5000 or so drug candidates
succeed
 Hit and miss, trial and error – educated
guesswork
 No guarantee of success
New Drug Development

 Drug research dominated by major

drug companies- invest lots of $$
 Very few independent academic
researchers
 Drug companies are willing to invest,
governments are not
New Drug Development

 What do drug companies invest in? They

invest in “Lead compounds”
 A “Lead Compound” is a prototype of a
chemical compound that appears to have
the desired characteristics of an effective
therapeutic molecule (biologic activity)
 Lead Compounds are investigated further to
help determine if they have promise with
regadrrto this
New Drug Development -
Steps
1. New chemical entity (NCE) proposed
2. Preclinical studies
3. Investigational New Drug application (IND)
4. Clinical trials- phases 1,2 and 3
5. Pre clinical studies continued as well
6. New Drug Application (NDA)
7. Approval and Post marketing activities
(See pg 27 of text)
Preclinical studies

 1-3 years
 Properties of new drug
 Chemical and physical properties
 Biological properties
 Enzyme assays, cell culture, animal
studies
 Must use appropriate models
throughout
 Toxicology studies (animals)
Preclinical studies

 Lots of drug candidates never make it

past this stage
 Lots of development money goes
down the tube
 If promising at this stage, start to work
on developing dosage forms,
preformulation, formulation studies
 If still promising, file an Investigational
New Drug Application (IND)
Preclinical

 If IND accepted, then do further studies,

both preclinical and clinical
 Long term animal toxicity tests
 Work on production issues
 Pharmacology, drug metabolism, toxicology
 Cell and tissue culture used, as well as
computer modelling, but still need animal
studies
Clinical testing

 Phase I clinical trial

 Healthy volunteers
 20-100 subjects
 Initial dose very low
 If tolerated well, then increase until some
evidence of drug activity indicated
 Determine human pharmacology, side
effects, early indications of effectiveness
Phase I clinical

 Basic data collected:

 Rate of absorption
 Conc of drug in blood vs time
 Drug metabolism and elimination
 Toxic effects
 Changes in physiology
 How well patient tolerates drug
Clinical phase 2

 Controlled clinical studies

 Evaluate effectiveness of drug in patients
with the condition
 Assess side effects and risks
 Additional pharmacokinetic info
 Dose-response curves
 Minimum effective dose
 Specific dose information for phase 3
Clinical phase 3

 May include several hundred to

thousands of patients
 Determine usefulness of drug in a
large patient base
 Many clinicians involved
 Investigate different dosage ranges
 Formulations used are those intended
for the final product
 Determine benefit/risk relationship
Clinical phase 3

 Controlled studies
 Effects compared to another agent –
eg placebo or an existing effective
drug

 Single blind – patient does not know

which drug used
 Double blind – both patient and
clinician unaware
 Open label – both are aware
Phase 4 and postmarketing
surveillance

 Performed after drug approved for

marketing
 May add to understanding of drug

New therapeutic uses

Additional side effects
Unexpected adverse drug reactions
New Drug Development

 Work on production and testing

protocols for the new drug – assume it
will be successful
 Initial marketing plans
 Gear up to produce product
New Drug Development cont’d

 NDA – New drug application

 SNDA – supplemental new drug

application (if want to reformulate
existing drug)
 ANDA – abbreviated new drug
application
 (for generic manufacturers)
 Treatment IND – for life threatening
illnesses
New Drug Development

UNIT 2

Text – “Pharmaceutical Dosage Forms

and Drug Delivery Systems” section 1,
chapter 2 pg 26-28 for introduction, pg
35, pg 41 – 43 “Early Formulation
Studies”, “Preformulation Studies” and
“Initial Product Formulation and Clinical
Trial Materials”, pg 64 “ International
Conference on Harmonization of
Technical Requirements for Registration
of Pharmaceuticals for Human Use”
New Drug Development – the
process in more detail

1. New Chemical Entity (NCE)

where do they come from?
Plants, animals, soil (microorganisms),
molecular biology (DNA research)
Often discovered by accident or by years
of cultivating and “tweeking” a
compound with promise
New Drug Development – the
process in more detail

1. New Chemical Entity cont’d…

- Are synthesized (man made), isolated
from source (plant or animal) or
molecularly modified
- Only after biologic activity is
demonstrated ( in vitro)
New Drug Development – the
process in more detail

2. Preclinical Studies ( performed on the

lead compound i.e.NCE)
-Chemical and physical characterization
-Biological, pharmacokinetic and toxicity
investigation ( in vitro and animals)
-Preformulation: can it be put in to a
dosage form that will actually work?
New Drug Development – the
process in more detail

2. Preclinical Studies cont’d…

- “ADME”: Absorption
Distribution
Metabolism
Elimination
This information helps to characterize a
molecules bioavailability – ie does it
have therapeutic potential?
New Drug Development – the
process in more detail

3. Investigational New Drug Application

(IND)
- All data collected to date and plan for
future safety, efficacy and
development is submitted to the
regulatory agency for review
- Agency will approve or dissaprove
based on this
New Drug Development – the
process in more detail

4. Clinical trials: Phase I,2,and 3

- Clinical studies are concerned with

safety and efficacy of drugs
- this is measured in large part by
reviewing the “ADME” characteristics
of the drug in humans
New Drug Development – the
process in more detail

4. Clinical trials: Phase I,2,and 3

Phase 1 - in humans to asses safety
- healthy volunteers
- very low dose with
progressing dosage amounts
- pharmacology (toxicity) of the
molecule is studied
New Drug Development – the
process in more detail

4. Clinical trials cont’d…

Phase 2 - unhealthy volunteers
- asses efficacy, side effects
and risks
- first time drug is administered
to sick patients ( more info gained,
more costs incured)
- if reg agency agrees, phase 3
New Drug Development – the
process in more detail

4. Clinical trials cont’d…

Phase 3 - larger patient base( 100’s to
1000’s)
- more PK data obtained
- studies are “controlled” and
drug candidate is challenged by
comparison to another drug or placebo
Why use placebo?
New Drug Development – the
process in more detail

5. Preclinical studies continuing parallel

to clinical trials
- Long term animal toxicity
- Product formulation, production and
packaging considerations ( i.e can we
actually make an effective, stable and
approvable product?) Hopefully yes,
but sometimes no !
New Drug Development – the
process in more detail
6. New Drug Application (NDA)
-application made to the agency if all data
indicates success (what would be success?
And would companies spend the money if
success wasn’t likely?)
- all data to date, final lab data on the
proposed “final” product generated and
regulatory inspections to commence
- sponsor is seeking approval to sell !
New Drug Development – the
process in more detail

7. Approval and Post Marketing Activities

- Phase 4 clinical studies: continuation of
patient monitoring and post marketing
adverse reactions – why?
-Annual Reporting: Sponsor must continue
to generate lab data (product stability) and
report all information related to the approved
new drug to the agency – patient
complaints, adverse events, doctors and
pharmacists feedback, etc