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OBJECTIVES

After completing this module, you should be able:

• To understand the process of development of
drug
• To recognise problems related to the drug
development and its assessment

Erna Kristin

THE PROCESS OF DRUG Depart. Pharmacology

Faculty of Medicine

DEVELOPMENT GMU

Preclinical
Preclinical development evelopment

Clinical drug development Phase I-III

Regulatory approval-product license Regulatory

approval

Phase IV
Postmarketing surveillance Postmarketing
surrveillance

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Phases of Drug Development

Clinical Trials
Preclinical
Phase I Phase II Phase III FDA Phase IV
Testing

15
Years 6.5 1.5 2 3.5 1.5
total
20 to 80 100 to 300 1000 to
Laboratory
Test Fil healthy patient 3000
and animal
Population e volunte volunteer patient
studies File Review
IN ers s volunteers Additional
NDA process
D Evaluate Verify Post
at /
at Determi effectiven effectivene marketing
Assess FDA Approva
FD ne ess ss, monitor testing
safety and A l required
Purpose safety adverse
biological by FDA
and Look for reactions
activity
dosage side from long-
long-
effects term use

5,000 1
Success
compounds 5 enter trials approve
Rate
evaluated d

Total average cost for one new drug approval $359 million to $1.7 billion
Average time from test tube to market: 12-15 years

The changed context of drug Sources of drugs

discovery and development
The 1800s: The 1990s: insulin (pig, cow)
Animal growth hormone (man) (Creutzfeldt-Jakob)
 natural sources;  synthetic source;
 limited possibilities;  unlimited possibilities;
prepared by individuals; prepared by companies; digitalis (digitalis purpurea - foxglove)
  Plant morphine (papaver somniferum)
 small scale;  massive scale;
 not purified,  highly purified,
 standardised or tested;  standardised and tested; arsenic mercury
Inorganic lithium
 limited administration;  world-wide administration;
 no controls;  tight legislative control;
 no idea of mechanisms.  mechanisms partly chemical (propranolol)
understood. Synthetic biological (penicillin)
biotechnology (human insulin)

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orphan drug status (drugs intended to treat rare diseases),

accelerated approval (drugs to treat serious or life-threatening illness and

provide meaningful therapeutic benefit over existing treatments)

Subpart E designations (procedures for speeding the availability of drugs

to treat severely debilitating or life-threatening diseases).

Where do you find new drugs?

Preclinical
testing
Effects on body
functions,
mechanism of
action, toxicity

Pre Clinical Pre Clinical

• During preclinical drug development, a sponsor
evaluates the drug's toxic and pharmacologic effects
through in vitro and in vivo laboratory animal
testing.
• Genotoxicity, mutagenecity, carcinogenecity,
teratogenecity screening is performed, as well as
investigations on drug absorption and metabolism,
the toxicity of the drug's metabolites, and the speed
with which the drug and its metabolites are excreted
from the body.
• At the preclinical stage, the FDA will generally ask, at
a minimum, that sponsors:
• (1) develop a pharmacological profile of the drug;
• (2) determine the acute toxicity of the drug in at least
two species of animals, and
• (3) conduct short-term toxicity studies ranging from 2
weeks to 3 months, depending on the proposed
duration of use of the substance in the proposed
clinical studies

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Preclinical development

PHARMACOLOGY

•Compounds must be shown to demonstrate specific

the fundamental tenet of testing drugs in pharmacological activity.
animals is that such information helps to •General pharmacological profiles of compounds are
predict the efficacy and toxicity of drugs also required (e.g. autonomic, cardiovascular, central
that are candidates for clinical use. nervous system

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ACUTE TOXICITY

1. Estimated lethal dose (LD50)

2. Usually evaluated in rodents

CHRONIC TOXICITY

• based on acute toxicity data,

• 3-4 dose levels are selected and
administered daily for certain periods
• to 2 species , one rodent (usually rat)
and one nonrodent (usually dog)

The doses selected are intended to include

• biochemical,
 a „no effect“ dose level • hematological and
 low dose • urinalysis profiles are performed
 mild dose • as well as physical examination,
 and of a top dose at which fatalities
• blood samples are taken for
will occur
 it is essential to include a placebo measurement of concentrations of the
dose group. drugs
• some animals are killed, and a full
histopathological examination is
performed on all organs.

Duration of chronic studies

What other testing will be provided
during preclinical development?
Doses to be given to human Duration of animal study

Up to 3 doses 14 days

repeat dosing up to animal toxicity testing

10 days for 28 days mutagenicity carcinogenicity reproductive testing
longer administration 6 or 12 months

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Clinical drug development
Phase I
• initial exposure of humans to investigational
drug (first in humans)
• safety evaluation
• assessment of pharmacokinetics and
pharmacodynamics in healthy subjects.
• These individuals volunteer to be given the
drug under strictly controlled, hospitalized,
expert medical supervision
Clinical drug development
Phase II
• initial safety evidence
• initial efficacy evidence
• identification of the dose range for phase III
trial
• well controlled with narrowly defined patients
population
• open trial
• 100-150 patients in total
Clinical drug development
Phase III
• efficacy and safety objective
• expanded and controlled
• collection of data on a large patient
population with indication
• provide information on overall benefit/risk
• can be placebo or active controls
• large multicenter
• 1000-5000 patients in total
• usually double blind
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Clinical drug development
Phase I
• to determine the metabolic and pharmacological
actions of the drug in humans, the side effects
associated with increasing doses, and, if possible,
to gain early evidence on effectiveness.
• to evaluate drug metabolism, structure-activity
relationships, and the mechanism of action in
humans.
• The total number of subjects 20-80.
Clinical drug development
Phase II
• Phase 2 includes the early controlled clinical studies
conducted to obtain some preliminary data on the
effectiveness of the drug for a particular indication
or indications in patients with the disease or
condition.
• This phase of testing also helps determine the
common short-term side effects and risks associated
with the drug. Phase 2 studies usually involve
several hundred people
Clinical drug development
Phase III
• Phase 3 studies are intended to gather the
additional information about effectiveness and
safety that is needed to evaluate the overall benefit-
risk relationship of the drug.
• Phase 3 studies also provide an adequate basis for
extrapolating the results to the general population
and transmitting that information in the physician
labeling.
• Phase 3 studies usually include several hundred to
several thousand people
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Regulatory approval-product license Regulatory approval-product license

• Formal application to the Licensing Authority
is made.
• The size of submission documents may
extend to several hundredweights of paper.
• Marketing approval may be general or
granted subject to certain limitations which
may include restriction to hospital practice
only, restriction in indications for use or a
requirement to monitor in a specified number
of patients.
• All prescribing doctores are provided
with a factual data sheet giving
information on each new medicine.
• It must provide all the information
necessary to make a proper decision as
to whether the drug is indicated (i.e. it is
not an advertizement) and must also
detail all known hazards of the drug.

Post marketing surveilance

Phase IV

• studies are prospective trials performed after

marketing approval (the granting of a Product
License).

They may be studies to investigate:

• new formulations
• dosage requirements
• drug interactions
• detection of previously unrecognized unwanted
events