DRUG DEVELOPMENT

Reference

Joseph Hanig, Ph.D.

 Drug Development - Methods used
to identify compounds with
potential therapeutic usefulness
Screening most new drugs discovered this way
screen is a specified set of procedures to which a
series of compounds is subjected to both in vivo
and in vitro
quantitative part of screening is the bioassay
bioassay used to establish relationship between
dose and response and compare unknowns to
standards
 SYNTHESIS, PURIFICATION &
DATA MINING
Synthesis of drug de novo
Modification of structure of existing drugs
structure activity studies (SAR)
Purification of drugs from natural sources such
as native, folklore or herbal medicines
Exploration of side effects of existing drugs -
awareness of potential usefulness of side
effects
Animal Studies - Preclinical
Studies

Acute toxicity tests

one administration of chemical to each animal
generation of dose response curves
Appropriate pharmacological testing to determine
ED50
Develop analytical methods for determining
absorption, excretion, distribution and
metabolism of chemical
Animal Studies - Preclinical
Studies

Subchronic toxicity tests

usually 60 90 days duration

multiple administrations or continuous

exposure via food or water to one dose
level of a chemical per animal
Animal Studies - Preclinical
Studies

Chronic toxicity tests

2 to 5 years duration depending on

species

multiple administrations or continuous

exposure via food or water to one dose
level of a chemical per animal
 Clinical Studies
Notice of Claimed Investigational Exception
for a New Drug (IND)
Phase I of clinical studies
pharmacological investigation
one or two clinical pharmacologists
healthy volunteers informed consent one
tenth of dose for PK studies
Clinical Studies (continued)

Phase II of clinical studies

initial controlled clinical evaluation

more than two clinical pharmacologists
selected volunteer patients with specific
disease indication for drug
double blind studies
Clinical Studies (continued)

Phase III of clinical studies

extended clinical evaluation

usually 50 100 clinicians
usually 500 1000 patients
8
 Phases of Clinical Drug Development
I IIa IIb III FDA IV
Healthy First time Patients Patients Patients
Subjects Normals in Patients

Number 20 - 100 25 - 75 50 - 200 >300 >1,000

Dosage, Dose range,

Kinetics, MOA Efficacy, Efficacy, Efficacy,
Measures Safety, Efficacy, Safety Safety Safety,
Equivalence Safety New uses
Confirm Surveillance,
Value Kinetics, Proof of Confirm Review extend patent
mechanism Approve or
Dynamics Concept usefulness expand market
of action disapprove
Varies with
Cost $8 $12 $7 $43 The drug and
(Millions)
?
its use

Time 1 - 1.5 1 1 - 1.5 3-6 2-3 1-2

(Years)
Clinical Trials Phases
Time
Phase Purpose Subjects Sample Duratio
n
Safety, ADME, Healthy
bioactivity, volunteers or
I drug-drug subj. w/
20-80 6-12 mos
interaction indications
Short-term side Subjects with Several 1-2 yrs
II effects & efficacy indications hundred
Safety & efficacy
Subjects with Hundreds-
III Basis for labeling,
indications thousands
2-3 yrs
new formulations
New indications, Subjects with Hundreds-
IV QoL, surveillance indications thousands
1-5 yrs

Chile Presentation-Dr Dilip Pawar-

Oct 2009 13
 Drug Development Frame

Early Full Life Cycle

Research
Development Development Management
Candidate Pre- Clinical Trials
Discovery
Profiling clinical Phase0, 1 Phase IIa Phase IIb Phase III Phase IV
Phase
Phase Phase

CSP sPoC DDP FDP 3CP SDP

Development Point
Proof of Concept

Decision Point
Selection Point

Decision Point
Development
Selected for

Checkpoint

Submission
Full
Candidate

Phase III

IND Investigational New Drug Chile

NDA New Drug Presentation-Dr
Application
14 Dilip Pawar-Oct 2009
 DEFINITION OF A NEW DRUG
Any chemical or substance not previously used in
humans for the treatment of a disease
Combinations of approved drugs or of old drugs
even though the individual components are not
new drugs
An approved drug employed for uses other than
those approved
Anew dosage form of an approved drug; and
Even a drug used in vitro as a diagnostic agent
when its uses will influence the diagnosis or
treatment of disease in a human patient
Drug Development Statistics
Drug discoverers file patent
Patent exclusivity (no generics) = 17 years
Drug development time = 7 - 10 years
Application review = 2 - 3 years
Market exclusivity = 4 - 8 years
Drug development cost = $250 M - $400M
Target income/drug/year = $250 M - $1B
16
Drug Development Standards
Good laboratory practices (GLP)
- Non-clinical safety studies
Good manufacturing practices (GMP)
- Production operations
- Drug Formulation Quality control
Good clinical practices (GCP)
- Clinical studies Phases I to IV
INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
The IND submitted to the FDA contains the
results of all preclinical investigations carried
out in animals, including complete toxicity
data, the full pharmacologic spectrum of the
drug and any studies of absorption,
distribution, biotransformation and excretion.
In addition, the IND must provide the
following information:
INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
Complete composition of the drug, its source and
manufacturing data with details of all quality control
measures employed to ensure exact reproducibility of
manufacture and identification of all ingredients
Specifications of the dosage forms to be given to humans
A description of the investigations to be undertaken,
including the doses to be administered, the route and
duration of drug administration and the specific clinical
observations and laboratory observations to be performed
The names and the qualifications of and the facilities
available to, each investigator who will participate in the
initial studies (Phase I)
INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
Copies of all informational material supplied to
each investigator (the data sheets supplied to the
investigator incorporate the data supplied in the
IND itself)
An agreement from the sponsor to notify FDA
and all investigators of any adverse effects that
arise during either the continuing animal studies
or human tests
Agreement to submit annual progress reports
Certification that "informed consent" will be
obtained from the subjects or patients to whom
the drug will be given
 PHASE I STUDIES

Requires an FDA approved IND to commence

Conducted in normal healthy human volunteers
Performed under carefully controlled conditions
Toxicological and pharmacological data
obtained by a trained clinical pharmacologist
Drug first administered at one tenth the
ultimate projected effective dose
 PHASE I STUDIES
Primary objective is to obtain a safe and
tolerated dose in humans
Parameters of absorption, metabolism and
excretion are measured
The pharmacokinetic study relies on
measurements of levels of the test drug in blood
and urine at various times after administration
(route usually oral)
If drug is ineffective at the given dose, the
above measurements resolve issues of efficacy
vs. poor absorption or rapid elimination
 PHASE II STUDIES

Randomized control trials in patients with the

disease for which the drug is intended or as a
pretreatment to prevent disease
Numbers of patients are limited, but may be
up to several hundred
Doses are higher than those in Phase I
Studies may last several months to two years
 PHASE II STUDIES

Safety still an important concern, but efficacy is

the major emphasis
Flexibility in the design of studies is very
desirable at this stage
Extremely slow metabolism of drug with
accumulation of subsequent doses and toxicity
might require additional studies at this point
Changes in the original protocol require the
submission of amendments to IND and
additional review by IRBs
 PHASE III STUDIES
Large-scale controlled studies
Major objective is to develop data to permit the drug
to be marketed and used safely and effectively
Multi-patient multi-center study
May involve as many as 150 clinicians, many of
whom are experienced clinical pharmacologists
Usually involves 1500 to as many as 4000 patients
 PHASE III STUDIES
Study generally lasts anywhere from 2 10 years
with an average length of 5 years
Study examines safety and effectiveness, but
emphasizes proper dose determination
The following studies may be conducted at this
stage:
drug biotransformation
capacity of drug to bind to plasma proteins
to induce or inhibit enzymes
to interact in various ways with other drugs
THE NEW DRUG APPLICATION
(NDA)
When the sponsor is convinced that the data
obtained in Phase III studies justify approval for
safety and efficacy for the use(s) intended, the
NDA is submitted
Usually, at least 5 years has elapsed since the
drug was originally screened
The NDA contains all of the chemical,
pharmacologic, toxicologic., clinical and
maufacturing data that have been collected in
the whole process
The NDA also contains bioequivalence and
bioavailability data
THE NEW DRUG APPLICATION
(NDA)
Samples of the drug, its labels and the package
insert that will accompany the drug in all shipments
to physicians and pharmacies
Submission of the NDA starts a "review clock" in
which the FDA has 180 days to respond
The NDA submission generally occurs essentially
when the sponsor and FDA agree that studies are
complete. Thus the NDA is approved fairly
promptly
926 NDAs were approved between 1980 and 1986
THE NEW DRUG APPLICATION
(NDA)
If the NDA is deemed for some reason to be
incomplete, the sponsor is required to resubmit
additional
If there is a disagreement between FDA and the
sponsor then a hearing may be held and the
outcome is appealable in Court
Less than 25% of all new drugs for marketing are
novel or new molecular entities (NMEs). The rest
are new salts, new formulations, new indications or
duplicates of drugs previously approved for
marketing
 PHASE IV POSTMARKETING
SURVEILLANCE
Applies to all aspects of investigation following NDA
approval and general availability of drug in
widespread clinical use
Claims for safety and efficacy appearing or
advertising are reviewed and approved by FDA
Reports concerning clinical studies must be sent to
FDA:
every three months during the first year
every six months in the second year
annually thereafter
 PHASE IV POSTMARKETING
SURVEILLANCE
Reports must include the following information
about:
quantity of drug distributed
copies of mailing pieces and labeling
examples of advertising for prescription drugs
Immediate reports on unexpected side-effects,
injury, toxic or allergic reactions and failure of the
drug to exert its expected pharmacologic reaction
 CLASSIFICATION SYSTEM
Type - Review Priorities
New Molecular Entity (NME)
P - Priority review clear therapeutic gain
New salt
S Std Review similar to previously marketed drug
New Formulation
New Combination
AA AIDS/HIV Related
 CLASSIFICATION SYSTEM
Type - Review Priorities
Already Marketed Drug Product Duplication
(New MFR)
V Designated Orphan Drug or E -Subpart E
Drug
New Claim for already Marketed Drug
F Pending Outcome of Validity Assessment
Already Marketed Drug Product No Approved
NDA
G Data Validated