DEVELOPMENT AND EVALUATION OF NEW DRUGS.

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
 .
• Drug development comprises of two steps :-
• Preclinical development and

• Clinical development
 Pre-clinical development

• The aim of the pre-clinical development phase for a potential

new medicine is
• to explore the drug’s efficacy and safety before it is
administered to patients.
• In this preclinical phase, varying drug doses are tested
on animals and/or invitro systems.

• If active compounds are found, then studies on animals are

done which includes pharmacodynamics, pharmacokinetics
and toxicology studies .
 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
 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
 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
 Clinical development

• About one in thousand new chemical entities reach this

stage. The steps included in this stage are:-
– Pharmaceutical study- Stability, compatibility.
– Pharmacological study- Chronic toxicological study in animals,
metabolic and pharmacokinetic studies.
• Clinical Trial- is a means by which the efficacy of drug is
tested on human being.

• It is devided in to four phases.

• With each phase, safety and efficacy are tested

progressively.
 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
• one or two clinical pharmacologists
• Carried on 20-50 subjects in one center.
.
• 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)
 PHASE II STUDIES

• Randomized control trials in patients with the disease for

which the drug is intended or as a pretreatment to prevent
disease
• selected volunteer patients with specific disease
indication for drug

• Doses are higher than those in Phase I

• Studies may last several months to two years

– Carried on 100-500 patients in several centers.
– double blind studies (both investigator and patient)
 PHASE II STUDIES
• Safety still an important concern, but efficacy is the major
emphasis.

• 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 IRB’s
 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. In multiple centres
 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 NDA’s were approved between 1980 and 1986

 THE NEW DRUG APPLICATION (NDA)
 
• Less than 25% of all new drugs for marketing are novel or
new molecular entities (NME’s).

• 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 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
 Cotd…

• Reports about efficacy & toxicity are received from the

medical practitioners and reviewed by the committee of
review of medicines.

• Renewal or cancellation of the product licence depends on

the comment of the review committee.
 .
• Eg. Thalidomide
Phocomelia