NEW DRUG REGISTRATION APPLICATION

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NEW DRUG REGISTRATION APPLICATION
PRE-CLINICAL SAFETY EVALUATION STUDIES
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PRE-CLINICAL SAFETY EVALUATION STUDIES

• DRUG DEVELOPMENT PROGRAMME (R D LAB.).
• INVOLVES
• CHEMISTS, BIOLOGISTS, PHARMACOLOGISTS.
• MICROBIOLOGISTS, TOXICOLOGISTS, PHARMACEUTICAL /
  ANALYTICAL CHEMISTS.
• MEDICAL (CLINICAL) ASSOCIATE, MARKETING

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• SELECTION OF MOLECULES, BASED ON
• CHEMICAL STRUCTURE LEAD AND SCOPE OF
  DEVELOPMENT.
• SYNTHESIS SCREENING
• BIOLOGICAL ACTIVITY
• ACUTE TOXICITY

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• BIOLOGICAL STUDIES IN-VIVO / IN-VITRO.
• SCREENING ANIMAL MODELS DEPEND UPON
• THERAPEUTIC GROUPS SUCH AS,
• ANTI-HYPERTENSIVES, ANTI- ANGINAL, ANXIOLYTICS,
  ANTIDIABETICS, ANTIMOTILITY,
• ETC.
• GENERAL PHARMACOLOGICAL SCREENING
• SPECIAL PHARMACOLOGICAL SCREENING

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• ACUTE TOXICOLOGY STUDIES(1)
• THE TOXICITY TEST PROCESS INITIATED WITH ACUTE
  TOXICLOGY STUDIES.
• COMMONLY MENTIONED AS LD50 .
• THE ESTIMATION OF DOSE THAT IS LETHAL TO 50 OF
  THE ANIMALS IN A TEST SITUATION.
• IT IS USUALLLY PERFORMED IN TWO SPECIES RATS
  MICE.
• ROUTE OF ADMINISTRATION AS INTENDED FOR CLINICAL
  USE.
• MORTALITY OBSERVED AFTER 72 Hrs. (PARENTERAL)
• MORTALITY OBSERVED AFTER 7 Days.(ORAL)

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• ACUTE TOXICOLOGY STUDIES(2)
• OBSERVATIONS
• SIGNS, SYMPTOMS, CAUSE OF DEATH TO BE RECORDED
  WITH MACROSCOPIC MICROSCOPIC FINDINGS.
• OBSERVATION OF LD50 AFTER ORAL PARENTERAL
  ROUTE. TO BE CORRELATED WITH ABLE (Absorption,
  Blood Level Elimination) STUDY.

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• THE DRUG WITH LOW THERAPEUTIC RATIO, BUT WITH
  LIFE SAVING POTENTIAL (e.g. ANTI CANCER DRUGS,
  REFRECTORY COLLAGEN DISEASES MAY BE EVALUATED IN
  SHORT TERM TOXICITY STUDIES (1-2 WEEKS OR ONCE A
  WEEK DOSING FOR 6-8 WEEKS).
• The U.S, FDA RECOMMENDATION

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• SUB-ACUTE, CHRONIC TOXICITY STUDIES (1)
• ARE OF 2- 4 WEEKS DURATION.
• PERFORMED ON ATLEAST TWO SPECIES, RODENT
  NON-RODENT. ROUTE OF ADMINISTRATION, ONE OF THE
  ROUTE TO BE AS PER USE IN CLINICAL PRACTICE,
• AT 3 DOSE LEVELS. NUMBER OF ANIMALS AT EACH
  DOSE LEVEL ARE RODENTS (6-10) MALE FEMALE
• NON-RODENTS (DOGS) (2-3) MALE FEMALE
• THIS IS PLACEBO CONTROLLED STUDY.

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• SUB-ACUTE, CHRONIC TOXICITY STUDIES (2)
• PARAMETERS STUDIED
• BODY WT, FOOD CONSUMPTION, BEHAVIOR
• HAEMATOLOGY (Pre-Test Final)
• HEMOGRAM
• COAGULATION TEST (Non- Rodent Only)
• CLIN. CHEMISTRY (Pre-Test Final)
• Liver Function
• Kidney Function
• Bl. Sugar
• OPHTHALMIC
• GROSS MICROSCOPIC EXAMINATION REPORTS OF MAJOR
  ORGANS

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PRE-CLINICAL SAFETY EVALUATION STUDIES
ROUTE OF ADMINISTRATION DURATION OF HUMAN ADMIN. PHASE LONGTERM TOXICITY REQUIREMENT
SINGLE DOSE / SEVERAL DOSES IN A DAY I III, MP 2 SP. 2WK
ORAL OR PARENTERAL/ TRANSDERMAL UP TO 2WK I, II III, MP 2 SP. UPTO 4WK 2SP, UPTO 3 MO
UP TO 3WK I, II III MP 2 SP. UPTO 4WK 2 SP, 3 MO 2SP. 6 MO
OVER 3 MO I. II III,MP 2 SP, 3 MO 2SP. 6 MO
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PRE-CLINICAL SAFETY EVALUATION STUDIES
ROUTE OF ADMINISTRATION DURATION OF HUMAN ADMIN. PHASE LONGTERM TOXICITY REQUIREMENT
INHALATION (GEN. ANAESTHETICS) I III, MP 4 SP. 5DAY, 3Hrs / DAY
AEROSOL REPEATED / CHRONIC USE I, II III, MP 1 SP. SINGLE 24 Hr EXP. 2 WK OBSERVATION.
DERMAL SINGLE / MULTIPLE I, II III MP 2 SP. UPTO 4WK 2 SP, 3 MO 2SP. 6 MO
OVER 3 MO I. II III,MP 2 SP, 3 MO 2SP. 6 MO
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PRE-CLINICAL SAFETY EVALUATION STUDIES
ROUTE OF ADMINISTRATION DURATION OF HUMAN ADMIN. PHASE LONGTERM TOXICITY REQUIREMENT
OCULAR, OTIC OR NASAL SINGLE / MULTIPLE APPLICATION I II, III IRRIGATION TESTS GRADED DOSES. 1 SP. 3 WK , DAILY
VAGINAL OR RECTAL SINGLE / MULTIPLE APPLICATION I, II III, MP 1 SP.
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PRE-CLINICAL SAFETY EVALUATION STUDIES
NUMBER OF ANIMALS FOR CHRONIC TOXICITY STUDY 2-6
WEEKS
GROUP RODENTS (RATS) M F NON-RODENTS (DOGS) M F
CONTROL 6-10 6-10 15-30 15-30
LOW DOSE
INTERMEDIATE DOSE
HIGH DOSE
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PRE-CLINICAL SAFETY EVALUATION STUDIES
NUMBER OF ANIMALS FOR CHRONIC TOXICITY STUDY 7-26
WEEKS
GROUP RODENTS (RATS) M F NON-RODENTS (DOGS) M F
CONTROL 15-30 15-30 4-6 4-6
LOW DOSE
INTERMEDIATE DOSE
HIGH DOSE
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PRE-CLINICAL SAFETY EVALUATION STUDIES

• REPRODUCTION STUDIES
• FERTILITY STUDIES (SEGMENT I)
• TO STUDY THE EFFECT OF DRUG ON REPRODUCTIVE
  SYSTEM.
• MALE RATS EFFECT ON SPERMATOGENASIS GENERAL
  GONADAL FUNCTION.
• FEMALE RATS TO STUDY EFFECT ON PREGNANCY,
  SURVIVAL RATE OF LITTER
• NO. OF ANIMALS USED 20 IN EACH GROUP

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• (b)SEGMENT II III STUDIES
• STUDY PERFORMED IN RATS, MICE, RABBITS.
• TO SEE WHETHER THE DRUG HAS ANY TERATOGENIC
  EFFECT, CAUSES DEFORM FOETUS.
• (c)SEGMENT III STUDIES
• TO DETERMINE ANY ADVERSE EFFECT OF DRUG ON
  CHRONIC USE DURING PREGNANCY ON LATE FOETAL
  DEVELOPMENT, LACTATION, DELIVERY OF VIABLE
  FOETUS.

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• MUTAGENICITY CARCINOGENICITY
• THESE TESTS ARE REQUIRED IF, THE DRUG OR ITS
  METABOLITES ARE RELATED / SIMILAR TO KNOWN
  CARCINOGEN OR POSSESSES MUTAGENIC EFFECT.
• THE STUDY IS CONDUCTED IN 2 SPECIES OF ANIMALS.
  CURRENTLY SPECIAL STRAINS OF MICE AND RATS HAVE
  BEEN DEVELOPED FOR THESE STUDIES.
• DOSE 3 DOSE LEVELS . HIGHEST DOSE IS
  SUB-LETHAL, LOWEST DOSE COMPARABLE TO INTENDED
  HUMAN THERAPEUTIC DOSE. INTERMEDIATE DOSE IS
  LOGERITHMICLLY BETWEEN THE TWO DOSES.

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PRE-CLINICAL SAFETY EVALUATION STUDIES
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PRE-CLINICAL SAFETY EVALUATION STUDIES

• MUTAGENICITY TESTING
• AMES TEST
• CHROMOSOME ABERRATION TEST
• MAMMALIAN CELL GENE MUTATION TEST (MLA)

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• MUTAGENICITY TESTING
• BACTERIAL REVERSE MUTATION TEST
• (AMES TEST) PERFORMED ON SELECTED STRAINS OF
  SALMONELLA TYPHIMURIUM
• (TA 98, TA100, TA 1535, TA 1537, TA 1538, TA102)
• STD. MUTANT COMPOUND STRAIN SPECIFIC
• 2-NITROFURANE TA 98, TA 1538
• T BUTYL HYDROPEROXIDE (TBHP) TA102
• 9-AMINO ACRIDINE (9AA) TA 1535

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• APPLICATION TO SEEK PERMISSION TO CONDUCT
  CLINICAL TRIALS IN INDIA
• INTRODUCTION
• CHEMICAL AND PHARMACEUTICAL INFORMATION
• CHEMICAL NAME, GENERIC NAME
• DOSAGE FORM AND COMPOSITION
• SPECIFICATIONS OF API INACTIVES
• ANALYTICAL TESTS PROCEDURE, API
• BRIEF METHOD OF MANUFACTURE
• STABILITY DATA
• ANIMAL PHARMACOLOGY
• ANIMAL TOXICOLOGY
• PHASE I CLINICAL TRIAL PROTOCOL, CRF, CENTER

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• FIRST TIME IN MAN (PHASE I)
• STUDY DESIGN TO DETERMINE THE FIRST DOSE IN
  HUMAN. THE DOSE DETERMINATION IS BASED ON THE
  RESULTS OF ANIMAL PHARMACOLOGY AND TOXICITY
  STUDIES. THE USUAL PRACTICE IS TO GIVE ABOUT 1-2
  OF DOSE (PER UNIT WT.) FOUND EFFECTIVE IN
  ANIMALS. THE ROUTE OF ADMIN. THE SAME AS THAT
  USED IN ANIMALS.
• JAMES (1976) STATED THAT 2 OF SCALED DOSE
  IN ANIMALS AS A FIRST DOSE IN MAN.
• DOLLERY DAVIES (1970) SUGGEST 1-2 OF MAX.
  TOLERATED DOSE IN ANIMALS.
• VAIDYA VAIDYA (1981) SUGGESTED TO USE 3
  DIFFERENT MATHODS
• 10-20 OF MAX. TOLLERATED DOSE IN ANIMALS
• TO EXAMINE AND ASSESS DATA AND CORRELATE WITH
  DOSE
• SCRUTINY OF EFFECTIVE AND SAME DOSE

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PRE-CLINICAL SAFETY EVALUATION STUDIES

• RECOMBINANT / DNA BIOTECH PRODUCTS
• ACUTE TOXICITY STUDY
• 2 SPECIES OF ANIMALS (RODENTS AND NON RODENTS),
  2 ROUTE OF ADMINISTRATION
• SUB-ACUTE TOXICITY STUDY
• 2 SPECIES OF ANIMALS (RODENTS AND NON RODENTS),
  2 ROUTE OF ADMINISTRATION
• REPRODUCTIVE TOXICITY
• FERTILITY STUDY ( SEGMENT 1)
• TERATOGENICITY STUDY (SEGMENT 2)
• PRENATAL STUDY (SEGMENT 3)
• MUTAGENICITY AND CARCINOGENICITY

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STEPS FOLLOWED FOR APPROVAL OF RD AND MARKETING
PERMISSION

• IMPORTANT COMMITEES
• IBSC (INSTITUTIONAL BIO-SAFETY COMMITEE)
• RCGM (REVIEW COMMITTEE ON GENETIC
  MANIPULATION).
• GEAC (GENTIC ENGINEERING ADVISORY COMMITEE).
• DCGI (DRUGS CONTROLLER GENERAL, INDIA)