Schedule Y for Toxicological StudyPresented By-Krushangi ShahNirma University
OVERVIEW OF PRESENTATION• Indian Medical Organizations• Drug Regulatory Laws• The Drugs And Cosmetics Act, 1940• Schedule Y –What it Covers And AssociatedRules• Appendices Of Schedule Y• Appendix III: Non-Clinical Animal ToxicityStudies• Bibliography
Indian Medical OrganizationsTo ensure uniformquality of clinicalresearch by GoodClinical Practicesthroughout the countryand to generate data forregistration of newdrugs before use in theIndian population.
CSIR• Council of Scientific and Industrial Research• is an autonomous body and Indias largest Research andDevelopment (R&D) organization.CDRI• Central Drug Research Institute• CDRI is the laboratory functioning under the aegis of thecouncil of scientific and Industrial Research of India.SAFETY &CLINICALDEVELOPMENT--TOXICOLOGY• Toxicology group is involved in profiling of candidate drugsaccording to schedule Y guidelines. Systemictoxicology, reproductive toxicology, genetictoxicity, immunotoxicity, local toxicity and carcinogenicityare being done for NCEs.
DRUG REGULATORY LAWS• 1940 -Drugs and Cosmetic Act• 1985 -Narcotic Drugs and PsychotropicSubstances Act• 2000 -Ethical Guidelines for Biomedical Researchon Human Subjects, ICMR• 2001 -Indian GCP Guidelines• 2002 -Amendment to Drugs & Cosmetics Act• 2005 -Revised Schedule Y• Future :– Guidelines for pre-clinical data for r-DNAvaccines, diagnostics & biological.– Draft Guidelines for Stem Cell Research/Regulation, ICMR.
THE DRUGS AND COSMETICSACT, 1940• An Act to regulateimport, manufacture, distribution and sale ofdrugs and cosmetics.• Passed by the Indian Parliament.• It extends to the whole of India• Both the Act and the Rules came into forcefrom April 1947• Schedule(organized plan for matters to beattended to) are from A to Y
Schedule YREQUIREMENTS AND GUIDELINES FORPERMISSION TO IMPORT AND / ORMANUFACTURE OF NEW DRUGS FOR SALE ORTO UNDERTAKE CLINICAL TRIALSRIGHTS SAFETY WELLBEING OF HUMANSUBJECTSSCOPENEW DRUGDEVELOPMENTPROCESS IN INDIAUTILITY
Appendices in Schedule YI. Data required for import/manufacture/ conduct CT of newdrugsIA. Drugs approved in other countryII. Format for clinical study reports(ICH E6)III. Animal toxicologyIV. Animal pharmacologyV. Informed consentVI. FDCVII. Undertaking by the investigatorVIII. Ethics committeeIX. Stability testingX. Proposed protocolXI. SAE Reporting
Appendix IIIANIMAL TOXICOLOGY(NON-CLINICAL TOXICITY STUDIES)General Principles:-• Laboratory parameters to be included intoxicity studies. GLP, Qualified staff.• Calibrated standardized equipments• SOPs• Test substances and test systems-characterized and standardized• Documents - 5 years (Histo slides, reports)• Toxicokinetic studies (– dose – tox)
Different Toxicity Studies mentionedin Appendix-III• Systemic Toxicity Studies– Single-dose Toxicity Studies– Repeated-dose Toxicity Studies• Special Toxicity Studies– Reproductive Toxicity• Male Fertility Study• Female Reproduction and Developmental Toxicity Studies• Teratogenicity Study• Perinatal Study– Local toxicity– Allergenicity/ Hypersensitivity– Genotoxicity– Carcinogenicity
Systemic Toxicity StudiesSingle-dose Toxicity Studies•2 rodent species.•using the same route asintended for humans.•Target organ of toxicity.•Mortality should be observedfor up to 7 days after parentraladministration and up to 14days after oral administration.•Symptoms, signs and mode ofdeath should be reported, withappropriate macroscopic andmicroscopic findings.•LD 10 and LD 50 with 95% CI.Repeated-dose Toxicity Studies•2 mammalian species(1 nonrodent)•Duration of the study will dependon the duration, therapeuticindication and scale of theproposed clinical trial.•Drug should be administered 7days a week by the route intendedfor clinical use.•Control group of animals giventhe vehicle alone should beincluded
Number of animals required forrepeated-dose toxicity studies14-28 days 84-182 daysGroup Rodent (Rat) Non-rodent(Dog orMonkey)Rodent (Rat) Non-rodent (Dogor Monkey)M F M F M F M FControl 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6Low dose 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6Intermediatedose6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6High dose 6-10 6-10 2-3 2-3 15-30 15-30 4-6 4-6
parametersto bemonitored inlong-termtoxicityPhysiologicalOrganPathology:Gross andMicroscopicECG andfunduscopy(non-rodent)BehavioralBiochemical µscopicobservations ofurine and blood
Reproductive Toxicity• Male Fertility Study• Female Reproduction and DevelopmentalToxicity Studies• Teratogenicity Study• Perinatal Study
Male Fertility Study• Species: (One rodent)• Dose selection: from the 14 or 28-daytoxicity study in rat.• Groups: Three dose groups. 6 adultmale animals in each group.• Dosing interval: Test substance by theintended route of clinical use for min 28days & max 70 days before they arepaired with female animals of provenfertility. Drug treatment of the maleanimals should continue during pairing.• Parameters: (i) Females getting thuspregnant should be examined for theirfertility index after day 13 of gestation.(ii) Weights of each testis andepididymis. (iii) Sperms from oneepididymis- their motility andmorphology.Female Reproduction andDevelopmental Toxicity Studies• Carried out for all drugs to be used inwomen of child bearing age.• Species: (one rodent)• Dose selection: administered to bothmales and females, beginning a sufficientnumber of days before mating• Groups: 15 males and 15 females perdose. Control and the treated groupsshould be of similar size.• Dosing interval: Three graded doses. Theroute of administration should be thesame as intended for therapeutic use.Drug treatment should continue duringmating and, subsequently, during thegestation period.• Dams should be allowed to litter and theirmedication should be continued till theweaning of pups.Reproductive Toxicity
Teratogenicity Study• Species: One rodent & a non-rodent (rabbit)• Dose selection: Drug administeredthroughout the period of organogenesis, usingthree dose levels. The route of administrationshould be the same as intended for humantherapeutic use.• Groups: The control and the treated groupsshould consist of at least 20 pregnant rats (ormice) and 12 rabbits, on each dose level.• All fetuses should to be subjected to grossexamination, Skeletal abnormalities andvisceral abnormalities. Observationparameters should include:• (Dams) signs of intoxication,• effect on body weight,• effect on food intake,• examination of uterus, ovaries and uterinecontents,• number of corpora lutea,• implantation sites, resorptions (if any);• the fetuses, the total number, gender, bodylength, weight and gross/ visceral/ skeletalabnormalities, if any.Perinatal Study• Carried out for the drugs to be given topregnant or nursing mothers for long periodsor if adverse effects on fetal development arethere.• Species: One rodent species (preferably rat)• Dose selection: should be administeredthroughout the last trimester of pregnancyand continued throughout lactation andweaning.• Groups: 4 groups, each having 15 dams.• Animals should be sacrificed at the end of thestudy and the observation parameters shouldinclude• (Dams) body weight,• food intake,• general signs of intoxication,• progress of gestation/ parturition periodsand gross pathology (if any);• pups, the clinical signs, sex-wise distributionin dose groups, body weight, growthparameters, gross examination, survival andautopsy (if needed) and wherenecessary, histopathology.
Local toxicity• Required when route ofadministration is somespecial route (other thanoral) in humans.• Applied to an appropriatesite (e.g., skin or vaginalmucous membrane) todetermine local effects in asuitable species.• Typical study designsincludes three dose levelsand untreated and/ orvehicle control, preferablywith use of 2 species.•Dermal toxicity study•Photo-allergy or dermalphoto-toxicity•Vaginal Toxicity Test•Rectal Tolerance Test•Parentral Drugs•Ocular toxicity studies•Inhalation
Genotoxicity• Genotoxic compounds, shall be presumed to betrans-species carcinogens, implying a hazard tohumans.• Such compounds need not be Subjected to long-term carcinogenicity studies.• However, if such a drug is intended to beadministered for chronic illnesses or otherwiseover a long period of time - a chronic toxicitystudy (up to one year) may be necessary todetect early tumorigenic effects.
Carcinogenicity• More than 6 months• Drugs used frequently in an intermittentmanner in the treatment of chronic orrecurrent conditions.• Structure-activity relationship suggestscarcinogenic risk.
Route ofadministrationDuration of proposedhumanadministrationHuman Phase(s) forwhich study isproposed to beconductedLong term toxicityrequirementsSystemic Toxicity StudiesOral or Parentral orTransdermalSingle dose or severaldoses in one day,Upto 1wkI,II,III 2sp,2wk> 1 wk but Upto 2wk I,II,III 2sp;4wk> 2 wk but Upto 4wk I,II,III 2sp;12wkOver 1mo I,II,III 2sp;24wkInhalation (generalanesthetics, aerosols)Upto 2 wk I,II,III 2sp;1mo; (Exposuretime 3h/d, 5d/wk)Upto 4wk I,II,III 2sp;12wk, (Exposuretime 6h/d, 5d/wk)> 14wk I,II,III 2sp;24wk, (Exposuretime 6h/d, 5d/wk)Animal Toxicity requirements for clinicaltrials and marketing of a new drug
Gross and Microscopic PathologyBrain*: Cerebrum,cerebellum, MidbrainLiver*(Rectum)Urinary bladderUterus*EpididymisOvaryTestis*SkinMammary glandMesentericlymph nodeSkeletal muscle(Middle Ear)Eye(Spinal Cord)(Parathyroid)ThyroidSpleen*(Trachea)Lung*StomachOesophagusAortaHeart*(Pancreas)Adrenal*ThymusKidney*ColonTerminal ileumJejunumDuodenum* Organs marked with an asterisk should be weighed.() Organs listed in parenthesis should be examined if indicated by the nature of thedrug or observed effects.
For Phase I studies: -• Systemic toxicity Studies• Single dose toxicity studies• Dose Ranging studies• Repeated dose systemic studies of appropriateduration to support the duration of proposedhuman exposure.– Male Fertility study– In-vitro Genotoxicity tests• Relevant local toxicity studies• Allergenicity/hypersensitivity tests• Photo-allergy or dermal photo-toxicity test
Phase II Clinical Trials• non-clinical safety data (listed previously) alreadysubmitted while obtaining the permissions forphase I trial, with appropriate references.• directly starting Phase II trial – complete details ofthe non-clinical safety data needed for obtainingpermission for Phase-I trial• Repeat dose systemic toxicity studies ofappropriate duration to support the duration ofproposed human exposure.• In-vivo genotoxicity tests- Segment II reproductive/developmental toxicitystudy
Phase III Clinical Trials• Summary of non-clinical safety and Phase I and Phase IItrials data already submitted while obtaining thepermissions• Directly starting Phase III trial – complete details of thenon-clinical safety data needed for obtaining permissionfor Phase-I trial and Phase II• Repeat dose systemic toxicity studies of appropriateduration to support the duration of proposed humanexposure• Reproductive/developmental toxicity studies. (femalereproduction or teratogenic toxicity)• Carcinogenicity studies ( when there is a cause forconcern or when the drug is to be used for more than 6months)
Phase IV Clinical Trials• Summary of all the non-clinical safety dataalready submitted while obtaining thepermissions or Phase I and Phase II trials withappropriate references
Application Of Good LaboratoryPractices (GLP)• The animal studies be conducted in anaccredited laboratory. Toxicology studies, alsobe conducted in an accredited laboratory.