FARDAN QADEER

Junior Resident, Dept. of Pharmacology

SCHEDULE Y

• Directorate General of Health Services

Ministry of Health and Family Welfare

• Drugs Controller General of India.

CDSCO-Central Drugs Standard Control Organization

Retail and

Distribution

ManufacturingPractice

Clinical Trials and new drug

development

DRUG REGULATION IN INDIA

• 1. Schedule X – Narcotics

2. Schedule H – Prescription drugs

3. Schedule C and C1- Biological Products (Serums and Vaccines)

Retail and Distribution

• 1. Schedule N

List of the equipment for the efficient running of manufacturing wing, Qualified personnel

2. Schedule M-GMP

Manufacturing Practice

• Schedule Y

Clinical Trials and new drug development

The drugs and cosmetics act and rules:

• GOVERNMENT OF INDIA MINISTRY OF HEALTH AND FAMILY WELFARE Introduced THE DRUGS AND COSMETICS ACT (1940)AND RULES (1945)

An Act to regulate the import, manufacture, distribution and sale of drugs and cosmetics in India.

SCHEDULE Y

Rules 122 A, 122 B, 122 D, 122 DA, 122 DAA, 122 DAB, 122 E, 122 DD.

• 122-A Application for permission to import new drug.

• 122-B Application for approval to manufacture new drug.

• 122-D Permission to import or manufacture FDC.

1. APPLICATION FOR PERMISSION:Application for permission to import or manufacture new drugs along with following data:

Introduction Chemical and pharmaceutical information Animal Pharmacology Animal toxicology Human / Clinical pharmacology (Phase I) Therapeutic exploratory trials (Phase II) Therapeutic confirmatory trials (Phase III) Special studies Regulatory status in other countries Prescribing information

Chemical and pharmaceutical information

• Information on active ingredients • Drug information (Generic Name, Chemical Name)

• Physical and chemical properties of drug

• Analytical Data

• Complete monograph specification including

• Validations

• Stability Studies

• Data on Formulation • Dosage form

• Composition

• Excipient compatibility study

Animal Pharmacology

• Summary

• Specific pharmacological actions

• General pharmacological actions

• Follow-up and Supplemental Safety Pharmacology Studies

• Pharmacokinetics: absorption, distribution; metabolism; excretion

SPECIFIC PHARMACOLOGICAL ACTONS

• Actions which demonstrate the therapeutic potential for humans.

• Scientifically validated methods should be used.

GENERAL PHARMACOLOGICAL ACTIONS

• Safety pharmacology studies

• Effects on different organs

Animal toxicology

• Systemic Toxicity studies• Single dose toxicity studies• Repeated dose toxicity studies

• Male fertility studies

• Female Reproduction and Developmental Toxicity Studies

• Local toxicity

• Allergy/Hypersensitivity

• Genotoxicity

• Carcinogenicity

Single dose toxicity

• Four graded doses should be given.

• Each group should contain at least 5 animals of either sex.

• At least Animals should be exposed to the test substance in a single bolus or by continuous infusionor several doses within 24 hours.

• Animals should be observed for 14 days

• Minimal lethal dose(LDmin)

• Maximum tolerated dose

Dose-ranging Study

• MTD is established from the single dose toxicity study

• Study is performed in one rodent and one non rodent species.

• 5 animals in each group and at least 4 graded doses should be given

• It is given consequently for 10 days

• Organ specific toxicity is established.

Male Fertility Study

• Six animals are taken in each group

• Animals should be treated with the test substance by the intended route of clinical use for minimum 28 days and maximum 70 days

• They are paired with female animals of proven fertility in a ratio of 1:2 for mating for at least 10 days.

• Females getting thus pregnant should be examined for their fertility after day 13 of gestation.

All the male animals should be sacrificed at the end of the study and organs of reproduction are examined

Female Reproductive Studies

• These studies need to be carried out for all drugs proposed to be studied or used in women of child bearing age

• These are done under 3 segments:

SEGMENT I Albino mice or rat Female Fertility Study

SEGMENT II Albino mice or rat Teratogenicity Study

SEGMENT III Albino mice or rat+

Albino rabbits

Perinatal Study

Local toxicity

These studies are required when the new drug is proposed to be used by some special route (other than oral) in humans:

It includes:

• Dermal toxicity

• Vaginal toxicity

• Rectal toxicity

• Parenteral toxicity: injection site toxicity

• Ocular and inhalational toxicity studies

Genotoxicity and Carcinogenicity

It is required for a drug that is intended to be used for a chronic illness or a drug that is used for a long period of time(>6 months)

Genotoxicity data are not required before Phase I and II trials. But these studies should be completed before applying for Phase III trials.

• 122-DA Permission to conduct clinical trials for new drug / investigational new drug.

• 122 - DAA Definition of CLINICAL TRIAL.

• 122- DAB Reports of Serious Adverse Events (SAEs) including deaths.

• 122- E New Drug

Clinical Trial

“Clinical trial” means a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and / or efficacy of the new drug.”

122 - DAA

New Drug

A new substance of chemical, biological or biotechnological origin, in bulk or prepared dosage form; used for prevention, diagnosis, or treatment of disease in man or animal; which except during local clinical, trials, has not been used in the country to any significant extent and which except during local clinical trials, has not been recognised in the country as effective and safe for the proposed claims.

122-E

Post Marketing Trials (Phase IV)

Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed.

The report is to be submitted every six months for the first two years after approval of the drug is granted to the applicant. For subsequent two years need to be submitted annually and may be extended if necessary.

It is done to detect unexpected adverse effects and drug interactions.

DRUG DISCOVERED IN INDIA

DRUG DISCOVERED OUTSIDE INDIA

STARTED FROM PHASE I

PHASE II TRIAL

PHASE II TRIAL

PREVIOUS PHASE I DATA

APPROVED

2. CLINICAL TRIALPERMISSION

Licensing AuthorityThe ethics committee.

INVESTIGATORSPONSER

• Quality assurance• Submission of status report.• Reporting of any serious

adverse effect• To ensure that laboratories

used for generating data for clinical trials should be compliant with Good Laboratory Practices

• Conduct of the trial according to the protocol and the GCP Guidelines

• Follow the SOP’s.• Ensure that adequate

medical care is provided to the participant for any adverse events.

Serious Adverse Events

• Any undesirable experience associated with the use of a medical product in a patient

• It should be reported within 14 days by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study

Death Life-threatening

Hospitalization Disability or Permanent Damage

Congenital Anomaly/Birth Defect Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Other Serious (Important Medical Events)

122- DAB

The Drugs and Cosmetics Rule made an amendment GSR 53(E) dated 30-01- 2013 inserting a Rule 122DABand a new Appendix-XII in Schedule Y

It determine the quantum of compensation, if any, to be paid by the Sponsor or his representative, whosoever have obtained permission from the Drugs Controller General(India) in a time bound manner.

B = Base amount (i.e. 8 lacs) F = Factor depending on the age of the subject (based on Workmen Compensation Act) R = Risk Factor

Age……………..F Factor Age……………..F Factor Age……………..F Factor

>16 . . . . . . . . 228.5417 . . . . . . . . . 227.4918 . . . . . . . . . 226.3819 . . . . . . . . . 225.2220 . . . . . . . . . 224.0021 . . . . . . . . . 222.7122 . . . . . . . . . 221.3723 . . . . . . . . . 219.9524 . . . . . . . . . 218.4725 . . . . . . . . . 216.9126 . . . . . . . . . 215.2827 . . . . . . . . . 213.5728 . . . . . . . . . 211.7929 . . . . . . . . . 209.9230 . . . . . . . . . 207.9831 . . . . . . . . . 205.9532 . . . . . . . . . 203.8533 . . . . . . . . . 201.6634 . . . . . . . . . 199.40

35 . . . . . . . . . 197.0636 . . . . . . . . . 194.6437 . . . . . . . . . 192.1438 . . . . . . . . . 189.5639 . . . . . . . . . 186.9040 . . . . . . . . . 184.1741 . . . . . . . . . 181.3742 . . . . . . . . . 178.4943 . . . . . . . . . 175.5444 . . . . . . . . . 172.5245 . . . . . . . . . 169.4446 . . . . . . . . . 166.2947 . . . . . . . . . 163.0748 . . . . . . . . . 159.8049…………….....156.4750………………..153.0951…………...…..149.6752………………..146.2053…………………142.68

54………………..139.1355………………..135.5656………………..131.9557………………..128.3358………………..124.7059………………..121.0560………………..117.4161………………..113.7762………………..110.1463 . . . . . . . . . 106.52 64 . . . . . . . . . 102.9365 or above … 99.37

RISK FACTOR INDEX(R) RISK FACTORS

0.50 terminally ill patient (expected survival not more than (NMT) 6 months)

1.0 Patient with high risk (expected survival between 6 to 24 months)

2.0 Patient with moderate risk

3.0 Patient with mild risk

4.0 Healthy Volunteers or subject of no risk

• 122 – DD Registration of Ethics Committee (EC).

ETHICS COMMITTEE

It is the responsibility of the ethics committees that reviews and accords its approval to a trial protocol to safeguard the rights, safety

and well being of all trial subjects.

• Care of the vulnerable group in the study: patients with incurable diseases, unemployed or impoverished persons, patients in emergency situation, others incapable of personally giving consent

• Ethics Committee(s) should make, at appropriate intervals, an ongoing review of the trials for which they review the protocol

122 – DD

• The number of persons in an Ethics Committee should have at least seven members

Chairpersonoutside the institution

Member Secretary

(a)basic medical scientists (preferably one pharmacologist). (b) clinicians (c) legal expert (d) social scientist/ representation of non-governmental voluntary agency / philosopher / ethicist / theologian or similar person (e) lay person from the community

INFORMED CONSENT

In all clinical trials freely given, informed written consent is required to be obtained from each study subject

• Verbal information of the study using a patient information sheet

• Language that is nontechnical and understandable by the study subject.

• Where a subject is not able to give informed consent, the same may be obtained from a legally acceptable representative.

STUDIES IN SPECIAL POPULATION• Geriatrics:

• Geriatric patients should only if the disease intended to be treated is characteristically a disease of aging

• The conditions to be treated should be common in the elderly are likely to be encountered

• When the new drug is likely to alter the geriatric patient’s response compared with that of the non-geriatric patient.

• Pregnant or nursing women:

Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or foetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable.

Paediatrics:

• When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants.

• Initial safety and tolerability data should be obtained from the adult population data before starting trial in children.

• Written informed consent should be taken from the legal guardians.

PRESCRIPTION INFORMATION

The full prescribing information should be submitted as part of the new drug application for marketing