SCHEDULE Y

PRESENTED BY-AKSHDEEP SHARMACLINICAL RESEARCH(STUDENT)

Lets Revise the History

• Drug and Cosmetic Act, 1940 was enacted(D/C Act)

• Pharmacy Act , 1948• Drug and Magic Remedies Act, 1954• The Narcotic and Psychotropic Substance Act

and Rules, 1985• Ethical guidelines for Biomedical Research on

Human Participants,2000 by ICMR

• Indian GCP Guidelines,2001• Amendments to Drug and Cosmetic

Act,2002• Revised Schedule Y, 2005• Guidelines for Pre Clinical Data for r-DNA

Vaccines,2007

Lets Revise the History

Drug and Cosmetics Act,1940 In 1940 D/C Act Was enacted

In 1945 Drug Rules were Promulgated in December and enforcement Start in 1947

Now have been called as D/C Act

Objective- To ensure that the drug is available to the People are safe and cosmetics marketed for safer use.

Schedules to Rules, 1945Schedule A- Forms for marketing application for licenses, issue, and renewalB- Fee for test/analysis by CDL or SDLC/C1- talk about I/M/S/D of sera, vaccinesD-List of drugs exempted from the provisions that are applicable to import of other drug.E1- list of poisonous substance under Ayurveda,Unani,Sidha system F- Production/testing/storage/packaging/labeling.F1- biological preparations F2- SD F3- umbilical tapesG- List of drug used under medical supervisionH- List of drug sold under PrescriptionI-OmittedJ-Diseases may not cure/prevent by drugsK-List of drugs exempted from the provisions that are applicable to manufacture of other drug

M-GMPN-List of minimum equipment in PharmacyO-Standards for disinfectionsP- Life period of drugQ-List of dyes/coloring agents in soap/cosmeticsR-Standards for Mechanical contraceptivesS-Standards for cosmeticsT-GMP for A/U/S system of medicinesU- Records for manufacturing/raw materials in drugsV- Standards for potent medicinesX- List of drugs whose I/M/S are governed by special provisionW- OmittedY- About CT

Schedules to Rules, 1945

Schedule YThe enforcement that came into existence in 1988 was an essential provision for providing support to the upscale of generic pharma scenario present in those days.

With the entry of large pharmaceutical companies along with the multiple multinationals in field of clinical research the needs changed and a revised version of Schedule Y in line with ICH-GCP (International Council of Harmonization and Good Clinical Practice) standard was put forth in 1995. Since then multiple revisions to Schedule Y took place to provide a healthy environment for clinical research to be conducted in India.

What actually Schedule Y is?

Schedule Y

It’s a Law not merely a Guideline

यह एक कानून न केवल एक दि शानिन �श है

Schedule Y

Schedule Y ,the current regulator (of CDSCO), enforced law in India has been established under Drug and Cosmetic Act,1945.The regulations to be followed when conducting Clinical Trial in India.

‘REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS IN INDIA’

Schedule Y

Amended Schedule Y

‘Regulations and Guidelines for permission for development (preclinical and/or clinical), import and manufacture of New Drugs for Marketing in India’DATE- 20TH JAN,2005

Why Changes in Schedule Y

To frame guidelines for the current scenario of Clinical research.CDSCO and DTAB(Drug Testing Advisory Board) formulated GCP under Schedule Y in 2005.Schedule Y 1988 relevant to predominantly generic industry.GCP trials since 1995, and arrival of IPR regime in 2005. Integration of India in global clinical development and legal support to GCP guidelines.Improvements in quality of clinical trials.It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines.

Application for permission

It shall made in Form 44 accompanied with the following data in accordance with appendices, namelyClinical and pharmaceutical informationAnimal pharmacology dataAnimal Toxicology data Human Clinical pharmacology dataRegulatory status in other countriesPrescribing information

FORM 12- To import Study drug for examination , test or analysis

Clinical Trial1. Approval for clinical trials2. Responsibilities of sponsor3. Responsibilities of Investigator4. Informed Consent5. Responsibilities of Ethics Committee6. Human Pharmacology (Phase l)7. Therapeutic Exploratory Trials (Phase ll)8. Therapeutic confirmatory Trials (Phase lll)9. Post Marketing Trials (lV)

Clinical Trials : Special Studies

Clinical trials required if the indication is relevant to special population e.g. pediatrics, geriatrics,and pregnancy

Members knowledgeable about pediatric, ethical, clinical and psychosocial issues

Mature minors and adolescents to sign an assent form

Other – Post-marketing surveillance, BA/BE

Approval for Clinical Trials

Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective ethics committees.

The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics committees as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site.

Responsibility of Sponsor Quality assurance to ensure compliance to GCP guidelines of CDSCO(Central Drug Standard Control Organization) Submission of status report at prescribed periodicity; reasons for premature termination to be communicated Serious adverse event to be communicated promptly (within 14 calendar days) to DCGI(Drug Controller General Of India) and other investigators

Responsibilities of Investigator Responsible for conduct of trial accordingto protocol and GCP Compliance as per undertaking formatMedical care for AEs SAE reporting to Sponsor within 24 hrs EC within 7 days Informed consent

Responsibilities of EC Safeguard rights, safety, wellbeing ofsubjectsSpecial care for vulnerable subjectsReason’s for revoking approval and information to investigator / regulatory authority Ongoing review

1.Human Pharmacology (Phase l)Safety and tolerability – Objective

2.Therapeutic Exploratory Trials (Phase ll)

To evaluate the effectiveness of a drug for particular indication.To determine the short term side effects and risk associated with the drugTo determine the dose and regimen for phase lll trials.

Clinical Trial

Clinical Trial

6.Therapeutic confirmatory Trials (Phase lll)

Demonstration of therapeutic benefitDrug is safe and effective for use and Provide and adequate basis for marketing approval

7.Post Marketing Trials (lV)

Performed after drug approval and related to the approved indicationIncludes drug-drug interaction, dose-response or safety studies, mortality/morbidity studies

Studies in Special Population

Information supporting the use of the drug in children, pregnant women, nursing women, elderly patients, patients with renal or other organ systems failure, and those on specific concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern (Appendix I, item 8.3).

Types1. Geriatrics2. Pediatrics3. Pregnant or Nursing Women

GeriatricsGeriatric patients should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if-

the disease intended to be treated is characteristically a disease of aging; or the population to be treated is known to include substantial numbers of geriatric patients

Pediatrics

The timing of pediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments.

The pediatric studies should include –

clinical trials, relative bioequivalence comparisons of the pediatric formulation with the adult formulation performed in adultsdefinitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used. These studies should be conducted in the pediatric patient population with the disease under study.

Pregnant or Nursing WomenPregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or fetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable. For new drugs intended for use during pregnancy, follow-up data (pertaining to a period appropriate for that drug) on the pregnancy, fetus and child will be required

Post Marketing Surveillance

PSUR : Periodic Safety Update Reports

New drugs should be closely monitored for their clinical safety; submission of in order to-report all the relevant new information (patient exposure)summarize the market authorization status in different countries and any significant variations related to safety; andindicate whether changes should be made to product information PSURs shall be submitted every 6 months for the first two years after approval

For subsequent two years – the PSURs need to be submitted annually

PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period.

PSUR : Periodic Safety Update Reports

Rules under Schedule YRule

122 A

122 B

122 D

122 DA

122DAA

122 E

Permission

To Import New Drugs

To manufacture New Drugs

To import or manufacture fixed dose Combinations

To conduct Clinical Trialsfor New Drug/Investigational New Drug

Definition of Clinical Trial

Definition of New Drug

Rule 122DA To conduct Clinical Trials for New Drug/Investigational New Drug

New chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings.

122-E122-E. -Not been used in the country under labeling conditions-Approved but now proposed to be marketed with modified or new claims –indications, dosage, dosage form , route of administration-FDC, individually approved, to be combined for the first time in a fixed ratio or if ratio is changed

APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY AUTHORITIES, FEES AND TEST LICENCE

Regulatory Authorities

Ministry of Chem & Fertilizers

NPPANational Pharmaceutical Pricing Authority

Pricing Regulations

Ministry of Sci & Tech

DBTDepartment of Biotechnology

Ministry of Enviro

Additional Secretary

State Drug Regulatory Authority :FDA

GEACGenetic Engineering Approval Committee

DCGIDrug Controller General of India

DGHSDirector General of Health Services

Health Secretary

Ministry of Health

CDRL/CDTLGov. Drug Testing Laboratories

DRUG REGULATION IN INDIA

• 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

Fee according to Schedule YImport ff/ Mfg ff/ Import bulk + Mfg ff = Rs 50,000/- of new drug

Application by same applicant, = Rs 15,000/- for modified dosage form or with new claim

Secondary applicants after 1 = Rs 15,000/- year of approval

Import / Mfg FDC = Rs 15,000/-

Conduct Clinical trial with ND/IND Phase I = Rs 50,000/-Phase II = Rs 25,000/- Phase III = Rs 25,000/-No separate fee to be paid along with application for import / mfg based on successful completion

Appendix I-AData required to be submitted by an applicant

for grant of permission to import &/or manufacture a new drug already approved

in the country.a) Introductionb) Chemical and pharmaceutical informationc) Marketing informationd) Special studies

Appendix IIIAnimal toxicology (Non-clinical toxicity studies)

1) SDTS(Single Dose Toxicity Study)- Minimum 5 animal, 24hr observation2) DRS(Dose Ranging Study)- On one Rodent Species3) RDTS(Repeated Dose Systemic Toxicity Study)- a) 14 to 28 days- on 1

Rodent and 1 Non Rodent b)90 days- same as above but introduction of HIGH DOSE

REVERSAL .4) MFS- Rodent Species, Dose selection should be done on basis of 14 to 28

days studies.5) FFS- should be carried out for all drugs( Appendix I- 4.4)

Appendix IV-Animal Pharmacology

Animal pharmacology studies are done to see the effect if IP on different systems like

CVS-(Cardiovascular System)CNS-(Central Nervous System)ANS-(Autonomic Nervous System)RS-(Respiratory System)US-(Urinary System)GIT-(Gastrointestinal System)

Appendix V- INFORM CONSENT

Trial involves research Purpose Trial treatments and randomization Trial procedures Risk Benefit Alternative treatments Compensation / treatment for injury Subject’s responsibilities Experimental aspects Any payment

Essential Elements of Informed Consent Confidentiality New information Voluntary participation Person/s to contact for study information Rights of subject, if study related injury Reasons for termination Duration of study Number of subjects Any other pertinent information

Format of Informed Consent Form Study Title Subject’s Initials e.g. Subject’s Name/ Date of

Birth / Age Consent Statements with initials in a) Signature (or Thumb impression) of the

Subjectb) Legally Acceptable Representative Signature of the Investigator Study Investigator’s Name Signature of the Witness Name of the Witness

Appendix VI- FDC’sData requirements of Fixed Dose CombinationsFixed Dose combinations (FDC) fall into four groups and their data requirements accordingly.The first group of FDC includes those in which one or more of the active ingredients is a new drug. The second group of FDC includes those in which active ingredients already approved/marketed . The third group of FDC includes those which are already marketedThe fourth group of FDC includes those whose individual active ingredients have been widely used.

Appendix VII Undertaking By The Investigator1) Full name, address and title of the Principal Investigator

2) Name and address of the medical college, hospital or other facility where the clinical trial will be conducted: Education, training &experience that qualify the Investigator for the clinical trial (Attach details including Medical Council registration number, and / any other statement of qualification

3) Name and address of all clinical laboratory facilities to be used in the study.

4) Name and address of the Ethics Committee ,responsible for approval and continuing review of the study.

5) Names of the other members of the research team (Co- or sub-Investigators) who will be assisting the Investigator in the conduct of the investigation.

6) Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator.

7) Signature with Date.

Appendix VII.2 Commitments by The Investigator

a. Study not to begin until EC / DCGI approvalb. Adherence to protocolc. Personal supervisiond. Ensure requirements of IC and EC reviewe. Report of AE to sponsorf. Understanding of investigator’s brochureg. Ensure that all associates, colleagues and employees suitably qualified and experienced and

aware of their obligationsh. Report all unexpected serious adverse events to the Sponsor in 24 hrs and EC within 7 days.i. Maintenance of records and availability for audits / sponsor inspection / EC and DCGI.

Cooperation in audits

Appendix VIII ETHICS COMMITTEE COMPOSITION

ICH GCP Indian GCP Schedule-Y

• At least 5 members. •At least 1 member -nonscientific area.

•Quorum members number not detailed.

•Maximum number is not detailed.

•Not recommended.

•Fairly small (5-7 members).• 1 member from non-scientific area

•The quorum should have a minimum of 5 members.

•12 to 15 is the maximum recommended number.

•Member Secretary belongs to the same Institution.

•At least 7 members. •Not Explained.

•The quorum should have at least 5 members.

•Maximum number is not detailed.

•Not recommended.

Appendix IX- Stability testing of New Drugs

Stability testing is to be performed to provide evidence on how the quality of a drug substance or formulation varies with time under the influence of various environmental factors such as-

a. Temperatureb. Humidity andc. LightObjective. - To establish shelf life for the formulation and

recommended storage conditions.

STABILITY TESTINGStress testing of the drug substance should be conducted to identify-a. The degradation pathwaysb. Evaluate the intrinsic stability of the molecule and c. Validate the stability indicating power of the analytical procedures used.Stress testing may generality be carried out on a single batch of the drug substance. It should include the effect of-Temperature, humidity, oxidation, photolysis on the drug substance.

TWO TYPES OF STUDY IS DONE1)Long-term testing should cover a minimum of 12 months’ duration on at

least three primary batches of the drug substance or the formulation at the time of submission

STABILITY TESTING2)Accelerated testing should cover a minimum of 6 months duration at the

time of submission. Study conditions for drug substances and formulations intended to be stored

under general conditions. Study conditions and Duration of study i)Long term 30°C± 2°C/65% RH ± 5%RH 12 months ii)Accelerated 40°C± 2°C/75% RH ± 5% RH 6 months If at any time during 6 months’ testing under the accelerated storage condition,

such changes occur then further studies are done.NOTE- The nature of the stress testing will depend on the individual drug

substance and the type of formulation involved.

Appendix X – Contents of the Proposed Protocol Title page Table of content

a) a) introduction

b) Study rationale

c) Study design

d) Study population

e) Subject eligibility

f) Study treatment

g) AE

h) Data analysis

i) Undertaking by investigator

NOTE- Protocol is assigned by sponsor after getting CDA from investigator

Appendix XI- Data Elements For Reporting SAE in a Clinical Trial

a) Patient details(Age, sex, weight, height)b) Suspected drug( Generic name, DFD, ROA)c) Detail of SUSPECTED ADR( severity, start date, stop

date, hospitalization or not)d) Details about investigator

New Amendments on 30.06.2009

CLINICAL RESEARCH ORGANISATION – REGISTRATIONThese guidelines have been approved by DTAB

1)Rule 122 DAB. – Registration of clinical research organization for conducting clinical trials.

The clinical research organization, contracted in writing by the sponsor to carry out any or all obligations transferred to it by the sponsor, shall perform such functions only, if it is duly registered, under the rules, by the Licensing Authority defined in Clause (b) of Rule 21.

New Amendments on 18th Nov.2011

1)Rule 122-DAB- compensation during injury or death during clinical trial In case of injury in clinical trial the compensation is based as per the recommendation of EC/IRB , it may be financial or medical.2) In case of death his/her legal heirs are entitled for the financial compensation, subject to the confirmation to EC