6 schedule y jntu pharmacy

1

BYDr. Suman PattanayakAssociate ProfessorDepartment of Pharma Analysis & QA.

Vijaya Institute of Pharmaceutical Sciences for Women

B. Pharm IV year/ II SemDRA, IPR & Patents

AppendicesAppendicesI : Data required for

import/manufacture/ conduct CT of new drugs I A : …. Drugs approved in other

countryII : Format for clinical study

reports(ICH E6)III : Animal toxicologyIV : Animal pharmacologyV : Informed consent

AppendicesAppendicesVI : FDCVII : Undertaking by the

investigatorVIII : Ethics committeeIX : Stability testingX : Proposed protocolXI : SAE Reporting

APPENDIX IAPPENDIX IDATA TO BE SUBMITTED ALONG

WITH THE APPLICATION TO CONDUCT CLINICAL TRIALS / IMPORT / MANUFACTURE OF NEW DRUGS FOR MARKETING IN THE COUNTRY.

APPENDIX IAPPENDIX I1. Introduction2. Chemical and pharmaceutical information3. Animal Pharmacology4. Animal Toxicology5. Human / Clinical pharmacology (Phase I)6. Therapeutic exploratory trials (Phase II)7. Therapeutic confirmatory trials (Phase III)8. Special studies9. Regulatory status in other countries10. Prescribing information11. Samples and Testing Protocol/s

APPENDIX IAPPENDIX I 1.Introduction brief description of the drug therapeutic class to which it belongs.

2. Chemical and pharmaceutical information

2.1. Information on active ingredientsDrug information

(Generic Name, Chemical Name or INN)

2.2. Physicochemical Data2.2. Physicochemical Dataa. Chemical name and Structure

Empirical formula Molecular weight

b. Physical properties Description Solubility Rotation Partition coefficient Dissociation constant

2.3. Analytical Data2.3. Analytical DataElemental analysisMass spectrumNMR spectraIR spectraUV spectraPolymorphic identification

2.4. Complete monograph 2.4. Complete monograph specification includingspecification including

IdentificationIdentity/quantification of

impuritiesEnantiomeric purityAssay

2.5. Validations2.5. ValidationsAssay methodImpurity estimation methodResidual solvent/other volatile

impurities (OVI) estimation method

2.6. Stability Studies2.6. Stability Studies

Final release specificationReference standard

characterizationMaterial safety data sheet

2.7. Data on Formulation2.7. Data on FormulationDosage form CompositionMaster manufacturing formulaDetails of the formulation In process quality control checkFinished product specificationExcipient compatibility studyValidation of the analytical method

Data on Formulation Data on Formulation (Contd..)(Contd..)Comparative evaluation with

international brand(s) or approved Indian brands,

Pack presentationDissolutionAssayImpurities

Data on Formulation Data on Formulation (Contd..)(Contd..)Content uniformitypHForce degradation studyStability evaluation in market

intended pack at proposed storage conditions

Packing specificationsProcess validation

3.3. Animal PharmacologyAnimal Pharmacology3.1. Summary3.2. Specific pharmacological

actions3.3. General pharmacological

actions3.4. Follow-up and

Supplemental Safety Pharmacology Studies

3.5. PK

4.4. Animal ToxicologyAnimal Toxicology4.1. General Aspects4.2. Systemic Toxicity Studies4.3. Male Fertility Study4.4. Female Reproduction and

Developmental Toxicity Studies

4.5. Local toxicity4.6. Allergenicity/Hypersensitivity4.7. Genotoxicity4.8. Carcinogenicity

5.5. Human / Clinical Human / Clinical pharmacology (Phase I)pharmacology (Phase I)5.1. Summary5.2. Specific Pharmacological

effects5.3. General Pharmacological

effects5.4. PK5.5. PD / early measurement of

drug activity

6.6. Therapeutic exploratory Therapeutic exploratory trials (Phase II)trials (Phase II)

6.1. Summary6.2. Study report(s) as given in

Appendix II

7.7. Therapeutic confirmatory Therapeutic confirmatory trials (Phase III)trials (Phase III)7.1. Summary7.2. Individual study reports

with listing of sites and Investigators

8.8. Special studiesSpecial studies8.1. Summary8.2. BA/BE8.3 Other studies e.g. geriatrics,

paediatrics, pregnant or

nursing women

9.9. Regulatory status in other Regulatory status in other countriescountries

9.1. Countries where the drug isa. Marketedb. Approvedc. Approved as INDd. Withdrawn, if any, with

reasons 9.2. Restrictions on use, if any, in

countries where marketed /approved9.3. Free sale certificate or certificate of analysis, as appropriate.

10.10. Prescribing informationPrescribing information10.1. Proposed full prescribing information10.2. Drafts of labels and cartons

11.11. Samples and Testing Samples and Testing Protocol/sProtocol/s11.1. Samples of pure drug

substance and finished product, with testing protocol/s, full impurity profile and release specifications.

APPENDIX I-AAPPENDIX I-ADATA REQUIRED TO BE

SUBMITTED BY AN APPLICANT FOR GRANT OF PERMISSION TO IMPORT AND / OR MANUFACTURE A NEW DRUG ALREADY APPROVED IN THE COUNTRY.

APPENDIX I-AAPPENDIX I-A1. Introduction2. Chemical and pharmaceutical

information3. Marketing information4. Special studies conducted with

approval of Licensing Authority

2. Chemical and 2. Chemical and pharmaceutical informationpharmaceutical information2.1 Chemical name, code name or number,

if any; non-proprietary or generic name, if any, structure; physico-chemical properties

2.2 Dosage form and its composition2.3 Test specifications

(a) active ingredients(b) inactive ingredients

2.4 Tests for identification of the active ingredients and method of its assay

2.5 Outline of the method of manufacture of active ingredients

2.6 Stability data

3. Marketing information3. Marketing information3.1 Proposed package insert /

promotional literature3.2 Draft specimen of the label

and carton

4. Special studies conducted 4. Special studies conducted with approval of Licensing with approval of Licensing AuthorityAuthority

4.1 BA/BE and comparative dissolution studies for oral dosage forms

4.2 Sub-acute animal toxicity studies for IV infusions and injectables

Appendix IIAppendix IISTRUCTURE, CONTENTS AND FORMAT FOR CLINICAL STUDY REPORTS

Appendix IIAppendix II1. Title Page2. Study Synopsis (1 to 2 pages)3. GCP Compliance4. List of Abbreviations and Definitions5. Table of contents6. Ethics Committee7. Study Team8. Introduction - product development

rationale9. Study Objective 10. Investigational Plan - design

Appendix IIAppendix II11. Trial Subjects - accounting 12. Efficacy evaluation 13. Safety Evaluation

13.1 all serious adverse events, whether expected or unexpected 13.2 unexpected adverse events whether serious or not

15. List of References

Appendix IIAppendix II16. Appendices: a. Protocol and amendmentsb. Specimen of Case Record Formc. Investigators name(s) with contact

addresses, phone, email etc.d. Patient data listingse. List of trial participants treated with

IP.f. Discontinued participants

Appendix IIAppendix IIAppendices to Clinical trial reportAppendices to Clinical trial reportg. Protocol deviationsh. CRFS of cases involving death and

life threatening AEsi. Publications from the trial j. Important publications referenced in

the studyk. Audit certificate, if availablel. Investigator’s certificate

Appendix IIIAppendix IIIANIMAL TOXICOLOGY

(NON-CLINICAL TOXICITY STUDIES)

Appendix IIIAppendix III1. General Principles2. Laboratory parameters to be

included in toxicity studies

General PrinciplesGeneral PrinciplesGLP, Qualified staffCalibrated standardized

equipments SOPs Test substances and test systems

characterized and standardized Documents - 5 years (Histo slides,

blocks)Toxicokinetic studies (– dose – tox)

1.1 1.1 Systemic Toxicity Systemic Toxicity StudiesStudies1.1.1 Single-dose Toxicity Studies

2 rodent species (mice and rats) using the same route as intended for humans

Single-dose Toxicity Single-dose Toxicity StudiesStudiesTarget organ of toxicity Mortality should be observed for

up to 7 days after parenteral administration and up to 14 days after oral administration

Symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings

LD10 and LD50 95% CI

1.1.21.1.2 Repeated-dose Systemic Repeated-dose Systemic Toxicity StudiesToxicity Studies

2 mammalian species (1 nonrodent)

Duration of the final systemic toxicity study will depend on the duration, therapeutic indication and scale of the proposed clinical trial.

Repeated-dose Systemic Repeated-dose Systemic Toxicity StudiesToxicity StudiesDrug should be administered 7

days a week by the route intended for clinical use.

Control group of animals given the vehicle alone should be included

Repeated-dose Systemic Repeated-dose Systemic Toxicity StudiesToxicity StudiesThe parameters to be monitored and

recorded in long-term toxicity studies should include ◦ behavioral, ◦ physiological, ◦ biochemical and microscopic observations.

Sites of injection should be Subjected to gross and microscopic examination

Initial and final ECG and funduscopy - non-rodent

1.21.2 Male Fertility StudyMale Fertility Study One rodent species (preferably rat) Dose selection - done from the results of the

previous 14 or 28-day toxicity study in rat. Three dose groups, Each group should consist of 6 adult male

animals. Animals should be treated with the test substance

by the intended route of clinical use for minimum 28 days and maximum 70 days before they are paired with female animals of proven fertility

Male Fertility StudyMale Fertility StudyDrug treatment of the male animals should

continue during pairing. Females getting thus pregnant should be

examined for their fertility index after day 13 of gestation.

All the male animals should be sacrificed at the end of the study.

Weights of each testis and epididymis should be separately recorded.

Sperms from one epididymis should be examined for their motility and morphology.

1.31.3 Female Reproduction and Female Reproduction and Developmental Toxicity Studies Developmental Toxicity Studies Carried out for all drugs proposed

to be studied or used in women of child bearing age.

1.3.11.3.1 Female Fertility Female Fertility Study (Segment I): Study (Segment I): Done in one rodent species (rat

preferred). The drug should be administered

to both males and females, beginning a sufficient number of days before mating.

Drug treatment should continue during mating and, subsequently, during the gestation period.

Female Fertility Study Female Fertility Study (Segment I):(Segment I):Three graded doses should be

used At least 15 males and 15 females

per dose group. Control and the treated groups

should be of similar size. The route of administration

should be the same as intended for therapeutic use.

Female Fertility Study Female Fertility Study (Segment I):(Segment I):Dams should be allowed to litter and their medication should be continued till the weaning of pups. Observations on

◦ body weight, ◦ food intake, ◦ clinical signs of intoxication, ◦ mating behaviour, ◦ progress of gestation/ parturition periods, ◦ length of gestation, ◦ parturition, ◦ post-partum health and gross pathology (and histopathology of affected organs) of dams

Female Fertility Study Female Fertility Study (Segment I):(Segment I):The pups from both treated and

control groups should be observed for ◦ General signs of intoxication, ◦ sex-wise distribution in different treatment

groups, ◦ Body weight, ◦ Growth parameters, ◦ Survival, ◦ Gross examination, and autopsy. ◦ Histopathology of affected organs

1.3.21.3.2 Teratogenicity Study Teratogenicity Study (Segment II): (Segment II): One rodent (preferably rat) and one non-

rodent (rabbit) species Drug should be administered throughout

the period of organogenesis, using three dose levels

The route of administration should be the same as intended for human therapeutic use.

Teratogenicity Study (Segment Teratogenicity Study (Segment II):II):The control and the treated

groups should consist of at least 20 pregnant rats (or mice) and 12 rabbits, on each dose level.

All foetuses should to be subjected to gross examination,

Skeletal abnormalities and visceral abnormalities.

Teratogenicity Study (Segment Teratogenicity Study (Segment II):II):Observation parameters should

include: ◦ (Dams) signs of intoxication, ◦ effect on body weight, ◦ effect on food intake,◦ examination of uterus, ovaries and uterine

contents, ◦ number of corpora lutea, ◦ implantation sites, resorptions (if any); ◦ the foetuses, the total number, gender,

body length, weight and gross/ visceral/ skeletal abnormalities, if any.

1.3.31.3.3 Perinatal Study Perinatal Study (Segment III): (Segment III): This study is specially recommended

if the drug is to be given to pregnant or nursing mothers for long periods or where there are indications of possible adverse effects on foetal development.

One rodent species (preferably rat)

Perinatal Study (Segment III):Perinatal Study (Segment III):At least 4 groups (including control), each

consisting of 15 dams. The drug should be administered

throughout the last trimester of pregnancy and continued throughout lactation and weaning.

Dams should then be sacrificed and examined

Perinatal Study (Segment III):Perinatal Study (Segment III):Animals should be sacrificed at the end of

the study and the observation parameters should include ◦ (Dams) body weight, ◦ food intake, ◦ general signs of intoxication, ◦ progress of gestation/ parturition periods and

gross pathology (if any); ◦ pups, the clinical signs, sex-wise distribution in

dose groups, body weight, growth parameters, gross examination, survival and autopsy (if needed) and where necessary, histopathology.

1.41.4 Local toxicityLocal toxicity Required when the new drug is

proposed to be used by some special route (other than oral) in humans.

Applied to an appropriate site (e.g., skin or vaginal mucous membrane) to determine local effects in a suitable species.

Typical study designs for these studies should include three dose levels and untreated and/ or vehicle control, preferably use of 2 species

Local toxicityLocal toxicity Dermal toxicity study Photo-allergy or dermal photo-toxicity Vaginal Toxicity Test Rectal Tolerance Test Parenteral Drugs Ocular toxicity studies Inhalation

1.51.5 Allergenicity/ Allergenicity/ Hypersensitivity: Hypersensitivity: (i) Guinea Pig Maximization Test (ii) Local Lymph Node Assay

1.61.6 GenotoxicityGenotoxicity Genotoxic compounds, shall be

presumed to be trans-species carcinogens, implying a hazard to humans.

Such compounds need not be Subjected to long-term carcinogenicity studies.

However, if such a drug is intended to be administered for chronic illnesses or otherwise over a long period of time - a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects.

1.71.7 Carcinogenicity Carcinogenicity More than 6 months Drugs used frequently in an

intermittent manner in the treatment of chronic or recurrent conditions.

Structure-activity relationship suggests carcinogenic risk

1.8 Animal toxicity 1.8 Animal toxicity requirements for clinical trials requirements for clinical trials and marketing of a new drug.and marketing of a new drug.

Route of administration

Duration of proposed human administration

Human Phase(s) for which study is proposed to be conducted

Long term toxicity requirements

Oral or Parenteral or Transdermal

Single dose or several doses in one day, Upto 1wk

I,II,III 2sp,2wk

> 1 wk but upto 2wk I,II,III 2sp;4wk

> 2 wk but upto 4wk I,II,III 2sp;12wk

Over 1mo I,II,III 2sp;24wk

Inhalation (general anaesthetics, aerosols)

Upto 2 wk I,II,III 2sp;1mo; (Exposure time 3h/d, 5d/wk)

Upto 4wk I,II,III 2sp;12wk, (Exposure time 6h/d, 5d/wk)

> 1 4wk I,II,III 2sp;24wk, (Exposure time 6h/d, 5d/wk)

Dermal Upto 2 wk I,II 1sp;4wk

III 2sp;4wk

> 2 wk I,II,III 2sp;12wk

Ocular or Otic or Nasal

Upto 2 wk I,II 1sp;4wk

III 2sp;4wk


Vaginal or Rectal

Upto 2 wk I,II 1sp;4wk

III 2sp;4wk


1.9 Number of animals 1.9 Number of animals required for repeated-dose required for repeated-dose toxicity studiestoxicity studies

14-28 days 84-182 days

Group Rodent (Rat) Non-rodent(Dog or

Monkey)

Rodent (Rat) Non-rodent(Dog or Monkey)

M F M F M F M F

Control 6-10 6-10 2-3 2-3 15-30 15-30

4-6 4-6

Low dose 6-10 6-10 2-3 2-3 15-30 15-30

4-6 4-6

Intermediate dose

6-10 6-10 2-3 2-3 15-30 15-30

4-6 4-6

High dose 6-10 6-10 2-3 2-3 15-30 15-30

4-6 4-6

2.0 Laboratory 2.0 Laboratory parameters to be included parameters to be included in toxicity studies.in toxicity studies.Haematological parametersUrinalysis ParametersBlood Biochemical ParametersGross and Microscopic Pathology

Haematological Haematological parametersparameters

Haemoglobin Total RBC Count Haematocrit Reticulocyte

Total WBC Count Differential WBC Count

Platelet Count Terminal Bone Marrow Examination

ESR (Non-rodents only)

General Blood Picture: A special mention of abnormal and immature cells should be made.

Coagulation Parameters (Non-rodents only): Bleeding Time, Coagulation Time, Prothrombin Time, Activated Partial Thromboplastin Time

Urinalysis ParametersUrinalysis Parameters

Colour Appearance Specific Gravity

24-hour urinary output

Reaction (pH) Albumin Sugar Acetone

Bile pigments Urobilinogen Occult Blood

Microscopic examination of urinary sediment.

Blood Biochemical Blood Biochemical ParametersParameters

Glucose Cholesterol Triglycerides HDL Cholesterol (Non-rodents only)

LDL Cholesterol (Non-rodents only)

Bilirubin SGPT (ALT) SGOT (AST)

Alkaline Phosphatase (ALP)

GGT (Non-rodents only)

Blood Urea Nitrogen

Creatinine

Total Proteins Albumin Globulin (Calculated values)

Sodium

Potassium Phosphorus Calcium

Gross and Microscopic Gross and Microscopic PathologyPathology

Brain*: Cerebrum, cerebellum, Midbrain

(Spinal Cord) Eye (Middle Ear)

Thyroid (Parathyroid) Spleen* Thymus

Adrenal* (Pancreas) (Trachea) Lung*

Heart* Aorta Oesophagus Stomach

Duodenum Jejunum Terminal ileum Colon

(Rectum) Liver* Kidney* Urinary bladder

Epididymis Testis* Ovary Uterus*

Skin Mammary gland Mesenteric lymph node

Skeletal muscle

For Phase I studies:For Phase I studies:-Systemic toxicity Studiesi. Single dose toxicity studiesii. Dose Ranging studiesiii. Repeated dose systemic studies

of appropriate duration to support the duration of proposed human exposure.

- Male Fertility study- In-vitro Genotoxicity tests

For Phase I studies:For Phase I studies:Relevant local toxicity studiesAllergenicity/hypersensitivity testsPhoto-allergy or dermal photo-toxicity

test

Phase II Clinical TrialsPhase II Clinical Trials non-clinical safety data (listed previously)

already submitted while obtaining the permissions for phase I trial, with appropriate references.

directly starting Phase II trial – complete details of the non-clinical safety data needed for obtaining permission for Phase-I trial

Phase II Clinical TrialsPhase II Clinical TrialsRepeat dose systemic toxicity studies

of appropriate duration to support the duration of proposed human exposure.

In-vivo genotoxicity tests- Segment II

reproductive/developmental toxicity study

Phase III Clinical TrialsPhase III Clinical Trials

o Summary of all the non-clinical safety data already submitted while obtaining the permissions or Phase I and Phase II trials, with appropriate references

Directly starting Phase III trial – complete details of the non-clinical safety data needed for obtaining permission for Phase-I trial and Phase II

Repeat dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure

Phase III Clinical TrialsPhase III Clinical Trialso Reproductive/developmental toxicity studies.o Segment I* (if female patients of

reproductive age group are going to be involved) and

o Segment III* ( for drugs to be given to pregnant or nursing mothers or where there are indications of possible adverse effects on fetal development)

o Carcinogenicity studies ( when there is a cause for concern or when the drug is to be used for more than 6 months)

Phase IV Clinical TrialsPhase IV Clinical TrialsSummary of all the non-clinical safety

data already submitted while obtaining the permissions or Phase I and Phase II trials with appropriate references

Application Of Good Application Of Good Laboratory Practices (GLP)Laboratory Practices (GLP) The animal studies be conducted

in an accredited laboratory. Toxicology studies, also be

conducted in an accredited laboratory.

Appendix IVAppendix IV

Animal Pharmacology

Appendix IVAppendix IV1. General Principles:

In the early stages of drug development when enough information may not be available to select a study design for safety assessment a general approach to safety pharmacology studies can be applies.

Safety pharmacological studies: study the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure within or above the therapeutic range

Specific Pharmacological studiesGeneral Pharmacological studies

Appendix IVAppendix IV1.1 Specific Pharmacological Actions:

Demonstrate the therapeutic potential for humans.

Design of studies based on individual properties and intended uses of investigational drug.

Method used should be scientifically validated.

New technology and methodologies with sound scientific principles should be preferred.

Appendix IVAppendix IV1.2 general pharmacological actions

1.2.1 Essential safety pharmacology:-Investigate the potential undesirable effects of a

substance on physiological functions in relation to to exposure within and above the therapeutic range.

-studies should be designed to: Identify undesirable PD properties of a substance

that may have relevance to its human safety Evaluate adverse PD and/or pathophysiological

effects observed in toxicology and/or clinical studies

Investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected.

Appendix IVAppendix IV

Aim: study the effects of the test drug on vital functions such as CVS, RS and CNS

1.2.1 Essential Safety Pharmacology

1.3 Follow up & supplemental safety pharmacological studies:

ANS

Gastrointestinal SystemDependency potential, Immune Endocrine functions etc

Appendix IVAppendix IV1.6 Application of Good Laboratory

Practices:accredited laboratory. Toxicology studies - also be

conducted in an accredited laboratory.

Appendix VAppendix V Informed consent

Appendix VAppendix V1.Checklist for study subjects informed

consent documents1.1 Essential elements:1. Statement that the study involves

research & explanation for the purpose of research

2. Expected duration of subject’s participation

3. Description of procedures to be followed including invasive procedures

Appendix VAppendix V4. Description of any reasonably

foreseeable risks or discomforts to the subject.5. Description of any reasonably expected benefits to the subject or to others expected. If no benefit is expected the subject, be made aware of this.6. Specific alternative procedures or therapies available to the subject.

1.1 Essential Elements of ICF

Appendix VAppendix V7. Extent to which the confidentiality of

records identifying the subject will be maintained & person’s having access to Subject’s medical records.

8. Trial treatment schedule(s) and in case of randomized trials the probability for random assignment to each treatment.

9. Compensation &/or treatment available to the subject in the event of trial related injury.


Appendix VAppendix V10. Whom to contact for : - trial related queries, - rights of the subjects - in the event of any injury11. Anticipated prorated payment if any to the subject for participating in

the trial.12. Subject’s responsibilities on

participation in the trial.


Appendix VAppendix V13. Statement that the: - participation is voluntary - Subject can withdraw from

the study at any time - refusal to withdraw will not

involve any penalty or loss of benefits to which the subject is otherwise entitled.

14. Any other pertinent information.


Appendix VAppendix V1.2 Additional elements, which may

be required:a. Statement of foreseeable

circumstances under which the subject’s participation may be terminated by the Investigator without the subject’s consent.

b. Additional costs to the subject that may result from participation

Appendix VAppendix V

c. Consequences of a subject’s decision to withdraw from the study and procedures for orderly termination of participation.

d. Subject or subject’s representative will be notified in a timely manner of significant new findings

1.2 Additional elements, which may be required

Appendix VAppendix V

e. Particular treatment may involve risks to the subject/embryo/fetus, if the subject is or may become pregnant, which are currently unforseeable.

f. Approximate number of subjects enrolled in the study.

1.2 Additional elements, which may be required

Format of ICFFormat of ICF………. sign……….sign……….sign……….sign

SubjectInvestigatorWitness

Appendix VIAppendix VI Fixed Dose Combinations

(FDCs)

Appendix VIAppendix VIFDCs: products containing one or

more active ingredients used for a particular indication.

(a) First group: one or more of the active ingredients is a new drug.

- Data submitted for marketing approval will be similar that for any new drug (including clinical trials)

Appendix VIAppendix VI(b) (i) Second group: active ingredients

are already approved/marketed individually and are combined for the first time

-Reports of clinical trials carried out in other countries with the FDC.

- Regulatory status in other countries if marketed abroad.

Appendix VIAppendix VIFor marketing permission, appropriate

chemical and pharmaceutical data will be submitted

-In case such a combination is not marketed anywhere in the world but these drugs are already in use concomitantly (not as an FDC but individually) for the said claim, marketing permission may be granted based on chemical and pharmaceutical data.

-Data showing stability of the proposed dosage form will also have to be submitted.

Appendix VIAppendix VI(c) Third group: Those which are

already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim.

Data to be submitted for obtaining marketing permission:

- Appropriate rationale including published reports if any.

Appendix VIAppendix VI(d) Fourth group: those whose - individual active ingredients (or

drugs from the same class) have been widely used in a particular indication(s) for years

- Their concomitant use is often necessary

- No claim is proposed other than convenience.

Appendix VIAppendix VI(d) contd: Data required for marketing

permission:- stability- Ingredients are unlikely to have

significant interaction of a PD or PK nature

- No additional animal or human data are generally required

Appendix VIIAppendix VII

Undertaking from the Investigator

Appendix VIIAppendix VII1. - Full name - Address - Title of Principal Investigator (or Investigator if no PI)2. – Name & Address of the medical

college, hospital or facility. - Education training & experience of

the Investigator3. Name & address of all clinical

laboratory facilities

Appendix VIIAppendix VII4. Name and address of EC5. Name of other members of the

research team6. Protocol title & Study number (if

any)7. Commitments8. Signature of the Investigator

with Date.

Appendix VIIIAppendix VIII

Ethics Committee

Appendix VIIIAppendix VIII1.Atleast 7 members Chairperson from outside the institution and

a member secretary Quorum- 5 members with following

representation: (a) Basic medical scientists (preferably one

pharmacologist) (b) Clinicians (c) Legal expert (d) Social scientist/Nongovernmental

voluntary organisation/eticist/theologian etc. (e) Lay person

Appendix VIIIAppendix VIIIAtleast One person who is nonscientificAtleast One person who is independent

of the Institution/trial site.Appropriate gender representation.Subject experts or specific patient

groups may be invited if necessary.Only those EC members who are

independent of the clinical trial and the Sponsor should vote.

Appendix IXAppendix IX

Stability Testing Of New Drugs

Appendix-IXAppendix-IX Why do we need Stability testing?

Performed to provide evidence on 1. How the quality of a drug substance

or formulation varies with time under the influence of environmental factors like temperature, humidity & light.

2. To establish the shelf life for the formulation

3. Recommended storage conditions.

Appendix-XAppendix-X

Contents Of The Proposed Protocol For

conducting Clinical Trial

Appendix-XAppendix-X1. Title Page

a. Full title of the clinical study,b. Protocol/Study number & protocol

version number with datec. The IND name/number of the

investigational drugd. Complete name & address of the

Sponsor and Contract research organization if any

Appendix-XAppendix-XTitle Page contdTitle Page contd

e. List of Investigators conducting the study, their respective institutional affiliations and the site locations

f. Name(s)of clinical laboratories and other departments &/or facilities participating in the study.


2. Table of ContentsA complete Table of Contents

including a list of all Appendices.1. Background and Introductiona. Preclinical experienceb. Clinical experience


2. Study Rationale: brief summary of the background information relevant to the study design and protocol methodology.

Reasons for performing the study in the particular population included by the protocol.

3. Study Objective(s) (Primary as well as secondary) and their logical relation to the study.

Appendix-XAppendix-X4. Study Designa. Overview of the study design:

Including- A description of the type of study

(i.e., double blind, multicentric etc)- Detail of the specific treatment group- Number of study subjects in each

group and investigative site- Subject number assignment- Type, sequence and duration of

study periods.

Appendix-XAppendix-X5. Study Population:-Number of subjects required to be enrolled

in the study site- Number of subjects required to be enrolled

by all sites- Brief description of the population to

required is also mentioned.6. Subject eligibility:-Inclusion criteria-Exclusion criteria


7. Study Assessments- plan, procedures and methods to be described in detail.

8. Study Conduct: the type of study activities that would be included: medical history, type of physical examination, blood & urine testing, AE review etc.

Each visit should be described separately as visit1, visit2 etc.

Appendix-XAppendix-X8. Study conduct contd.- Discontinued subjects: Circumstances for

subject withdrawal, dropouts or other reasons for discontinuation of subjects.

Management of dropouts & if they would be replaced.

- Method of handling protocol waivers if any.Person(s) who approves all such waivers should be identified.Criteria used for specific waivers should be provided.

- Protocol violations: how it will be treated,Conditions where study will be terminated for noncompliance with the protocol.


9. Study Treatmenta. Dosing schedule: dose frequency &

duration of the experimental treatment.

- Administration of placebos &/or dummy medications if they are part of treatment plan.

- Concomitant drug(s), their doses, frequency, and duration of concomitant treatment should be stated.


b. Study drug supplies and administration: Details of

- who is going to provide the study medication & that the investigational drug formulation has been manufactured following all regulations.

- Product stability, storage requirements and dispensing requirements should be provided.


c. Dose modification for study drug toxicity: rules for changing the dose or stopping the study drug should be provided

d. Possible drug interactionse. Concomitant therapy: description of - drugs permitted and the conditions under

which they may be used.- Drugs that a subject is not allowed to use

during parts of or the entire study.- Any washout periods for prohibited

medications that are needed prior to enrolment

Appendix-XAppendix-Xf. Blinding procedures: A detailed

description of the blinding procedure if the study employs a blind.

g. Unblinding procedures: - Circumstances under which unblinding

may be done- mechanism used for unblinding 10. Adverse events: expected adverse

events should be described.

Appendix-XAppendix-X11. Ethical considerations:

Summary of:a. Risk/benefit assessmentb. Ethics committee review &

communicationsc. Informed consent processd. Statement of Subject

confidentiality including ownership pf data and coding procedures

Appendix-XAppendix-X12. Study Monitoring and Supervision: Description

of - Monitoring policies and procedures- Proposed frequency of monitoring visits- & who is expected to perform the monitring- Case Record Form(CRF) completing

requirements, who gets which copies of the form, specifics required in filling out the forms, CRF correction requirements, person authorized to make corrections on CRF and procedure for handling data queries and how errors are to be corrected.

Appendix-XAppendix-XInvestigator files: description of what needs

to be stored following study completion.

13. Investigational product management: a. Give Investigational product description

and packagingb. Precise dosing required during the studyc. Method of packaging, labeling and

blinding of study substancesd. Method of assigning treatments to study

subjects & the subject identification code numbering system.

Appendix-XAppendix-X13. Investigational product

management contd.e. Storage conditions for study

substancesf. IP accountability: instructions for

receipt, storage, dispensation and return of IP

g. Describe policy and procedure for handling unused IP.

Appendix-XAppendix-X14. Data analysis: Details of statistical approach to

be followed including - sample size- How the sample size was determined- Assumptions made in this determination- Efficacy end points ( primary as well as

secondary)- Safety end pointsStatistical analysis: Complete details of how the

results will be analyzed & reported along with description of statistical tests to be used to analyze the primary and secondary end points.

Appendix-XAppendix-X Statistical analysis contd.

olevel of significance, ostatistical tests to be used, and the omethods used for missing data; omethod of evaluation for treatment

failures, onon-compliance and subject withdrawals; orationale and conditions for any interim

analysis if planned.oDescribe statistical analysis for

Pharmacokinetic analysis (PK) if applicable.

Appendix-XAppendix-X15. Undertaking by the investigator 16. Appendices: Provide

- Study synopsis- Copies of informed consent documents- CRF and other data collection forms- Summary of relevant pre-clinical safety

information and any other documents referenced in the clinical protocol.

Appendix-XIAppendix-XI

Data Elements For Reporting Serious Adverse Events

Occurring In A Clinical Trail

Appendix-XIAppendix-XI1. Patient Details- Initials & other relevant identifier

(hospital/ OPD record number etc)*

- Gender- Age &/or date of birth- Weight- Height

Appendix-XIAppendix-XI2. Suspected Drug(s)- Generic name of the drug*- Indication(s) for which suspect drug

was prescribed or tested- Dosage form and strength- Daily dose & regimen (specify units-

e.g. mg, ml, mg/kg)- Route of administration- Starting date & time of the day- Stopping date and time, or duration of

treatment

Appendix-XIAppendix-XI3.. Other treatment(s)- Provide the same information for concomitant

drugs (including non prescription/OTC drugs) & non drug therapies, as for the suspected drug(s)

4. Details of suspected Adverse Drug Reaction(s)- Full Description of reaction(s) including: - body site - severity - criterion for considering the report as serious.In addition to the description of signs &

symptoms whenever possible describe a specific diagnosis for the reaction.*

Appendix-XIAppendix-XI4. Details of ADR(s) contd.- Start date (& time) of onset of

reaction- Stop date (& time) of duration of

reaction- Dechallenge and rechallenge

information- Setting (e.g., hospital, out-patient

clinic, home, nursing home)

Appendix-XIAppendix-XI5. Outcome- Information on recovery and any sequelae- Results of specific tests &/or treatment that

may have been conducted for a fatal outcome.

- Cause of death & a comment on its possible relationship to the suspected reaction

- Any postmortem findings- Other information: any relevant information

to facilitate assessment of the case e.g. medical history including allergy, family history of drug or alcohol abuse etc.

Appendix-XIAppendix-XI6. Details about Investigator*- Name- Address- Telephone number- Profession(Speciality)- Date of reporting the event to the

Licensing Authority- Date of reporting the event to Ethics

Committee over seeing the site- Signature of the Investigator#”Information marked* must be provided”

“Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study.

“Investigator(s) shall report all serious and unexpected adverse events to the Sponsor within 24 hours and to the Ethics Committee that accorded approval to the study protocol within 7 working days of their occurrence”.

24 H

7 D14 D

14 D

Loopholes in Schedule YLoopholes in Schedule Y

New drug remains new for 4 years. Thus, Phase IV trials require permission. However, Approved drug and indication need not require permission.

Approval of Amendment could be a problem.

SOPs for investigators and documentation of tasks – Template required.

Unmet medical needs to be added to CT waiver.

Loopholes in schedule YLoopholes in schedule Y

EC chairman outside institute is a rarity.

Exhaustive species data (App.I-A)and comparative evaluation (App. I) not helpful for differentiation.

Requirement to support data protection

Unattended AreasUnattended AreasRegulations for :1. Biologics : vaccines

Blood products Tissue Cellular/gene therapy

2. Herbals3. Medical devices 4. Pharmacovigilance5. Electronic records