Schedule Y

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Schedule Y:

Schedule Y By: Kirtikrishna


Appendices I : Data required for import/manufacture/ conduct CT of new drugs I A : …. Drugs approved in other country II : Format for clinical study reports(ICH E6) III : Animal toxicology IV : Animal pharmacology V : Informed consent


Appendices VI : FDC VII : Undertaking by the investigator VIII : Ethics committee IX : Stability testing X : Proposed protocol XI : SAE Reporting




APPENDIX I 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 Samples and Testing Protocol/s


APPENDIX I 1.Introduction brief description of the drug therapeutic class to which it belongs. 2. Chemical and pharmaceutical information 2.1.  Information on active ingredients Drug information (Generic Name, Chemical Name or INN)

2.2. Physicochemical Data:

2.2. Physicochemical Data a. Chemical name and Structure Empirical formula Molecular weight b. Physical properties Description Solubility Rotation Partition coefficient Dissociation constant

2.3.      Analytical Data:

2.3.      Analytical Data Elemental analysis Mass spectrum NMR spectra IR spectra UV spectra Polymorphic identification

2.4. Complete monograph specification including:

2.4. Complete monograph specification including Identification Identity/quantification of impurities Enantiomeric purity Assay

2.5. Validations:

2.5. Validations Assay method Impurity estimation method Residual solvent/other volatile impurities (OVI) estimation method

2.6.  Stability Studies:

2.6.  Stability Studies Final release specification Reference standard characterization Material safety data sheet

2.7. Data on Formulation:

2.7. Data on Formulation Dosage form Composition Master manufacturing formula Details of the formulation In process quality control check Finished product specification Excipient compatibility study Validation of the analytical method

Data on Formulation (Contd..):

Data on Formulation (Contd..) Comparative evaluation with international brand(s) or approved Indian brands, Pack presentation Dissolution Assay Impurities

Data on Formulation (Contd..):

Data on Formulation (Contd..) Content uniformity pH Force degradation study Stability evaluation in market intended pack at proposed storage conditions Packing specifications Process validation

3.      Animal Pharmacology:

3. Animal Pharmacology 3.1.      Summary 3.2.      Specific pharmacological actions 3.3.      General pharmacological actions 3.4. Follow-up and Supplemental Safety Pharmacology Studies 3.5.      PK

4.      Animal Toxicology:

4. Animal Toxicology 4.1.      General Aspects 4.2.      Systemic Toxicity Studies 4.3.      Male Fertility Study 4.4.      Female Reproduction and Developmental Toxicity Studies 4.5.      Local toxicity 4.6.      Allergenicity/Hypersensitivity 4.7.      Genotoxicity 4.8.      Carcinogenicity

5.  Human / Clinical pharmacology (Phase I):

5. Human / Clinical pharmacology (Phase I) 5.1.      Summary 5.2.      Specific Pharmacological effects 5.3.      General Pharmacological effects 5.4.      PK 5.5.      PD / early measurement of drug activity

6.      Therapeutic exploratory trials (Phase II):

6. Therapeutic exploratory trials (Phase II) 6.1.      Summary 6.2.      Study report(s) as given in Appendix II

7.      Therapeutic confirmatory trials (Phase III):

7. Therapeutic confirmatory trials (Phase III) 7.1.      Summary 7.2.      Individual study reports with listing of sites and Investigators

8.      Special studies:

8. Special studies 8.1.      Summary 8.2.      BA/BE 8.3 Other studies e.g. geriatrics, paediatrics, pregnant or nursing women

9.      Regulatory status in other countries:

9. Regulatory status in other countries 9.1.  Countries where the drug is a. Marketed b. Approved c. Approved as IND d. Withdrawn, if any, with reasons 9.2.   Restrictions on use, if any, in countries where marketed /approved 9.3.   Free sale certificate or certificate of analysis, as appropriate.

10.  Prescribing information:

10. Prescribing information 10.1.   Proposed full prescribing information 10.2.   Drafts of labels and cartons

11.  Samples and Testing Protocol/s:

11. Samples and Testing Protocol/s 11.1.   Samples of pure drug substance and finished product, with testing protocol/s, full impurity profile and release specifications.




APPENDIX I-A 1. Introduction 2. Chemical and pharmaceutical information 3. Marketing information 4. Special studies conducted with approval of Licensing Authority

2. Chemical and pharmaceutical information:

2. Chemical and pharmaceutical information 2.1 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 composition 2.3 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 information:

3. Marketing information 3.1 Proposed package insert / promotional literature 3.2 Draft specimen of the label and carton

4. Special studies conducted with approval of Licensing Authority:

4. Special studies conducted with approval of Licensing Authority 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 II:


Appendix II:

Appendix II Title Page Study Synopsis (1 to 2 pages) GCP Compliance List of Abbreviations and Definitions Table of contents Ethics Committee Study Team Introduction - product development rationale Study Objective Investigational Plan - design

Appendix II:

Appendix II 11. 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 II:

Appendix II 16. Appendices: Protocol and amendments Specimen of Case Record Form Investigators name(s) with contact addresses, phone, email etc. Patient data listings List of trial participants treated with IP. Discontinued participants

Appendix II Appendices to Clinical trial report:

Appendix II Appendices to Clinical trial report Protocol deviations CRFS of cases involving death and life threatening AEs Publications from the trial Important publications referenced in the study Audit certificate, if available Investigator’s certificate

Appendix III:


Appendix III:

Appendix III General Principles Laboratory parameters to be included in toxicity studies

General Principles:

General Principles GLP, Qualified staff Calibrated standardized equipments SOPs Test substances and test systems characterized and standardized Documents - 5 years (Histo slides, blocks) Toxicokinetic studies (– dose – tox)

1.1 Systemic Toxicity Studies:

1.1 Systemic Toxicity Studies 1.1.1 Single-dose Toxicity Studies 2 rodent species (mice and rats) using the same route as intended for humans

Single-dose Toxicity Studies:

Single-dose Toxicity Studies Target 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 LD 10 and LD 50 95% CI

1.1.2  Repeated-dose Systemic Toxicity Studies:

1.1.2 Repeated-dose Systemic Toxicity 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 Toxicity Studies:

Repeated-dose Systemic Toxicity Studies Drug 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 Toxicity Studies:

Repeated-dose Systemic Toxicity Studies The 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

1.2  Male Fertility Study:

1.2 Male 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 Study:

Male Fertility Study Drug 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.

1.3   Female Reproduction and Developmental Toxicity Studies :

1.3 Female Reproduction and Developmental Toxicity Studies Carried out for all drugs proposed to be studied or used in women of child bearing age.

1.3.1 Female Fertility Study (Segment I): :

1.3.1 Female Fertility 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 (Segment I)::

Female Fertility Study (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 (Segment I)::

Female Fertility Study (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 (Segment I)::

Female Fertility Study (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

1.3.2   Teratogenicity Study (Segment II): :

1.3.2 Teratogenicity Study (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 II)::

Teratogenicity Study (Segment 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 II)::

Teratogenicity Study (Segment 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.

1.3.3   Perinatal Study (Segment III): :

1.3.3 Perinatal Study (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.

1.4 Local toxicity :

1.4 Local 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 toxicity:

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

1.5 Allergenicity/ Hypersensitivity: :

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

1.6       Genotoxicity :

1.6 Genotoxicity 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.

1.7  Carcinogenicity :

1.7 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 requirements for clinical trials and marketing of a new drug.:

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

Slide 61:

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)

Slide 62:

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 > 2 wk I,II,III 2sp;12wk Vaginal or Rectal Upto 2 wk I,II 1sp;4wk III 2sp;4wk > 2 wk I,II,III 2sp;12wk

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

1.9 Number of animals required for repeated-dose toxicity 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 parameters to be included in toxicity studies.:

2.0 Laboratory parameters to be included in toxicity studies. Haematological parameters Urinalysis Parameters Blood Biochemical Parameters Gross and Microscopic Pathology

Haematological parameters:

Haematological parameters 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 Parameters :

Urinalysis 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 Parameters :

Blood Biochemical Parameters 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 Pathology :

Gross and Microscopic Pathology 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 Studies Single dose toxicity studies Dose Ranging studies 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 studies Allergenicity/hypersensitivity tests Photo-allergy or dermal photo-toxicity test

Phase II Clinical Trials:

Phase 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 Trials:

Phase II Clinical Trials Repeat 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 Trials:

Phase III Clinical Trials 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 Trials:

Phase III Clinical Trials Reproductive/developmental toxicity studies. Segment I* (if female patients of reproductive age group are going to be involved) and Segment III* ( for drugs to be given to pregnant or nursing mothers or where there are indications of possible adverse effects on fetal development) 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 Trials :

Phase IV Clinical Trials Summary 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 Laboratory Practices (GLP) :

Application Of Good Laboratory Practices (GLP) The animal studies be conducted in an accredited laboratory. Toxicology studies, also be conducted in an accredited laboratory.

Appendix IV:

Appendix IV Animal Pharmacology

Appendix IV:

Appendix IV 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 studies General Pharmacological studies

Appendix IV:

Appendix IV 1.1 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 IV:

Appendix IV 1.2 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 IV:

Appendix 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 System Dependency potential, Immune Endocrine functions etc

Appendix IV:

Appendix IV 1.6 Application of Good Laboratory Practices: accredited laboratory. Toxicology studies - also be conducted in an accredited laboratory.

Appendix V:

Appendix V Informed consent

Appendix V:

Appendix V 1.Checklist for study subjects informed consent documents 1.1 Essential elements: Statement that the study involves research & explanation for the purpose of research Expected duration of subject’s participation Description of procedures to be followed including invasive procedures

Appendix V:

Appendix V 4. 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 V :

Appendix V 7. 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. 1.1 Essential Elements of ICF

Appendix V :

Appendix V 10. Whom to contact for : - trial related queries, - rights of the subjects - in the event of any injury 11. Anticipated prorated payment if any to the subject for participating in the trial. 12. Subject’s responsibilities on participation in the trial. 1.1 Essential Elements of ICF

Appendix V :

Appendix V 13. 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. 1.1 Essential Elements of ICF

Appendix V:

Appendix V 1.2 Additional elements, which may be required: Statement of foreseeable circumstances under which the subject’s participation may be terminated by the Investigator without the subject’s consent . Additional costs to the subject that may result from participation

Appendix V :

Appendix 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 V :

Appendix 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 ICF:

Format of ICF ………. sign ……….sign ……….sign ……….sign Subject Investigator Witness

Appendix VI:

Appendix VI Fixed Dose Combinations (FDCs)

Appendix VI:

Appendix VI FDCs: products containing one or more active ingredients used for a particular indication. 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 VI:

Appendix 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 VI:

Appendix VI For 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 VI:

Appendix 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 VI:

Appendix 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 VI:

Appendix 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 VII :

Appendix VII Undertaking from the Investigator

Appendix VII:

Appendix VII 1. - 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 Investigator 3. Name & address of all clinical laboratory facilities

Appendix VII:

Appendix VII 4. Name and address of EC 5. Name of other members of the research team 6. Protocol title & Study number (if any) 7. Commitments 8. Signature of the Investigator with Date.

Appendix VIII:

Appendix VIII Ethics Committee

Appendix VIII:

Appendix VIII 1.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 VIII:

Appendix VIII Atleast One person who is nonscientific Atleast 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 IX:

Appendix IX Stability Testing Of New Drugs


Appendix-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. To establish the shelf life for the formulation Recommended storage conditions.


Appendix-X Contents Of The Proposed Protocol For conducting Clinical Trial


Appendix-X Title Page Full title of the clinical study, Protocol/Study number & protocol version number with date The IND name/number of the investigational drug Complete name & address of the Sponsor and Contract research organization if any

Appendix-X Title Page contd:

Appendix-X Title 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.

Appendix-X :

Appendix-X 2. Table of Contents A complete Table of Contents including a list of all Appendices. Background and Introduction Preclinical experience Clinical experience

Appendix-X :

Appendix-X 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-X :

Appendix-X 4. Study Design 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-X :

Appendix-X 5. 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

Appendix-X :

Appendix-X 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-X :

Appendix-X 8. 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.

Appendix-X :

Appendix-X 9. Study Treatment 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.

Appendix-X :

Appendix-X 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.

Appendix-X :

Appendix-X c. Dose modification for study drug toxicity: rules for changing the dose or stopping the study drug should be provided d. Possible drug interactions e. 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-X f. 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-X 11. Ethical considerations: Summary of: Risk/benefit assessment Ethics committee review & communications Informed consent process Statement of Subject confidentiality including ownership pf data and coding procedures


Appendix-X 12. 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-X Investigator files: description of what needs to be stored following study completion. 13. Investigational product management: Give Investigational product description and packaging Precise dosing required during the study Method of packaging, labeling and blinding of study substances Method of assigning treatments to study subjects & the subject identification code numbering system.


Appendix-X 13. Investigational product management contd. e. Storage conditions for study substances f. IP accountability: instructions for receipt, storage, dispensation and return of IP g. Describe policy and procedure for handling unused IP.


Appendix-X 14. 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 points Statistical 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-X Statistical analysis contd. level of significance, statistical tests to be used, and the methods used for missing data; method of evaluation for treatment failures, non-compliance and subject withdrawals; rationale and conditions for any interim analysis if planned. Describe statistical analysis for Pharmacokinetic analysis (PK) if applicable.


Appendix-X 15. 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-XI Data Elements For Reporting Serious Adverse Events Occurring In A Clinical Trail


Appendix-XI 1. Patient Details - Initials & other relevant identifier (hospital/ OPD record number etc)* Gender Age &/or date of birth Weight Height


Appendix-XI 2. 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-XI 3. . 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-XI 4. 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-XI 5. 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-XI 6. 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”

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“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.

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“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”.

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24 H 7 D 14 D 14 D

Loopholes in Schedule Y:

Loopholes 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 Y:

Loopholes 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 Areas:

Unattended Areas Regulations for : 1. Biologics : vaccines Blood products Tissue Cellular/gene therapy Herbals Medical devices Pharmacovigilance Electronic records

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Thank you

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