Schedule Y Guidelines

• Clinical Trial – at a glance……:•Sponsor/ CRO

•R&D

Investigator Selection

•Subject Recruitment

•Sponsor/ CRO

Clinical Trials

Statistical Analysis

Data Entry & Review

Approved Protocol

SAE/ Amendment

Schedule Y Guidelines:• Schedule Y Guidelines Requirements and Guidelines

for Permission to Import and /or Manufacture of New Drugs for Sale or to undertake Clinical Trials

• Rules 122A,122B,122D,122DA,122DAA and 122E • It has outlined extensive study criteria in line with

the globally accepted formats such as ICH and US FDA guidelines

Drug & Cosmetics Rule, 1945:• Rules 122A,122B,122D,122DA,122DAA and 122E

• 122A : Appln. for permission to Import of Drugs • 122B : Appln. for approval to Manufacture of Drug • 122D : Permission to import/manufacture Fixed Dose Concentration • 122DA : Permission to conduct Clinical Trials • 122DAA : Clinical Trial Definition:

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

• 122E : New Drug Definition: • 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 • Vaccines are new drugs unless otherwise certified • Considered new drug for 4 yrs from date of first approval or inclusion in IP

• Investigational new drug: New chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings

• Purpose:– Purpose To frame guidelines for conduct of

Clinical Research – Creating opportunities for Foreigners in India – Control and Regulation for new drugs – CDSCO and DTAB formulated GCP under Schedule

Y in 2005.

Why India…:• Large patient population with diverse gene pool • Potential for multi patient recruitment at major

cities across the country • Majority of investigators western educated Pool

of Highly skilled and well trained doctors, investigators, and medical personnel

• Compliance with International regulatory and GCP standards.

• Low Trial Cost

Requirements and Guidelines on Clinical Trials for Import/Manufacture of a New Drug:• Application for permission

• Chemical and pharmaceutical information • Animal pharmacology data • Animal toxicology data • Human clinical pharmacology data • Permission for different stages of CT • Regulatory status in other countries for IP • Full prescribing information • Complete testing • Others…

• Approval for Clinical Trials • Human pharmacology (Phase I) • Therapeutic exploratory trials (Phase II) • Therapeutic confirmatory trials (Phase III) • Post Marketing trials (Phase IV) • Studies in special populations • Special studies • Fixed Dose Concentration

• Responsibilities … • Sponsor • Monitor • Investigator • Informed consent • Ethics committee

• Post marketing surveillance • PSUR

• Application for permission :• Application for permission Application for

permission to import or manufacture new drugs for sale or to undertake clinical trials shall be made in Form 44 (Schedule A)

• The following data need to be submitted along with filled Form 44.

(I) Chemical and Pharmaceutical information (item 2 of Appendix I):

Appendix I • Item 2 Chemical and Pharmaceutical information

of Investigational new drug • 2.1. Information on active ingredients• 2.2. Physicochemical Data 2.3. Analytical Data• 2.4. Complete monograph specification • 2.5. Validations (for methodology) • 2.6. Stability Studies (Appendix IX) • 2.7. Data on Formulation (and Forced stability

studies)

(II) Animal Pharmacology Data (item 3 of App. I & App. IV):• This information gives Efficacy of New drug • General Principles: Specific and general pharmacological

studies should be conducted to support use of therapeutics in humans.

• (a) Specific pharmacological actions ( Item 3.2 of App. I ): Therapeutic potential for humans described according to animal models used. If possible Dose-response relationships and ED 50s shall be submitted. Special studies should be conducted & designed based on the individual properties & intended uses of IP. Scientifically validated, new technology/methods should be used.

Cont…..:• Cont ….. (b) General Pharmacological Actions ( 3.3 of

App. I) (Essential Safety Pharmacology )( item 1.2 of App. IV ) • Safety pharmacological studies need to be conducted to

investigate the potential undesirable pharmaco dynamic effects of a substance on physiological functions in therapeutic range and above.

• Aim to study the effects of test drug on vital functions of vital organs and systems like Cardiovascular system, CNS and Respiratory system.

• (c) Pharmacokinetic Data ( 3.5 of App. I ) - ADME studies of test substance This helps to relate the drug effect with plasma concentration and should be given to the extent available.

(III) Animal Toxicology Data (item 4 of App. I & App. III):

• Principle: Toxicokinetics studies to assess the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study.

• Objectives: To relate these data to clinical safety, choice of species, to design and treatment regimen in non-clinical toxicity tests and its findings.

• All animals are more tolerable than humans. So multiple levels of drug dosages need to be given for animals to check drug toxicity effect.

• This study should comply with the norms of GLP. SOPs should be followed for all laboratory tasks and all the data need to be preserved at least for 5 yrs after making the drug.

Systemic Toxicity Studies (item 4.2 of App. I):Acute toxicity/ single dose toxicity: • This studies should be carried out at least in 2 rodent species (mice

& rats) using the same route as intended for humans. • In addition at least two more routes should be used to ensure

systemic absorption of the drug. • A limit of 2 g/kg (or 10 times the normal dose that is intended in

humans, whichever is high) is recommended for oral dosing. • Animals should be observed for 14 days after the drug

administration and MLD, MTD & LD 50s should be established. • The target organ toxicity should also be determined. • Mortality should be looked for

– up to 72 hrs after parentral administration and – up to 7 days after oral administration.

• Symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary.

Cont…:

Long-term toxicity/Repeated- Dose toxicity:

• These studies should be carried out in at least 2 mammalian species, of which one should be a non-rodent.

• Duration of the study will depend on whether the application is for marketing purpose or clinical trials.

• In these studies drug should be administered 7 days a week by the route intended for clinical use in humans.

• A minimum number of animals required on which data should be available. • Dose ranging studies should precede the 14-, 28-, 90- or 180- days toxicity studies. • The parameters should include behavioral, physiological, biochemical and

microscopic observations. • These studies are appropriate for compounds with long half-life, incomplete

elimination or unanticipated organ toxicity. The longest chronic toxicity study duration is 9-12 months.

• Control group of animals should also be included for the comparison of TD and ED

b) Reproduction Studies (item 4.3-4.4 of App. I & App. III):• Male Fertility Study (4.3)

• At least one rodent species should be used (rat). • Dose selection should be done from the results of the previous

14/28 days toxicity study in rat. • They should be treated with test drug min. of 28 days and max.

of 70 days before they are paired with female animals of proven fertility in a ratio of 1:2 for mating.

• Drug treatment of the male animals should be continued during pairing and pairing should continue till the detection of vaginal plug/10 days.

• 3- graded dose should be used and all the animals are sacrificed at the end and parameters are tested/observed.

• This study should be done prior to Phase III trials.

Cont…..:• Female Reproduction and Developmental Toxicity Studies ( 4.4 of

App. I ) • This study need to carried out if the new drug is proposed to study or

use in women on childbearing age • Segment I,II & III studies performed in albino mice/rats • Segment II study should also include albino rabbits. • 3- graded dose should be used for all the studies • Route of drug administration should be same as intended for human

therapeutic use • All test animals are sacrificed at the end of the study • Observation parameters (S-I &III):

• Dams: Body weight, food intake, clinical signs of intoxication, mating behavior, progress of gestation/partuition periods, length of gestation, parturition, post-partum health and gross pathology, histopathology of affected organs should be recorded.

• Pups : general signs of intoxication, sex-wise distribution in different treatment groups, body weight, growth parameters, survival, gross examination, autopsy, histopathology

Cont...:• Segment I: Carried out in one rodent species (rat) Drug should be

administered to both male and female before & during mating and also during gestation period.

• Segment II: One rodent (rat) and one non-rodent (rabbit) species need to be used. Drug should be administered throughout the period of organogenesis.

• observation: • Dams: signs of intoxication, body weight, food intake, examination of

uterus, ovaries, uterine contents, number of corpora lutea, implantation sites, resorptions.

• Foetus: Total number of gender, body length, weight, gross/visceral/skeletal abnormalities.

• Segment III: This study is recommended only if the drug is to be given to pregnant/nursing women for long periods (effect on unborn/litters). One rodent species (rat) need to be used. Drug is administered throughout the last trimester of pregnancy and continued till lactation weaning. Possible adverse effect on foetus need to be studied.

c) Local Toxicity (Item 4.5 of App. I & App. III):• These studies required when the new drug is proposed to be used

by some specific route (other than oral) in humans.• The drug should be applied to an appropriate site to determine

local effects in a suitable species such as guinea pigs or rabbits, if the drug is absorbed from the site of application, toxicity studies will also be required. • Dermal toxicity study – rabbit and rat • Photo-allergy/ dermal photo-toxicity – guinea pigs• Vaginal toxicity test – rabbit/dog (cream/ointment) • Rectal – tolerance test – rabbits/dogs • Parenteral drugs – intravenous/intramuscular/ subcutaneous/

intradermal injection • Ocular toxicity studies – albino rabbit • Inhalation toxicity studies – rodent and non-rodent species

d) Allergenicity / Hypersensitivity (item 4.6 of App. I & App. III):

• Standard tests include… • Guinea Pig Maximization Test (GPMT): The test is to be

performed in two steps; first, determination of maximum nonirritant and minimum irritant doses, and second, the main test. 4 dose level should be done. Minimum of 6 animals in each group is mandatory.

• Local Lymph Node Assay (LLNA): Mice used in this test should be of the same sex, either only males or only females. Drug treatment is to be given on ear skin. Minimum of 6 animals need to be used in each group. 3- graded dose level studies need to be done.

e) Mutagenicity / Carcinogenicity (item 4.7-4.8 of App. I, App. III):

• Studies are required to be carried out if the drug or its metabolite is related to a known carcinogen or when the nature and action of the drug is such as to suggest a carcinogenic/mutagenic potential.

• For carcinogenicity studies, at least two species should be used • Species should not have high incidence of spontaneous tumors and

should preferably be known to metabolize the drug in the same manner as humans.

• At least three dose levels should be used; the highest dose should be sub-lethal but cause observable toxicity; lowest dose should be comparable to the intended human therapeutic dose or a multiple of it. A control group should always be included.

• (IV) Human Clinical Pharmacology Data (item 5,6,7 of App. I):

• I) Appendix I: • Item 5 Human / Clinical pharmacology (Phase I)

• 5.1 Summary • 5.2 Specific Pharmacological effects • 5.3 General Pharmacological effects • 5.4 Pharmacokinetics (ADME) • 5.5 Pharmacodynamics / early measurement of drug activity

• Item 6 Therapeutic exploratory trials (Phase II) • 6.1 Summary • 6.2 Study report(s) (Appendix II – Format of CSR)

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

• (V) Permission for Clinical Trials:• A. New drug discovered in India – Clinical trials required to be

carried out in India right from Phase I and data should be submitted as required under items 1,2,3,4,5 and 9 of Appendix I . • Item 1 Introduction • 2 Chemical and Pharmaceutical information • 3 Animal Pharmacology (App. IV) • 4 Animal toxicology (App. III) • 5 Human/Clinical Pharmacology (Phase I) • 9 Regulatory status in other countries

• 9.1 Countries where the drug is Marketed, Approved, Approved as IND, withdrawn, if any , reasons

• 9.2 Restrictions on use • 9.3 Free sale certificate / certificate of analysis

• Cont......:• B. New drug discovered other than India – Phase I data

as required under item 1,2,3,4,5 (from other countries) 9 of App. I should be submitted along with application. • Legal Authority will permit to repeat Phase I trials or to

conduct Phase II trials subsequently Phase III (must in India).

• C. Data required will depend on the purpose of NDA. Number of sites, number of subjects depend upon the nature/objective of study. • Permission to carry out these trials will be given in stages.

Cont….:

• D. Application for permission should include • Investigator Brochure, • Proposed Protocol ( App. X- contents of the proposed protocol for conducting clinical trials) • Case Record Form • Informed Consent Form ( App. V- Format for ICF) • Investigator’s undertaking ( App. VII- complete Investigator details) • Ethics Committee clearance ( App. VIII – Format of Approval of EC

• E. Reports of all Clinical Studies • Item 5,6 and 7 of App. I (Phase I,II,III) • Item 8 – Special Studies of App. I • 8.1 Summary • 8.2 BA/BE Studies • 8.3 Other Studies – Geriatrics, Pediatrics, Pregnant / Nursing women

All these reports should be submitted in the Format of CSR (Clinical Study Report – App. II ) and certified by Principal Investigator / all Investigators from all sites. Each page should be numbered.

(VI) Regulatory Status in Other Countries (item 9.2 of App. I):

• It is important to state the details about the restrictions on use in other countries where the drug is marketed/approved need to be given (e.g. Dosage limits, restriction for certain age groups, adverse drug reactions, etc.)

• Likewise, if the drug is withdrawn from any country by manufacturer/RA, such information also need to be included with reasons.

• These details should be submitted by Sponsors to LA to market those drugs in India.

(VII) Full Prescribing Information (item 10 of App. I):• Appendix I : Item 10 Prescribing information

• 10.1 Proposed full prescribing information • 10.2 Drafts of labels and cartons

Full prescribing information should be submitted to LA for approval (e.g. generic name; composition; dosage form/s, indications; dose and method of administration; use in special populations (such as pregnant women, lactating women, pediatric patients, geriatric patients etc.) ; contra-indications; warnings; precautions; drug interactions; undesirable effects; overdose; pharmacodynamic and pharmacokinetic properties; incompatibilities; shelf-life; packaging information; storage and handling instructions)

If there is any change in the package insert after approval, that also need to be approved by LA.

(VIII) Complete testing (item 11 of App. I – Samples and Testing Protocols):• Protocols for quality control, full impurity profile and

release specifications need to be furnished to RA. • If the study drug is intended to be imported for the

purposes of examination, test or analysis, the application for import of small quantities of drugs for such purpose should also be made in Form 12.

• For drugs indicated in life threatening / serious diseases or diseases of special relevance to the Indian health scenario, the toxicological and clinical data requirements may be abbreviated, deferred or omitted, as deemed appropriate by the Licensing Authority.

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 Committee.

• All trial sites need to get approval for protocol from EC • All trial Investigators should possess relevant qualification, training and

experience, laboratories should complaint with Good Laboratory Practices.

• If services of a lab or facilities outside the country are to be availed, those details should be furnished to LA

• Protocol amendments at any stage should be notified to LA/EC and those changes need to be approved.

• Exceptions in case of immediate hazards elimination to the subject(s) or changes involves logistic/administrative aspects of the trial.

• Such exceptions must be immediately notified to EC & LA within 30 days

Phases of Clinical Trails:

Clinical trials are to find out whether a medication/treatment regimen is safe and effective for the treatment of a specific condition/disease. • Human Pharmacology (Phase I)

• Objectives: • To test safety and tolerability (non-therapeutic) of a potential new

product with a small number of healthy volunteers, usually between 50-100 for best dosage and potential side effects.

• Investigators must be trained in clinical pharmacology • Studies include…

• a. Maximum tolerated dose • b. Pharmacokinetics • c. Pharmacodynamics • d. Early Measurement of Drug Activity

Cont….:• Therapeutic exploratory trails (Phase II) • Objectives: • To evaluate the effectiveness of a new drug for

particular indication in patients with known side effects. • Larger population (only patients) around 100-500 • Relatively homogeneous population • To determine the dose and regiment for Phase III trials • Doses usually less than the highest doses used in phase

I

Cont….:• Therapeutic confirmatory trials (Phase III) • Objectives:

• To compare the new product with a commonly used product for both safety and efficacy

• Population between 1500-4000 • For chronic diseases patients tested for 1-3 yrs, if successful NAD

need to be submitted and approved by Regulatory agencies

• Post Marketing Trials (Phase IV) • Objectives:

• Conducted after product approval and launched • Continue to evaluate a product’s long term effects • Population between 2000-5000 patients • To optimize drug’s use, drug-drug interactions, epidemiological

studies, etc.

• Studies in Special Populations:• Geriatrics :

• the disease intended to be treated is characteristically a disease of aging

• to include substantial numbers of geriatric patients in study • If the expected conditions common in geriatrics • If new drug alters therapeutic responses in geriatircs

• Pediatrics : • For new drug having potential for use in children, permission

for CT in the paediatric age group is normally given after phase III trails as required, in adults are completed.

• However, if the drug is of value primarily in a disease of children, early trials in the paediaric age group may be allowed.

• They are legally unable to provide ICF, so it can be taken from legally authorised representatives.

Cont…..:• Pregnant / Nursing Women: • They should be included in clinical trials only when

the drug is intended for use by pregnant/nursing women or foetuses/nursing infants.

• New drugs intended for use during pregnancy, follow-up data is required.

• Excretion of the drug/its metabolites into human milk should be examined and the infant should be monitored for predicted pharmacological effects of the drug.

• Special studies:• Include studies on solid oral dosage forms, such as BA and

dissolution studies. These are required to be submitted on the formulations manufactured in the country. (App. I items. 8.1, 8.2)

• These include studies to explore additional aspects of the drug. e.g. use in elderly patients or patients with renal failure, secondary or ancillary effects, interactions, etc

• For drugs approved elsewhere in the world and absorbed systemically, BE with reference formulation should be carried out.

• All BA/BE studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed. • BA: refers to a relative amount of drug from an administered dosage

from which enters the systemic circulation and the rate at which the drug appears in the systemic circulation.

• BE: achieved , if its extent and rate of absorption are not statistically significantly different from those of the reference product when administered at the same Molar dose.

Fixed Dose Combination:Date requirements of Fixed Dose Combinations:FDC fall into four groups and their data requirements

accordingly ( App. VI ). • 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 • Third group of FDC includes 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.

• The fourth group of FDC includes those whose individual active ingredients have been widely used.

Responsibilities…:• Sponsor: who initiates a clinical investigation and who does not

conduct the investigation ( 21 CFR part 50.3 Definition ). • Sponsors should submit annual status report to Licensing Authority on

each clinical trial, namely, ongoing, completed, or terminated (Rule 21).

• Quality assurance to ensure compliance with GCP guidelines. • Reasons for premature termination should be communicated. • Any serious adverse event to be communicated promptly (within 14

calender days) to DCGI and Investigators. • In all trials an informed , written consent is required to be obtained

from each volunteer/patient in the prescribed form (App. V), which must be signed, by the patient/volunteer and the chief investigator.

• Investigator and Institution selection • SOP • Allocation of duties and responsibilities • Study management, data handling and record keeping • Information on Investigational Products • Adverse Drug Reaction Reporting, Monitoring and audit.

Cont…..:• Monitor: Act to oversee the progress of the study and to ensure

that the study conduct and data handling comply with the protocol, GCP and applicable ethical and regulatory requirements. • The monitor should have adequate medical, pharmaceutical and/or

scientific qualifications and clinical trial experience. • should be aware of all the aspects of the product under investigation

and the protocol (annexes and amendments also). • Ascertain that the institutional facilities like laboratories, equipment,

staff, storage space etc. are adequate for safe and proper conduct of the study.

• Should verify that the investigational product are supplied only to subjects who are eligible to receive it and at the specified dose(s) and time(s)

• subjects are provided with the necessary instructions on proper handling of the product(s)

• Should promptly inform the sponsor and the ethics committee in case any unwarranted deviation from the protocol or GCP guidelines.

Cont….:• Investigator: An individual who conducts a clinical

investigation ie., under whose immediate direction the test article is administered/dispensed to subject/event of an investigation ( 21 CFR part 50.3 Definition ) • Qualifications • Medical care of the study subjects • Monitoring and auditing of records • Communication with EC • Compliance with the protocol • Records/reports • Progress reports • Termination and final report • Should report any unexpected SAE to the Sponsor within 24

hours and to the EC with in 7 working days.

Cont…..:• Informed Consent ( App. V-Format ). :

• A freely given, informed, written consent should be obtained from each study subject.

• If subject is not able to give ICF, then it can be obtained from legally acceptable representative.

• In case of children Assent need to be submitted to IRB. • If LAR is unable to read/write then impartial witness should be

present during the entire informed consent process.• All elements need to be included in a specified format given in App. V

and it has to be complete and accurate. • All the details need to be clearly explained to the subject by

investigator. • Human subject: An individual who is or becomes a participant in

the research, either as a recipient of test article/ as a control. Subject may be a healthy person/ patient ( 20 CFR 50.3 Def .).

Cont…:• Ethics Committee (App. VIII-Format)

• Review and approval for clinical trials • Safeguard rights, safety and well being of subjects. Special care for

vulnerable subjects (e.g. prisoners, staff, students of medical, etc.) • Should maintain SOP and all the records Review periodic study

reports. • Communicate LA, Sponsor and Investigator for all kind of decisions. • Reasons for revoking approval and information to investigator & RA • Composition:

• 1. Chairperson • 2. Basic Medical pharmacist • 3. Clinicians • 4. Legal expert/retired judge • 5. Social Scientist • 6. Philosopher/ethicist/theologian • 7. Layperson • 8. Member Secretary

Post Marketing Surveillance:

• After approval, the new drug should be closely monitored for their clinical safety in the market.

• The applicants shall furnish Periodic Safety Update Reports (PSUR) in order to.. • To report all the relevant information • Relate these data to patient exposure • Summarize the market status in different countries • Optimization of the product use • Initially for 2 yrs , every 6 months once need to be submitted. • After that annual report need to be given for a period of 2 yrs. • Besides the PSUR, all serious unexpected adverse events in India

known to the license holder should be reported within 15 days.

Appendices:

• I Data to be submitted along with the application to conduct clinical trials/import/manufacture of new drugs for marketing in the country.

• I-a Data required to be submitted by an applicant for grant of permission to import and / or manufacture a new drug already approved in the country.

• II Structure, Contents and Format for Clinical Study Reports • III Animal Toxicology (Non-clinical) • IV Animal Pharmacology • V Informed Consent • VI FDC • VII Undertaking by Investigator • VIII Ethics committee • IX Stability testing of new drugs • X Contents of the proposed protocol for clinical trial • XI Data elements for reporting Serious Adverse Events occurring in a

clinical trial

Appendix II:

• Title page • Study synopsis • Statement of compliance with GCP guidelines issued by CDSCO. • List of Abbreviations and Definitions • Table of Contents • Ethics committee • Study Team • Introduction • Study objective • Investigational plan • Trial subjects • Efficacy evaluation • Safety evaluation • Discussion and Conclusion • List of References • Appendices

Appendix V:• Essential Elements:

• Purpose of the research • Duration of the subject’s participation • Procedures to be followed • Risks and Benefits • Disclosure of alternative procedures/therapies available • Confidentiality • Trial treatment schedule • Compensation/Treatments • Study Contact details • Anticipated prorated payment • Subject’s responsibility • Statement of voluntary participation • Any other information

• Additional Elements: • Termination of subject’s participation by Investigator • Additional costs to the subjects • Study withdrawal by subject • Notification of any new findings during the study • Treatment/ procedure may involve risks which are unforeseeable • Approximate number of subjects enrolled

Appendix VII:• Undertaking by Investigator • Full name, address and title of PI/Investigator • CV of investigator(s) • Name and address of

• trial conducting hospital, medical college/ other facility • all clinical lab facility

• Ethics committee • Protocol title and study number • Commitments of investigator • Signature of investigator with date

Appendix IX:• Stability testing by various environmental factors

such as temperature, humidity and light • To establish shelf life for the formulation • To recommend the storage conditions • Drugs to be stored in • General conditions (Long term 30 °C±2°C &

accelerated 40 °C±2°C) • Refrigerator (Long term 5°C±3°C & accelerated 25

°C±2°C ) • Freezer (Long term - -20°C±5°C)

Appendix X:• Title page • List of Abbreviations and Definitions • Table of Contents • Study Rationale • Study objective • Study design • Study population • Subject eligibility • Study assessment • Study conduct • Study treatment • Adverse Events (described in App. XI) • Ethical considerations • Study monitoring and supervision • Investigational product management • Data analysis • Undertaking by Investigator (described in App. IX) • Appendices

Appendix XI:• SAE reporting form – Patient details – Suspected Drug(s) – Other treatments Details of suspected adverse

drug reaction – Outcome – Details about Investigator – Signature of the Investigator