Trial

g Schedules

Dr. R. K. DixitProfessor

Pharmacology and Therapeutics C. S. M. Medical University Lucknow

What is meant by schedule• A plan for performing work or achieving an objective, specifying the order and

allotted time for each part• A timetable• Plan for something to happen or for to do something• A supplemental statement of details appended to a document• A federally regulated list of controlled substances, ranked in classes by potential for

abuse.• (Law) Law a list or inventory, usually supplementary to a contract, will, etc.• a written or printed statement of details, often in classified

or tabular form, especially one forming an appendix or explanatory addition to another document.

• Auxiliary, explanatory, or supplemental document that forms part of a principal document, such as a list of individual items (with their descriptions and values)

• Written or printed catalog or list of charges, items, prices, etc., arranged or organized in alphabetical, chronological, magnitudinal, or any other classification or order.

• The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia.

• The role of therapeutic goods regulation is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed. There is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers.

In other countries• Australia• Therapeutic goods in Australia are regulated by the Therapeutic

Goods Administration (TGA). The availability of drugs and poisons is regulated by scheduling under individual state legislation, but is generally under the guidance of the national Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

• Under the SUSDP, medicinal agents generally belong to one of five categories:

• Unscheduled/exempt• Schedule 2 (S2) - Pharmacy Medicines• Schedule 3 (S3) - Pharmacist Only Medicines• Schedule 4 (S4) - Prescription Only Medicines• Schedule 8 (S8) - Controlled Drugs

• Brazil• Therapeutic goods in Brazil are regulated by the Brazilian Health Ministry through its Sanitary

Surveillance Agency (equivalent to USA's FDA). There are 5 main categories:• Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely

in pharmacies and some large supermarkets.• Red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti

allergenics, Anti inflammatories, and other medicines. In Brazil, governmental control is loose on this type; it is not uncommon to buy this type of prescription medicine over the counter without a prescription.

• Red Stripe Psychoactive Medicines - These medicines are sold only with a "Special Control" white medical prescription with carbon copy, which is valid for 30 days. The original must be retained by the pharmacist after the sale and the patient keeps the carbon copy. Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category.

• Black Stripe Medicines - These medicines are sold only with the "Blue B Form" medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includessedatives (benzodiazepines), some anorexic inducers and other habit-inducing controlled medicines.

• "Yellow A Form" prescription medicines - These medicines are sold only with the "Yellow A Form" medical prescription - the most tightly controlled, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes amphetamines and other stimulants (such as methylphenidate), opioids (such as morphine and oxycodone) and other strong habit-forming controlled medicines.

• Canada• In Canada, regulation of therapeutic goods are

governed by the Food and Drug Act and associated regulations. In addition, the Controlled Drugs and Substance Act requires additional regulatory requirements for controlled drugs and drug precursors.

• China• The regulation of drugs in China is governed

by the State Food and Drug Administration.

• United Kingdom• Medicines for Human Use in the United Kingdom are regulated by

the Medicines and Healthcare products Regulatory Agency (MHRA). The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product.

• The United Kingdom has a three-tiered classification system:• General Sale List (GSL)• Pharmacy medicines (P)• Prescription Only Medicines (POM)• Within POM, certain agents with a high abuse/addiction liability are

also separately scheduled under the Misuse of Drugs Act 1971 and the Misuse of Drugs Regulations 2001; and are commonly known as Controlled Drugs (CD).

• Norway• Medicines in Norway are divided into five groups:• Class A Narcotics, sedative-hypnotics, and amphetamines in this

class require a special prescription form:• morphine and its immediate

family, heroin, desomorphine, nicomorphine;• codeine and its immediate

family, dihydrocodeine, ethylmorphine, nicocodeine;• Class B Restricted substances which easily lead to addiction like:• co-codamol, diazepam, nitrazepam, and all

other benzodiazepines(with the exception of temazepam and flunitrazepam), phentermine;

• Class C - All prescription-only substances• Class F - Substances and package-sizes not requiring a prescription• Unclassifieds - Brands and packages not actively marketed in

Norway

• Switzerland• Medicines in Switzerland are regulated by SwissMedic.The country

is not part of the European Union, and is regarded by many as one of the easiest places to conduct clinical trials on new drug compounds.

• There are 5 categories from A to E to cover different types of Delivery category:

• A: Single delivery on medical prescription• B: Repeated delivery on medical prescription• C: Prescription free delivery after consultation of a specialist,

restricted to pharmacy/chemist• D: Prescription free delivery after consultation of a specialist,

restricted to pharmacy, chemist and drugstore• E: Prescription free delivery without consultation in all shops/stores

• India• Medicines in India are regulated by CDSCO - Central Drugs Standard Control

Organization Under Ministry of Health and Family Welfare. Headed by Directorate General of Health Services CDSCO regulates the Pharmaceutical Products through DCGI - Drugs Controller General of India at Chair.

• Under Retail and Distribution:- Drugs classified under 5 heads• 1. Schedule X drugs – Narcotics• 2. Schedule H and L – Injectables, Antibiotics, Antibacterials• 3. Schedule C and C1- Biological Products-example Serums and Vaccines•

Under Manufacturing Practice• 1. Schedule N• List of the equipment for the efficient running of manufacturing wing, Qualified

personnel• 2. Schedule M

• United States• Main article: Regulation of therapeutic goods in the

United States• Therapeutic goods in the United States are regulated

by the U.S. Food and Drug Administration (FDA), which makes some drugs available over the counter at retail outlets and others by prescription only.

• The possession of some substances is prohibited by scheduling under the Controlled Substances Act, under the joint jurisdiction of the FDA and the Drug Enforcement Administration (DEA).

• Schedule I,n a category of drugs not considered legitimate for medical use. Included are heroin, lysergic acid diethylamide (LSD), and marijuana.

• Schedule II,n a category of drugs considered to have a strong potential for abuse or addiction but that also have legitimate medical use. Included are opium, morphine, and cocaine.

• Schedule III,n a category of drugs that have less potential for abuse or addiction than Schedule I or II drugs and have a useful medical purpose. Included are short-acting barbiturates and amphetamines.

• Schedule IV,n a medically useful category of drugs that have less potential for abuse or addiction than those of Schedules I, II, and III. Included are diazepam and chloral hydrate.

• Schedule V,n a medically useful catiegory of drugs that have less potential for abuse or addiction than those of Schedules I through IV. Included are antidiarrheals and antitussives with opioid derivatives.

The Drugs and Cosmetics Act and Rules

• GOVERNMENT OF INDIA MINISTRY OF HEALTH AND FAMILY WELFARE (Department of Health) Introduced THE DRUGS AND COSMETICS ACT AND RULES 1940 ([PASSED BY THE INDIAN LEGISLATURE]

(Received the assent of the Governor General on the 10th April, 1940) , An Act to regulate the import, manufacture, distribution and sale of drugs 1[and cosmetics];

amended • the Drugs (Amendment) Act, 1955, • the Drugs (Amendment) Act, 1960,• the Drugs (Amendment) Act, 1962, • the Drugs and Cosmetics (Amendments) Act, 1964,• the Drugs and Cosmetics (Amendments) Act, 1972,• the Drugs and Cosmetics (Amendments) Act, 1982,• the Drugs and Cosmetics (Amendments) Act, 1986 • the Drugs and Cosmetics (Amendments) Act, 1995.• the Drugs and Cosmetics (Amendments) Act, 2003

Chapters in the “Drugs and Cosmetics Act and Rules” book

• CHAPTER IINTRODUCTON Short title, extent and commencement and

Definitions• CHAPTER IITHE DRUGS TECHNICAL ADVISORY BOARD, THE

CENTRAL DRUGS LABORTORY AND THE DRUGS CONSULTATIVE COMMITTEE

Chapters (Contd.)

• CHAPTER IIIIMPORT OF DRUGS AND COSMETICS Standards

of quality, Misbranded drugs, Adulterated drugs ,Spurious drugs., Misbranded cosmetics., Spurious cosmetics etc.

• CHAPTER IV MANUFACTURE, SALE AND DISTRIBUTION OF

DRUGS AND COSMETICS

Chapters (Contd.)

• CHAPTER IVAPROVISIONS RELATING TO AYURVEDIC SIDDHA

AND UNANI DRUGS• CHAPTER V• MISCELLANEOUS like Publication of sentences

passed under this Act, Magistrate’s power to impose enhanced penalties

Some important Definitions• Spurious drugs. -- For the purposes of this Chapter, a drug shall be deemed to be• spurious—• (a) if it is imported under a name which belongs to another drug; or• (b) if it is an imitation of , or a substitute for, another drug or resembles another• drug in a manner likely to deceive or bears upon it or upon its label or container

the name• of another drug unless it is plainly and conspicuously marked so as to reveal its

true• character and its lack of identity with such other drug ; or• (c) if the label or the container bears the name of an individual or company• purporting to be the manufacturer of the drug, which individual or company is

fictitious• or does not exist; or• (d) if it has been substituted wholly or in part by another drug or substance; or• (e) if it purports to be the product of a manufacturer of whom it is not truly a• product .

• Adulterated drugs. -- For the purposes of this Chapter, a drug shall be deemed to be

• adulterated,--• (a) if it consists, in whole or in part, of any filthy, putrid or decomposed substance;• or• (b) if it has been prepared, packed or stored under insanitary conditions whereby it• may have been contaminated with filth or whereby it may have been rendered

injurious to• health; or• (c) if its container is composed in whole or in part, of any poisonous or deleterious• substance which may render the contents injurious to health; or• (d) if it bears or contains, for purposes of colouring only, a colour other than one• which is prescribed; or• (e) if it contains any harmful or toxic substance which may render it injurious to• health; or• (f) if any substance has been mixed therewith so as to reduce its quality or• strength

Some important Definitions

• Misbranded drugs. ---For the purposes of this Chapter a drug shall be deemed to be

• misbranded---• 1[(a) if it is so coloured, coated, powdered or polished that damage

is concealed or if• it is made to appear of better or greater therapeutic value than it

really is; or• (b) if it is not labelled in the prescribed manner; or• (c) if its label or container or anything accompanying the drug bears

any statement,• design or device which makes any false claim for the drug or which

is false or misleading• in any particular; ]

Some important Definitions

First Schedule• [See section 3(a)]• A. —AYURVEDIC AND 2SIDDHA SYSTEMS• Serial No. Name of book• Ayurveda• 1. Arogya Kalpadruma• 2. Arka Prakasha• 3. Arya Bhishak• 4. Ashtanga Hridaya• 5. Ashtanga Samgraha• B.—UNANI 2TIBB SYSTEM• Serial No. Name of book• 1 Karabadin Qadri• 2 Karabadin Kabir• 3 Karabadin Azam

• (vi) the licensee shall maintain a record of all sales by him of substances for the import

• of which a licence is required, showing particulars of the substance and of the• person to whom sold and such further particulars, if any, as the licensing authority• may specify and such record shall be open to the inspection of any Inspector• authorised in that behalf by the licensing authority;• 1[ Provided that in respect of the sale or distribution of drugs specified in Schedule• X, the licensee shall maintain separate record or register showing the following• particulars, namely;• 1. Name of the Drug,• 2. Batch number,• 3. Name and address of the manufacturer,• 4. Date of transaction,• 5. Opening stock on the business day,• 6. Quantity of drug received, if any, and the source from which received,• 7. Name of the purchaser, his address and licence number,• 8. Balance quantity of drug at the end of the business day,• 9. Signature of the person under whose supervision the drugs have been supplied]

• OTC Drugs • The phrase „OTC‟ has no legal recognition in India, all the drugs not

included in the list of „prescription-only drugs‟ are considered to be non-prescription drugs (or OTC drugs). Hence „OTC Drugs‟ means drugs legally allowed to be sold „Over The Counter‟ by pharmacists, i.e. without the prescription of a Registered Medical Practitioner.

• Prescription-only drugs are those medicines that are listed in Schedules H and X of the Drug and Cosmetics Rules. Drugs listed in Schedule G (mostly antihistamines) do not need prescription to purchase but require the following mandatory text on the label: “Caution: It is dangerous to take this preparation except under medical supervision”.

• Currently, non drug-licensed stores (e.g. non-pharmacists) can sell a few medicines classified as „Household Remedies‟ listed in Schedule K of the D&C Rules in villages whose population is below 1 000 subject to certain other conditions.

• Ayurvedic Medicines • OTC drugs registered as „Ayurvedic Medicines‟ (i.e.

traditional Indian system of medicines containing natural / herbal ingredients) are also regulated by the DCA and DCR. Ayurvedic drugs are manufactured under a manufacturing licence issued by the Ayurvedic State Licensing Authorities. However, they do not require a drug sale licence and can be sold freely by non-chemists. Some of the largest OTC brands in India are registered as „Ayurvedic Medicines‟ because of their plant-based natural active ingredients (e.g. Vicks VapoRub, Amrutanjan Pain Balm, Zandu Pain Balm, Iodex Pain Balm, Moov Pain Cream, Itch Guard Cream, Eno Fruit Salt antacid, Vicks Cough Drops, Halls Lozenges, Dabur‟s Pudina Hara, Calcium Sandoz etc.).

• Considering the above framework, key categories with OTC potential in India would be: vitamins and minerals; health tonics, cough and cold; gastrointestinals; analgesics; dermatologicals; herbal / ayurvedic medicines, among others, which do not contain any substance listed in Schedules G, H or X. There is also a provision under schedule G and H which exempts Topical or external use (except ophthalmic and ear / nose preparations containing antibiotics and / or steroids) applications of the ingredients from these schedules e.g. while Diclofenac is listed in Schedule H but Topical form of the same is excluded. Some of the vitamin supplements come under price control, which can be addressed by making dosage / formulation combination modification. Some of the non-scheduled drugs like Aspirin also come under price control, through Drug Price Control Order (DPCO)

• Additionally, there is also The Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 and Rules, 1955. This Act controls the advertisements for certain category of drugs with a view to prevent people from self medication under the influence of misleading and exaggerated advertisements. There are 54 ailments covered under this action, of which Fever is one of them.

• MARKETING AUTHORISATION • The major legislation for pharmaceutical regulation is the Drugs and Cosmetics Act, 1940 (DCA) and

its subordinate legislation, the Drugs and Cosmetics Rules,1945 (DCR)1. Drug (Prices Control) Order, 1995, Drugs (Magic Remedies) Objectionable Advertisement Act, 1954 and Pharmacy Act, 1948 are other regulations which have a bearing on the pharmaceutical business in India.

• The legislations apply to the whole of India and to all categories of medicines (e.g., allopathic, ayurvedic, siddha, unani and homeopathy.), whether imported or manufactured in India. The legislation is regulated by the Central Government (Ministry of Health & Family Welfare2) in New Delhi, which is responsible for its overall supervision and enforced by State Government through its Food and Drug Administration (FDA).

• The office of the Drugs Controller General of India (DCGI) has the primary responsibility for approving new drugs, molecules and standards, Vaccines & Sera, new usage and claims, new method of administration, clinical research and trials, introductions of a new unique formulation and granting import and export licences. It oversees the activities of the Central Drugs Standard Control Organization (CDSCO)3. The DCGI also exercises control over medical devices imported or manufactured in India.

• However, power to provide manufacturing and selling licences - which are the two main stages required to manufacture and sell a drug - belongs to each individual State Government through its Food and Drug Administration (FDA). These Food and Drug Administrations (FDAs) also carry out enforcement of the DCA and the DCR.

• The DCGI office is established in modern premises in Delhi: • Central Drugs Standard Control Organization • Directorate General of Health Services • Ministry of Health and Family Welfare • Government of India • FDA Bhavan, ITO, Kotla Road, New Delhi - 110002 • Phone: +91-11-23 23 69 68 • Fax: +91-11-23 23 69 73

•ADVERTISING TO THE GENERAL PUBLIC •The Drug & Magic Remedies (Objectionable Advertisement) Act & Rules mentions a list of ailments for which no

advertising is permitted. It also prohibits false or misleading advertisements which, directly or indirectly, give false impressions regarding the true character of the drug, make false claims, or are otherwise false or misleading in any particular respect. There is an OPPI Code of Pharmaceutical Marketing Practices, 20101, based on the IFPMA code. Currently, there is no specific law which prohibits the advertising of prescription drugs. The following OTC medicines advertising can be seen on TV in India:

• digestives

• antacids

• antiflatulents

• cold rubs and analgesic balms/creams

• vitamins/tonics/health supplements (especially herbals and Ayurvedic-registered)

• medicated skin treatment

• analgesic /cold tablets

• antiseptic creams/liquids

• glucose powders

• cough liquids

• throat lozenges

• medicated dressings (band-aids)

• baby gripe water

• Ayurvedic medicines and preparations.

• 1. Laws related to Community Pharmacy• 1.1 The Drugs and Cosmetics Act, 1940 and Rules, 1945• 1.2 The Narcotic Drugs and Psychotropic Substances

Act and Rules, 1985.• 1.3 Drugs Price Control Order, 1995• 1.4 Consumer Protection Act, 1986• 1.5 Infant Milk Substitutes, Feeding Bottles and Infant

Foods Act, 1992• 1.6 Drugs and Magic Remedies Act and Rules, 1954.• 1.7 Prevention of Food and Adulteration Act, 1954.

• d) Schedule C and C(1)• (i) Schedule C• The drugs under this schedule include biological and special products.• Examples of a few drugs under Schedule C• Toxins Insulin• Vaccines (parenteral) Ophthalmic preparations• Antibiotics (parenteral) Adrenaline• The drugs in Schedule C are also listed under Schedule H, and thus are prescription medicines. A proper bill• of sale has to be made against their sale. The proof/record of details of purchase and sale must be maintained• for a period of at least three years.• (ii) Schedule C (1)• The drugs under this schedule include other special products• Examples of a few drugs under Schedule C (1)• · Fish Liver Oil and preparations containing Fish Liver Oil• · Vaccines not in a form to be administered parenterally• · Antibiotics and preparations thereof, not in a form to be administered parenterally• · In vitro Blood Grouping Sera• Those medicines from this schedule listed in Schedule H are to be sold against the prescription of a R.M.P.,• and against a proper bill of sale.• The proof/record of details of purchase and sale must be maintained for a period of at least 3 years.

The purpose of clinical trial is to find out whether a medication or treatment regimen is safe and effective for the treatment of a specific condition or disease.

Requirements and guidelines on clinical trials for import and manufacture of new drug

1. Clinical Trials Nature of trials Permission for trials Responsibilities of Sponsor/Investigator

2. Chemical and Pharmaceutical Information3. Animal Toxicology

Acute toxicity Long-term toxicity

Reproduction studies Local toxicity Mutagenicity and Carcinogenicity

4. Animal Pharmacology5. Human/Clinical Pharmacology trials (Phase I)6. Exploratory trials (Phase II)7. Confirmatory trials (Phase III)8. Special Studies9. Submission of Reports (Appendix II to Sch Y)10. Regulatory status in other countries11. Marketing Information

Nature of trials• Already approved/marketed drugs, phase III trials as

required under item 7 of Appendix I (to Sch. Y) usually are required. If not than is initiated from one phase earlier to the phase of trials in other countries.

• For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available.

• For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I as required from Item 5 of the said Appendix.

Permission for trials• May be obtained by applying in Form 12 for a test license (TL) to import or

manufacture the drug under the Rules. Data appropriate for the various phases of clinical trials to be carried out should accompany the application as per format given in Appendix I (Items I-4).

• The names of investigators and institutions should also be submitted for approval. The investigators selected should possess appropriate qualifications and experience .

• Permission to carry out clinical trials with a new drug is issued along with a test license in Form 11.

• It is desirable that protocols for clinical trials be reviewed and approved by the institution’s ethical committee.

• For new drugs having potential for use in children, permission for clinical trials in the paediatric age group is normally given after phase III trials as required under item 7 of the said Appendix, in adults are completed.

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

Responsibilities of Sponsor/ Investigator• Sponsors are required to submit to the Licensing Authority as

given under Rule 21 an annual status report on each clinical trial, namely, ongoing, completed, or terminated.

• In case a trial is terminated, reason for this should be stated. Any unusual, unexpected, or serious adverse drug reaction (ADR) detected during a trial should be promptly communicated by the sponsor to the Licensing Authority under Rule 21 and the other investigators.

• In all trials an informed, written consent is required to be obtained from each volunteer/patient in the

• prescribed form (See Appendix V), which must be signed, by the patient/volunteer and the chief investigator.

Chemical and Pharmaceutical Information

(See Appendix I to Sch. Y, Item 2)

• Most of the data under this heading are required with the application for marketing permission. When the application is for clinical trials only, information covered in item 2.1 to 2.3 of Appendix I will usually suffice.

Animal Toxicology (Appendix I – Sch. Y - Item 4.2)

Acute toxicity• Acute toxicity studies should be carried out in at

least two species, usually mice and rats using the same route as intended for humans.

• In addition, at least two more route should be used to ensure systemic absorption of the drug.

• 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

Reproduction studies (Appendix I – Sch. Y, item 4.4)

• Reproduction studies need to be carried out only if the new drug is proposed to be studied or used in women of childbearing age. Two species should generally be used, one of them being non-rodent if possible.

• It mainly includes three types of studies …. Fertility studiesTeratogenicity studies Perinatal studies

Local toxicity (See Appendix I, Sch. Y, Item 4.5)

• These studies are required when the new drug Is proposed to be used typically 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 applications, appropriate systemic toxicity studies will be required.

Long-term toxicity (See Appendix I – Sch. Y, Item 1.3)

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

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

• In these studies the drug should be administered 7 days a week by the route intended for clinical use in humans. The number of animals required for these studies, i.e. the minimum number on which data should be available.

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

Mutagenicity and Carcinogenicity (See Appendix I, Sch. Y Item 4,6)

• 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 does levels should be used; the highest does should be sub-lethal but cause

observable toxicity; the lowest does should be comparable to the intended human

therapeutic does or a multiple of it. A control group should always be included.

Animal Pharmacology (See Appendix I to Sch. Y, Item 3.2)

• Specific pharmacological actions are those with therapeutic-potential for

humans. These should be described according to the animal models and

species used. Wherever possible, dose response relationships and ED

50s should be given.

• Special studies to elucidate mode of action may also be described.

• General pharmacological action (see Appendix I to Sch. Y, Item 3.3) are

effects on other organs and systems, especially cardiovascular,

respiratory and central nervous systems.

• Pharmacokinetic data help to relate the drug effect with plasma

concentration and should be given to the extent available.

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. (See Appendix I, Items 8.1 and 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. (See Appendix I to Sch. Y, Item 8.1 and 8.2).

Submission of Reports (Appendix II to Schedule Y)

• The reports of completed clinical trials shall be submitted

by the applicant duly signed by the investigator within a

stipulated period of time.

• The applicant should do so even if he is no longer

interested to market the drug in the country unless there

are sufficient reasons for not doing so.

Regulatory status in other counties

• It is important to state if any restrictions have been placed on the use of the drug in any other country, e.g. dosage limits, exclusion of certain age groups, warnings about adverse drug reaction, etc. (See Appendix I, Sch. Y, Item 9.2)

• Likewise, if the drug has been withdrawn from any country especially by a regulatory directive such information should e furnished along with reasons and their relevance, if any, to India (See Appendix I, Item 9.1(d)).

Marketing Information

• The product monograph should comprise the full prescribing information necessary to enable a physician to use the drug properly.

• It should include description, actions, indications, dosage precautions, drug interactions, warnings and adverse reactions.

• The drafts of label and carton texts should comply with provisions of Rules 96 and 97 of the said rules.

RESPONSIBILITIES

1. Sponsor 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 &

Audit

2. Monitor

Qualifications

• The monitor should have adequate medical,

pharmaceutical and / or scientific qualifications and

clinical trial experience.

• Monitor should be fully aware of all the aspects of the

product under investigation and the protocol

(including its annexes and amendments).

Responsibility

• To oversee the progress of the study and to ensure that the study conduct and data handling comply with the protocol, GCPs and applicable ethical and regulatory requirements.

• 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(s) 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.

Investigator

• Qualifications• Medical care of the study subjects• Monitoring and Auditing of Records• Communication with Ethics Committee• Compliance with the protocol• Records/Reports• Progress Reports• Termination and final report

Appendix I to Schedule Y

• Introduction• Chemical and pharmaceutical information• Animal pharmacology• Animal toxicology • Human/clinical pharmacology (Phase I)• Exploratory clinical trials (Phase II)• Confirmatory clinical trials (Phase III)• Special studies• Regulatory status in other countries• Marketing information

APPENDIX I to Schedule YIFormat for submission of Clinical Trial Reports

• Title of the trial :• Name of the investigator and institution :• Objectives of the trial:• Design of study:• Number of patients:• Treatments given: • drugs and dosage forms: • Regimens:• Observations made: • Results:• Discussions of results:• Summary and conclusion:

APPENDIX V to Schedule Y

It includes following forms…….

Patient consent form for participation in a Phase I Clinical Trial

Patient consent form for participation in Phase II and Phase III Clinical Trial

APPENDIX VI to Schedule Y

Data requirements of Fixed Dose CombinationsFixed Dose combinations (FDC) fall into four groups and their

data requirements accordingly. The first group of FDC includes those in which one or more

of the active ingredients is a new drug. The second group of FDC includes those in which active

ingredients already approved/marketed . 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.

APPENDIX III FORMAT FOR SUBMISSION OF PRECLINICAL AND CLINICAL DATA FOR r-

DNA BASED VACCINES, DIAGNOSTICS AND OTHER BIOLOGICALS

SPECIFICATION AND CHARACTERIZATION INFORMATION ON r-DNA VACCINES AND BIOLOGICAL PRODUCTS.

Description in details of the method of r-DNA products Description on Identity-Physical, Chemical, Immunological and

Biological wherever applicable. Potency General Safety Test. Data on sterility tests as per Indian Pharmacopia guidelines. Data on purity of recombinant product.

DATA ON PRECLINICAL TESTING RECOMBINANT IMMUNODIAGNOSTIC REAGENTS. CLINICAL TRIALS

Phase I : Human/Clinical Pharmacology Immunogenic Potency Phase II: Exploratory Clinical Trials- Preventive/Therapeutic

Efficacy Phase III: Confirmatory Trials

APPENDIX IVINVESTIGATOR’S BROCHURE (IB) Introduction Contents of the IB:

Table of contents Introduction Physical, chemical, and pharmaceutical properties and

formulation parameters Non-clinical Studies

The following section should discuss the following… Non-clinical Pharmacological (Pharmacodymanics) Pharmacokinetics and Product Metabolism in Animals Toxicology

Effects in Humans Pharmacokinetics and Product Metabolism in Humans Safety and Efficacy Regulatory & Post-marketing Experiences

APPENDIX VESSENTIAL DOCUMENTS FOR THE CONDUCT OF

A CLINICAL TRIALThe various Essential Documents needed for

different stages of the study are classified under three groups…

before the clinical phase of the study commences,

during the clinical conduct of the study, and after completion or termination of the study.

Reproduction studies Local toxicity Mutagenicity and Carcinogenicity

4. Animal Pharmacology5. Human/Clinical Pharmacology trials (Phase I)6. Exploratory trials (Phase II)7. Confirmatory trials (Phase III)8. Special Studies9. Submission of Reports (Appendix II to Sch Y)10. Regulatory status in other countries11. Marketing Information

Nature of trials• Already approved/marketed drugs, phase III trials as

required under item 7 of Appendix I (to Sch. Y) usually are required. If not than is initiated from one phase earlier to the phase of trials in other countries.

• For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available.

• For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I as required from Item 5 of the said Appendix.

Permission for trials• May be obtained by applying in Form 12 for a test license (TL) to import or

manufacture the drug under the Rules. Data appropriate for the various phases of clinical trials to be carried out should accompany the application as per format given in Appendix I (Items I-4).

• The names of investigators and institutions should also be submitted for approval. The investigators selected should possess appropriate qualifications and experience .

• Permission to carry out clinical trials with a new drug is issued along with a test license in Form 11.

• It is desirable that protocols for clinical trials be reviewed and approved by the institution’s ethical committee.

• For new drugs having potential for use in children, permission for clinical trials in the paediatric age group is normally given after phase III trials as required under item 7 of the said Appendix, in adults are completed.

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

Responsibilities of Sponsor/ Investigator• Sponsors are required to submit to the Licensing Authority as

given under Rule 21 an annual status report on each clinical trial, namely, ongoing, completed, or terminated.

• In case a trial is terminated, reason for this should be stated. Any unusual, unexpected, or serious adverse drug reaction (ADR) detected during a trial should be promptly communicated by the sponsor to the Licensing Authority under Rule 21 and the other investigators.

• In all trials an informed, written consent is required to be obtained from each volunteer/patient in the

• prescribed form (See Appendix V), which must be signed, by the patient/volunteer and the chief investigator.

Chemical and Pharmaceutical Information

(See Appendix I to Sch. Y, Item 2)

• Most of the data under this heading are required with the application for marketing permission. When the application is for clinical trials only, information covered in item 2.1 to 2.3 of Appendix I will usually suffice.

Animal Toxicology (Appendix I – Sch. Y - Item 4.2)

Acute toxicity• Acute toxicity studies should be carried out in at

least two species, usually mice and rats using the same route as intended for humans.

• In addition, at least two more route should be used to ensure systemic absorption of the drug.

• 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

Reproduction studies (Appendix I – Sch. Y, item 4.4)

• Reproduction studies need to be carried out only if the new drug is proposed to be studied or used in women of childbearing age. Two species should generally be used, one of them being non-rodent if possible.

• It mainly includes three types of studies …. Fertility studiesTeratogenicity studies Perinatal studies

Local toxicity (See Appendix I, Sch. Y, Item 4.5)

• These studies are required when the new drug Is proposed to be used typically 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 applications, appropriate systemic toxicity studies will be required.

Long-term toxicity (See Appendix I – Sch. Y, Item 1.3)

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

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

• In these studies the drug should be administered 7 days a week by the route intended for clinical use in humans. The number of animals required for these studies, i.e. the minimum number on which data should be available.

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

Mutagenicity and Carcinogenicity (See Appendix I, Sch. Y Item 4,6)

• 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 does levels should be used; the highest does should be sub-lethal but cause

observable toxicity; the lowest does should be comparable to the intended human

therapeutic does or a multiple of it. A control group should always be included.

Animal Pharmacology (See Appendix I to Sch. Y, Item 3.2)

• Specific pharmacological actions are those with therapeutic-potential for

humans. These should be described according to the animal models and

species used. Wherever possible, dose response relationships and ED

50s should be given.

• Special studies to elucidate mode of action may also be described.

• General pharmacological action (see Appendix I to Sch. Y, Item 3.3) are

effects on other organs and systems, especially cardiovascular,

respiratory and central nervous systems.

• Pharmacokinetic data help to relate the drug effect with plasma

concentration and should be given to the extent available.

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. (See Appendix I, Items 8.1 and 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. (See Appendix I to Sch. Y, Item 8.1 and 8.2).

Submission of Reports (Appendix II to Schedule Y)

• The reports of completed clinical trials shall be submitted

by the applicant duly signed by the investigator within a

stipulated period of time.

• The applicant should do so even if he is no longer

interested to market the drug in the country unless there

are sufficient reasons for not doing so.

Regulatory status in other counties

• It is important to state if any restrictions have been placed on the use of the drug in any other country, e.g. dosage limits, exclusion of certain age groups, warnings about adverse drug reaction, etc. (See Appendix I, Sch. Y, Item 9.2)

• Likewise, if the drug has been withdrawn from any country especially by a regulatory directive such information should e furnished along with reasons and their relevance, if any, to India (See Appendix I, Item 9.1(d)).

Marketing Information

• The product monograph should comprise the full prescribing information necessary to enable a physician to use the drug properly.

• It should include description, actions, indications, dosage precautions, drug interactions, warnings and adverse reactions.

• The drafts of label and carton texts should comply with provisions of Rules 96 and 97 of the said rules.

RESPONSIBILITIES

1. Sponsor 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 &

Audit

2. Monitor

Qualifications

• The monitor should have adequate medical,

pharmaceutical and / or scientific qualifications and

clinical trial experience.

• Monitor should be fully aware of all the aspects of the

product under investigation and the protocol

(including its annexes and amendments).

Responsibility

• To oversee the progress of the study and to ensure that the study conduct and data handling comply with the protocol, GCPs and applicable ethical and regulatory requirements.

• 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(s) 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.

Investigator

• Qualifications• Medical care of the study subjects• Monitoring and Auditing of Records• Communication with Ethics Committee• Compliance with the protocol• Records/Reports• Progress Reports• Termination and final report

Appendix I to Schedule Y

• Introduction• Chemical and pharmaceutical information• Animal pharmacology• Animal toxicology • Human/clinical pharmacology (Phase I)• Exploratory clinical trials (Phase II)• Confirmatory clinical trials (Phase III)• Special studies• Regulatory status in other countries• Marketing information

APPENDIX I to Schedule YIFormat for submission of Clinical Trial Reports

• Title of the trial :• Name of the investigator and institution :• Objectives of the trial:• Design of study:• Number of patients:• Treatments given: • drugs and dosage forms: • Regimens:• Observations made: • Results:• Discussions of results:• Summary and conclusion:

APPENDIX V to Schedule Y

It includes following forms…….

Patient consent form for participation in a Phase I Clinical Trial

Patient consent form for participation in Phase II and Phase III Clinical Trial

APPENDIX VI to Schedule Y

Data requirements of Fixed Dose CombinationsFixed Dose combinations (FDC) fall into four groups and their

data requirements accordingly. The first group of FDC includes those in which one or more

of the active ingredients is a new drug. The second group of FDC includes those in which active

ingredients already approved/marketed . 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.

APPENDIX III FORMAT FOR SUBMISSION OF PRECLINICAL AND CLINICAL DATA FOR r-

DNA BASED VACCINES, DIAGNOSTICS AND OTHER BIOLOGICALS

SPECIFICATION AND CHARACTERIZATION INFORMATION ON r-DNA VACCINES AND BIOLOGICAL PRODUCTS.

Description in details of the method of r-DNA products Description on Identity-Physical, Chemical, Immunological and

Biological wherever applicable. Potency General Safety Test. Data on sterility tests as per Indian Pharmacopia guidelines. Data on purity of recombinant product.

DATA ON PRECLINICAL TESTING RECOMBINANT IMMUNODIAGNOSTIC REAGENTS. CLINICAL TRIALS

Phase I : Human/Clinical Pharmacology Immunogenic Potency Phase II: Exploratory Clinical Trials- Preventive/Therapeutic

Efficacy Phase III: Confirmatory Trials

APPENDIX IVINVESTIGATOR’S BROCHURE (IB) Introduction Contents of the IB:

Table of contents Introduction Physical, chemical, and pharmaceutical properties and

formulation parameters Non-clinical Studies

The following section should discuss the following… Non-clinical Pharmacological (Pharmacodymanics) Pharmacokinetics and Product Metabolism in Animals Toxicology

Effects in Humans Pharmacokinetics and Product Metabolism in Humans Safety and Efficacy Regulatory & Post-marketing Experiences

APPENDIX VESSENTIAL DOCUMENTS FOR THE CONDUCT OF

A CLINICAL TRIALThe various Essential Documents needed for

different stages of the study are classified under three groups…

before the clinical phase of the study commences,

during the clinical conduct of the study, and after completion or termination of the study.

• 128. Duration of import licence. __A licence unless, it is sooner suspended or cancelled, shall

• be valid 2[for a period of three years from the date of its issue]

• Provided that if application for a fresh licence is made three months before the expiry of the

• existing licence the current licence shall be deemed to continue in force until orders are passed

• on the application

• SCHEDULE A contains number of forms for various purposes. (about 50 in number)

• FORM 1• [See Rule 4]• Memorandum to the Central Drugs Laboratory• Certificate of test or analysis by the Central Drugs Laboratory• 2FORM 8• (See Rule 24)• Application for licence to import drugs (excluding those specified in Schedule

X) to the Drugs• and Cosmetics Rules 1945.• 1[FORM 10• [See rules 23 and 27]• Licence to import drugs (excluding hose specified in Schedule X) to the Drugs

and• Cosmetic Rules, 1945.• 1[FORM 11 – A• (See rule 33-A)• Licence to import drugs by a Government Hospital or Autonomous Medical

Institution for the• treatment of patients.

• *“SCHEDULE B”• [See rules 7 & 48)• Fees for test or analysis by the Central Drugs

Laboratories or State Drugs Laboratories :• 1. Fees for test and assay of Drugs requiring use of

animals -• Rupees• Adrenocorticotrophic hormone assay 1000• Gonadotrophic hormone for LH activity 1000• FSH Activity 1000• Posterior pituitary extract or its synthetic

substitute for oxytocin• activity• 400

• 1SCHEDULE C• [See Rules 23, 61 and 76 and Part X)• Biological and Special Products• 1. Sera.• 2. Solution of serum proteins intended for injection.• 23. Vaccines for parenteral injections.• 4. Toxins.• 5. Antigen.• 6. Antitoxins.• 7. Neo-arsphenamine and analogous substances used for the

specific treatment of• infective diseases.• 8. Insulin.• 9. Putuitary (Posterior Lobe) Extract.• 10. Adrenaline and Solutions of Salts of Adrenaline.• 3[11. Antibiotics and preparations thereof in a form to be

administered parenterally.]

• SCHEDULE D• [See Rule 43]• Class of drugs Extent and conditions of exemption• 1. Substances not intended for• medicinal use• All provisions of Chapter III of the Act and• Rules thereunder subject to the conditions that if• the substance is imported in bulk, the importer• shall certify that the substance is imported for• non-medicinal uses, and if imported otherwise• than in bulk, each container shall bear a label• indicating that the substance is not intended for• medicinal use or is intended for some purposes• other than medicinal use or is intended for some• purposes other than medicinal use or is of• commercial quality.

• SCHEDULE E• [Omitted as per GOI Notification No.G.S.R. 462(E) dt 22-6-1982]• *[SCHEDULE E (1)• [See Rule 161 (2)]• List of poisonous substances under the Ayurvedic (including Siddha)

and Unani Systems• of Medicine• A. AYURVEDIC SYSTEM• I Drugs of vegetable origin• Ahipena Papaver somniferum Linn.• Arka Calotropis gigantea (linn.)R. Br. ex. Ait.• Bhallataka Semecarpus anacardium Linn. F• Bhanga Cannabia eativa Linn.• Danti Baliospermum monatanum Mull. Arg• Dhattura Datura metal Linn..• Gunj Abrus precatirius Linn.• Jaipala (Jayapala) Croton tiglium Linn• Karaveera Rerium indicum Mill• Langali Gloriosa

• SCHEDULE F• Part I – Omitted as per G.O.I. Notification GSR 663(E) dt 3-7-1992 and

corrected as per• GOI Notification No. GSR 27 (E) dt 22-1-1993.• Part II, Part III, Part IV, Part V, Part VI, Part VII, Part VIII, Part IX, Part X,

Part X, Part• XI, Part XII and Part XII-A omitted as per G.O.I. Notification No. GSR 663(E)

dt 3-7-• 1992.• ____________________________________________• 320• 1PART XII B• REQUIREMENTS FOR THE FUNCTIONING AND OPERATION OF A BLOOD

BANK• AND / OR FOR PREPARATION OF BLOOD COMPONENTS.• BLOOD BANKS / BLOOD COMPONENTS.• 2SCHEDULE F(I)• PART 1- VACCINES• (A) PROVISIONS APPLICABLE TO THE PRODUCION OF BACTERIAL

VACCINES.• PART II ANTISERA• Provisions applicable to the production of all Sera from Living Animals

• 1SCHEDULE FF• ( See rule 126-A)• Standards for ophthalmic preparations.• Part-A. Ophthalmic Solutions and suspensions.

• *[SCHEDULE G]• (See Rule 97)• Aminopterin• L-Asparaginase• Bleomycin• Busulphan; its salts• Carbutamide• Chlorambucil;its salts• Chlorothiazide and other derivatives of 1, 2, 4 benzothiadrazine• Chlorpropamide; its salts• Chlorthalidone and other derivatives of Chlorobenzene compound.• **[(Cis-Platin)]• Cyclophosphamide; its salts• **[(Cytarabine)]• Daunorubicin• Di-

• ¨[SCHEDULE H• (See Rules 65 and 97)• PRESCRIPTION DRUGS• Acebutolol Hydrochloride• Aclarubicin Inj• Actilyse• Acyclovir• Adrenocorticotrophic hormone (ACTH)• Alclometasone Dipropiponate• Allopurinol• Alphachymotrypsin• Alprazolam• Amantadine Hydrochloride

• SCHEDULE. I• [See Rule 101 (4)]• PARTICULARS AS TO PROPORTION OF POISION

IN CERTAIN CASES

• ¨¨ [SCHEDULE J• (See rule 106)• Diseases and ailments (by whatever name described) which a drug

may not purport to prevent• or cure or make claims to prevent or cure.• 1. AIDS• 2. Angina Pectoris• 3. Appendicitis• 4. Arteriosclerosis• 5. Baldness• 6. Blindness• 7. Bronchial Asthma• 8. Cancer and Benign tumour• 9. Cataract• 10. Change in colour of the hair and growth of new hair.• 11. Change of Foetal sex by drugs.

• SCHEDULE K• [ See Rule 123]• Class of Drugs Extent and Conditions of Exemption• 1. Drugs falling under clause (b) (i)• of Section 3 of the Drugs &• Cosmetics Act not intended for• medicinal use.• All the provisions of Chapter IV of the Act and• the Rules thereunder subject to the conditions• that the drug is not sold for medicinal use or• for use in the manufacture of medicines and• that each container is labelled conspicuously• with the words “NOT FOR MEDICINAL• USE”.

• SCHEDULE L• [see Rules 65(9) and 97]• ? [Omitted]

• ?? [SCHEDULE M• [See Rules 71, 74, 76 and 78]• GOOD MANUFACTURING PRACTICES AND

REQUIREMENTS OF PREMISES,• PLANT AND EQUIPMENT FOR

PHARMACEUTICAL PRODUCTS.

• GOOD MANUFACTURING PRACTICES FOR PREMISES AND MATERIALS.

• (1) GENERAL REQUIREMENTS• (A) Location and surroundings.- The factory building(s) for

manufacture of drugs shall• be so situated and shall have such measures as to avoid risk of

contamination from external• environmental including open sewage, drain, public lavatory or any

factory which product• disagreeable or obnoxious odour, fumes, excessive soot, dust,

smoke, chemical or biological• emissions.• (B)Building and premises.- The building(s) used for the factory shall

be designed,• constructed, adapted and maintained to suit the manufacturing

operations so as to permit• production of drugs under hygienic conditions. They shall conform

to the conditions laid• down in the Factories Act, 1948 (63 of 1948)

• (C ) Water Supply. - There shall be validated system for treatment of water drawn from• own or any other source to render it potable in accordance with standards specified by the• Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce• Purified Water conforming to Pharmacopoeial specification. Purified Water so produced shall• only be used for all operations except washing and cleaning operations where potable water• may be used. Water shall be stored in tanks, which do not adversely affect quality of water• and ensure freedom from microbiological growth. The tank shall be cleaned periodically and• records maintained by the licensee in this behalf.• (D)Disposal of waste. -• (i) The disposal of sewage and effluents (solid, liquid and gas) from the manufactory• shall be in conformity with the requirements of Environment Pollution Control• Board.• (ii) All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical• Waste (Management and Handling) Rules, 1996.• (iii)Additional precautions shall be taken for the storage and disposal of rejected drugs.• Records shall be maintained for all disposal of waste.• (iv) Provisions shall be made for the proper and safe storage of waste materials awaiting• disposal. Hazardous,toxic substances and flammable materials shall be stored in• suitably designed and segregated, enclosed areas in conformity with Central and• State Legislations.• (6.) Personnel.-• 6.1. The manufacture shall be conducted under the direct supervision of competent• technical staff with prescribed qualifications and practical experience in the relevant dosage• and / or active pharmaceutical products.

• PART 1• GOOD MANUFACTURING PRACTICES FOR PREMISES

AND MATERIALS.• (1) GENERAL REQUIREMENTS• PART I-A• SPECIFIC REQUIREMENTS FOR MANUFACTURE OF

STERILE PRODUCTS,• PARENTERAL PREPARATIONS (SMALL VOLUME

INJECTABLES AND LARGE VOLUME• PARENTERALS) AND STERILE OPHTHALMIC

PREPARATIONS

• PART I-B• SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL SOLID

DOSAGE• FORMS (TABLETS AND CAPSULES)• PART I-C• SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL LIQUIDS• (SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS)• PART I-D• SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL

PRODUCTS i.e.• EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES,

MULSIONS,• LOTIONS, SOLUTIONS, DUSTING POWDERS AND IDENTICAL

PRODUCTS)

• PART I-E• SPECIFIC REQUIREMENTS FOR MANUFACTURE OF• METERED-DOSE-INHALERS (MDI)• PART I-F• SPECIFIC REQUIREMENTS OF PREMISES, PLANT

AND MATERIALS FOR MANUFACTURE OF• ACTIVE PHARMACEUTIAL INGREDIENTS• (BULK DRUGS).

• PART- II• REQUIREMENTS OF PLANT AND EQUIPMENT• 1. External Preparations. -• The following equipments are recommended for

the manufacture of ‘External• preparations’ i.e. Ointments, Emulsion, Lotions,

Solutions, Pastes, Creams, Dusting powders• and such identical products used for external

applications whichever is applicable, namely :-

• *SCHEDUE M-I• [See Rule 85-E (2)]• 1. Requirements of factory premises for

manufacture of Homoeopathic preparations. –• *[SCHEDULE M-II• [See Rule 139]• REQUIREMENT OF FACTORY PREMISESFOR

MANUFACTURE• OF COSMETICS.

• ***[SCHEDULE M-III• [See Rule 76]• REQUIREMENTS OF FACTORY PREMISES FOR

MANUFACTURE OF• MEDICAL DEVICES

• ? [SCHEDULE N• [See Rule 64(1)]• List of minimum equipment for the efficient

runninig of a pharmacy:-

• 1[SCHEDULE O• [See Rule 126]• STANDARD FOR DISINFECTANT FLUIDS• PART 1• Provision applicable to Black fluids and White Fluids.• 1. Classification. - The disinfectants shall be classified as follows: -• (A) Black fluids (B)White fluids• (A) Black fluids. –• These shall be homogeneous dark brown solution of coal tar acid or

similar acids derived• from petroleum with or without hydrocarbon, and/or other

phenolic compounds, and their• derivatives and a suitable emulsifier.• (B) White fluids. –• These shall be finely dispersed homogeneous white to off-white

emulsion consisting of• coal tar acids or similar acids derived from petroleum, with or

without hydrocarbons, and/or• other phenolic compounds, and their derivatives.

• *[SCHEDULE P• [See Rule 96]• LIFE PERIOD OF DRUGS• Sl.• No.• Name of the drug Period in months (unless• otherwise specified)• between date of• manufacture and date of• expiry which the labeled• potency period of the• drug shall not exceed• under the conditions of• storage specified in• Column No.4.• Condition of storage• 1

• *[SCHEDULE P-1• [See Rule 105]• PACK SIZES OF DRUGS• Name of the Drug Dosage form Pack size• 1 2 3• Albendazole Suspension 10ml• Atenolol Tablets 14• Anti-Haemmorhoidal Topicals Rectal Capsules 20• Aspirin (Low-dose) Tablets 14• Cholecalciferol or Ergocalciferol Granules 1 gm.

• 2SCHEDULE Q• [ See rules134 and 144]• 3[Part I]• 4[List of Dyes, colours and Pigments permitted to be

used in Cosmetics and Soaps as given under• IS : 4707 (Part I)-1988 as amended by the Bureau of

Indian Standards].]• Common name of the• colour• Colour• Index• Number• Chemical name of the colour• 1 2

• 1[SCHEDULE R• [See Rule 125]• Standards for condoms made of rubber latex

intended for single use and other mechanical• contraceptives.• I-Condoms• 1. Description. -Condoms consist of cylindrical

rubber sheaths with one end open. The• open end shall terminate with an integral rim.

The closed end may have a receptacle. They may be

• supplied rolled and shall be free from tackiness and shall be capable of being unrolled readily.

• 2[SCHEDULE S• [See Rule 150-A]• STANDARDS FOR COSMETICS• Standards for cosmetics in finished form.- The

following cosmetics in finished form shall• conform to the Indian Standards specifications laid

down from time to time by the 3[Bureau of• Indian Standards (BIS)].• 1. Skin Powders• 2. Skin Powder for infants• 3. Tooth Powder• 4. Toothpaste• 5. Skin Creams• 6. Hair Oils

• 3SCHEDULE T• [See Rule 157]• GOOD MANUFACTURING PRACTICES FOR

AYURVEDIC,• SIDDHA AND UNANI MEDICINES.• The Good Manufacturing Practices (GMP) are

prescribed as follows in Part I and Part II to• ensure:• PART I• GOOD MANUFACTURING PRACTICES

• PART II• A. LIST OF MACHINERY, EQUIPMENT AND

MINIMUM• MANUFACTURING PREMISES REQUIRED FOR

THE• MANUFACTURE OF VARIOUS CATEGORIES OF

AYURVEDIC, SIDDHA SYSTEM OF• MEDICINES.

• *[SCHEDULE U• [ see I Rules 74, 74-A, 74-B, 78 and 78-A]• I. PARTICULARS TO BE SHOWN IN MANUFACTURING RECORDS• A. Substances other than parenteral in preparation in general.• 1. Serial number• 2. Name of the product• 3. Reference of Master Formula Records.• 4. Lot/Batch Size.• 5. Lot/Batch Number• 6. Date of commencement of manufacture and date of completion

of manufacture and• assigned date of expiry.

• 1SCHEDULE U (I)• (See rules 142 and 142-B)• I. Particulars to be shown in the manufacturing Records: -• 1. Serial number.• 2. Name of the product.• 3. Lot/Batch size.• 4. Lot/Batch number• 5. Date of commencement of manufacture and date when manufacture

wascompleted.• 6. Names of all ingredients, quantities required for the lot/batch size,

quantities• actually used.• 7. Control reference numbers in respect of raw materials used in

formulation.• 8. Reference to analytical report number.• 9. Actual production and packing particulars indicating the size and

quantity of• finished packings.• 10. Date of release finished packing for distribution sale.• 11. Signature of the expert staff responsible for the manufacture.

• 1SCHEDULE V• [ See rule 124-B]• Standards for patent or proprietary medicines.• 1. 2[ * * * ]• 32. Standards for patent or proprietary medicines, containing vitamins:• Patent or proprietary medicines containing vitamins for prophylactic,

therapeutic or• paediatric use shall contain the vitamins in quantities not less than and

not more than those• specified below in single or in two divided daily doses, namely: -• (See Table )• 43 5[* * *]• 6[4. General Standards for Different Categories of Patent or Proprietary

Medicines. -

• SCHEDULE W• (Schedule W) – Inserted as per G.O.I.

Notificiation No. GSR 27(E) dt 17.1.1981 and deleted

• as per G.O.I. Notification No. GSR 94(E) dt 8.2.2000.

• 1[SCHEDULE X• [See Rules 23, 61, 75, 97 and 105.A]• Amobarbital 2[ Omitted]• Amphetamina Methylphenidate• Barbital Methylphenobarbital• Cyclobarbital Pentobarbital• Dexamphetamine Phencyclidine• Ethclorvynol Phenmetrazine• Glutethimide 3[Omitted}• Meprobamate Secobarbital• Methamphetamine• Note:- 1. Any stereoisometric form of the substance specified in this

Schedule, any salt of• the substance and preparation containing such substances are also

covered by this Schedule.

• 2[SCHEDULE Y• REQUIREMENT AND GUIDELINES ON CLINICAL

TRIALS FOR IMPORT AND• MANUFACTURE OF NEW DRUG.

• 1. Clinical Trials.• 1.1.Nature of trials. - The clinical trials required to be carried out in the country before a new• drug is approved for marketing depend on the status of the drug in other countries. If the drug is• already approved/marketed, Phase III trials as required under Item 7 of Appendix 1 usually are• required. If the drug is not approved/marketed trials are generally allowed to be initiated at one• phase earlier to the phase of trials in other countries.• For new drug substances discovered in other countries phase I trials are not usually allowed to• be initiated in India unless Phase I data as required under Item 5 of the said Appendix from other• countries are available. However, such trials may be permitted even in the absence of Phase I

data• from other countries if the drug is of special relevance to the health problem of India.• For new drug substances discovered in India, clinical trials are required to be carried out in• India right from phase I as required under Item 5 of the said Appendix though Phase III as• required under Item 7 of the said Appendix, permission to carry out these trials is generally given• in stages, considering the data emerging from earlier phase

• 1.2.Permission for trials. - Permission to initiate clinical trials with a new drug may be• obtained by applying in Form 12 for a test licence (TL) to import or manufacture the drug under• the Rules. Data appropriate for the various phases of clinical trials to be carried out should• accompany the application as per format given in Appendix I (items 1-4). In addition, the protocol• for proposed trials, case report forms to be used, and the names of investigators and institutions• should also be submitted for approval. The investigators selected should possess appropriate• qualifications and experience and should have such investigations facilities as are germane to the• proposed trials protocol.

• Permission to carry out clinical trials with a new drug is issued along with a test licence in• Form 11.

• It is desirable that protocols for clinical trials be reviewed and approved by the institution’s• ethical committee. Since such committees at present do not exist in all institutions, the approval• granted to a protocol by the ethical committee of one institution will be applicable to use of that• protocol in other institutions which do not have an ethical committee. In case none of the trial• centers/institutions has an ethical committee, the acceptance of the protocol by the investigator

and• its approval by the Drugs Controller (India) or any officer as authorized by him to do so will be• adequate to initiate the trials.• For new drugs having potential for use in children, permission for clinical trials in the• paediatric age group is normally given after phase III trials as required under item 7 of the said• Appendix in adults are completed. However, if the drug is of

• 1.3.Responsibilities of Sponsor/Investigator. - Sponsors are required to submit to the

• licensing authority as given under Rule 21 an annual status report on each clinical trial, namely,

• ongoing, completed, or terminated. In case a trial is terminated, reason for this should be stated.

• Any unusual, unexpected or serious adverse drug reaction (ADR) detected during a trial should be

• promptly communicated by the sponsor to the licensing authority under Rule 21 and the other

• investigators.• In all trials an informal, written consent required to be

obtained from each• volunteer/patient in the prescribed Forms (See Appendix V)

which must be signed by the• patient/volunteer and the chief investigator.

• 2.Chemical and pharmaceutical information.• Most of the data under the heading (See

Appendix I, item 2) are required with the• application for marketing permission. When

the application is for clinical trials only, information

• covered in item 2.1 to 2.3 of Appendix I will usually suffice.

• 3. Animal Toxicology.• 3.1.Acute Toxicology. - Acute toxicity studies (See Appendix I item 4.2) should be carried• out in at least two species usually mice and rats using the same route as intended for humans. In• addition, at least one more route should be used to ensure systemic absorption of the drug; this• route may depend on the nature of the drug. Mortality should be looked for up to 72 hours after• parenteral 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. LD 50s should be reported preferably with 95 per cent confidence limited, if LD 50s• cannot be determined, reasons for this should be stated.• 3.2 Long term toxicity: - Long term toxicity (see appendix 1, item 1.3) should be carried• out in at least tow mammalian species, of which one should be a non rodent. The duration of study• 599• will depend on whether the application is for marketing permission or for clinical trial, and in the• latter case, on the phase of trials (see Appendix III). If a species is known to metabolize the drug• in the same way as humans, it should be preferred.• In long-term toxicity studies the drug should be administered 7 days a week by the route• intended for clinical use in humans. The number of animals required for these studies, i.e. the• minimum number on which data should be available, is shown in Appendix IV.• A control group of animals given the vehicle along should always be included and three• other groups should be given graded dose of the drug; the highest dose should produce observable• toxicity, the lowest dose should not cause observable toxicity, but should be comparable to the• intended therapeutic dose in humans of a multiple of it, e.g. 2.5 to make allowance for the• sensitivity of the species; the intermediate dose should cause some symptoms, but not gross• toxicity or death, and may be placed logarithmically between the other two doses.• The variables to be monitored and recorded in long-term toxicity studies should include• behavioral, physiological, biochemical, and microscopic observations.

• 3.3.Reproduction studies. - Reproduction studies (see Appendix I, item 4.4) need to be

• carried out only if the new drug is proposed to be studied or used in women or childbearing age.

• Two species should generally be used, one of them being a non-rodent if possible.• a. Fertility Studies. - The drug should be administered to both males and females,• beginning a sufficient number of days before mating. In females the medication

should be• continued after mating and the pregnant one should be treated throughout

pregnancy. The highest• dose used should not affect general health or growth of the animals. The route of

administration• should be the same as for therapeutic use in humans. The control and the treated

group should be• similar size and large enough to give at least 20 pregnant animals in the control

group of rodents• and at least 8 pregnant animals in the control group of non-rodents. Observations

should include• total examination of the litters from both the groups, including spontaneous

abortions, if any.

• b.Teratogenicity studies. - The drug should be administered throughout the period of

• organogenesis, using three dose levels. One of the doses should cause minimum maternal toxicity

• and one should be proposed dose for clinical use in humans or a multiple of it. The route of

• administration should be the same as for human therapeutic use. The control and the treated group

• should consist of at least 20 pregnant females in case of non-rodents, on each dose used.

• Observations should include the number of implantation sites; resorptions if any; and the number

• of foetuses with their sexes, weights and malformations, if any.• c. Perinatal studies. - The drug should be administered throughout the last third of• pregnancy and then through lactation of weaning. The control of each treated

group should have at• least 12 pregnant females and the dose which causes low foetal loss should be

continued• 600• throughout lactation weaning. Animals should be sacrificed and observations

should include• macroscopic autopsy and where necessary, histopathology.

• 3.4.Local toxicity. - These studies (see Appendix I, item 4.5) are required when the new• drug is proposed to be used topically 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 applications, appropriate systemic toxicity studies will be required.• 3.5Mutagenicity and Carcinogenicity. - These studies (see Appendix 1, item 4.5) 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. These species should not have a high• incidence of spontaneous tumors and should preferably be known to metabolize the drug in the• same manner as humans. At least three dose level should be used; the highest dose should be• sublethal out cause observable toxicity; the lowest dose should be comparable to the intended• human therapeutic dose or a multiple of it, e.g. 2.5 X; to make intermediate dose to be placed• logarithmically between the other two doses. A control group should always be included. The

drug• should be administered 7 days a week or a fraction of the life span comparable to the fraction of• human life span over which the drug is likely to be used therapeutically. Observations should• include macroscopic changes observed at autopsy and detailed histopathology.

• 4. Animal pharmacology.• Specific pharmacological actions (see Appendix I, item

3.2) are those with therapeuticpotential• for humans. These should be described according to

the animal models and species used.• Wherever possible, dose-response relationships and

ED 50s should be given. Special studies to• elucidate mode of action may also be described.• General pharmacological action (see Appendix I, item

3.3) are effects on other organs and• systems, specially cardiovascular, respiratory and

central nervous systems.• Pharmacokinetic data help relate drug effect to plasma

concentration and should be given• to the extent available.

• 5 Human/Clinical Pharmacology (Phase I).• The objective of phase I of trials (see Appendix I, item 5) is

to determine the maximum• tolerated dose in humans; pharmacodynamic effects;

adverse reactions, if any, with their nature• and intensity; and pharmacokinetic behaviour of the drug

as far as possible. These studies are• carried out in healthy adult males, using clinical,

physiological and biochemical observations. At• least 2 subjects should be used on each dose.• 601• Phase I trials are usually carried out by investigators trained

in clinical pharmacology and• having the necessary facilities to closely observe and

monitor the subjects. These may be carried• out at one or two centers.

• 6. Explanatory trials (Phase II).• In phase II trial (see appendix I, item 6) a limited number of patients are studies carefully• to determine possible therapeutic use, effective dose range and further evaluation of safety and• pharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studies are• usually limited to 3-4 centres and carried out by clinicians specialized in the concerned therapeutic• areas and having adequate facilities to perform the necessary investigations for efficacy and safety.• 7. Confirmatory trials (Phase III).• The purpose of these trials (see Appendix I, item 7) is to obtain sufficient evidence about• the efficacy and safety of the drug in a larger number of patients, generally in comparison with a• standard drug and/or a placebo as appropriate. These trials may be carried out by clinicians in the• concerned therapeutic areas, having facilities appropriate to the protocol. If the drug is already• approved/marketed in other countries, phase III data should generally obtained on at least 100• patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug, in• Indian patients when used as recommended in the product monograph for the claims made.• If the drug is a new drug substance discovered in India and not marketed in any other• country, phase III data should be obtained at least 500 patients distributed over 10-15 centres. In• addition, data on adverse drug reactions observed during clinical use of the drug should be• collected in 1000-2000 patients; such data may be collected through clinicians who give written• consent to use the drug as recommended and to provide a report on its efficacy and adverse

during• reactions in the treated patients. The selection of clinicians for such monitoring and supply of drug• to them will need approval of the licensing authority under Rule 21.

• 8. Special Studies.• A. These include studies on solid oral dosage

form, such as, bio-availability and• dissolution studies. These are required to be

submitted on the formulations manufactured in the

• country. (see Appendix I, items 8.2 and 8.3).• B. 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. (See• Appendix 8.2 and 8.3).

• 9. Submission of Reports (Appendix II).• The reports of completed clinical trials shall be submitted by the applicant duly signed by• the investigator with a stipulated period of time. The applicant should do so even if he is no longer• interested to market the drug in the country unless there are sufficient reasons for not doing so.• 10. Regulatory status in other countries.• It is important to state if any restrictions have been placed on the use of the drug in any• other country, e.g. dosage limited, exclusion of certain age groups, warnings about adverse drug• reaction, etc. (See Appendix I, item 9.2).• Likewise, if the drug has been withdrawn from any country specially by a regulatory• directive, such information should be furnished along with reasons and their relevance, if any, to• India (See appendix I, item 9.1 (d).

• 11. Marketing information.• The product monograph should comprise the full prescribing

information necessary to• enable a physician to use the drug properly. It should include

description, actions, indications,• dosage precaution, drug interactions, warnings and adverse

reactions.• The drafts of label and carton texts should comply with provisions

of Rules 96 and 97 of• the said rules.• *[12 Post-marketing surveillance study.• On approval of a new drug, the importer or the manufacturer shall

conduct post-marketing• surveillance study of that new drug after getting the protocols and

the names of the investigators• approved by the Licensing Authority as defined under clause (b) of

Rule 21 during the initial• period of two years of marketing.]

• APPENDIX I• Data required to be submitted with application for permission• to market a New Drug• 1. INTRODUCTION• A brief description of the drug and the therapeutic class to which it belongs.• 2. CHEMICAL AND PHARMACEUTICAL INFORMATION.• 2.1. Chemical name, code name or number, if any, non-proprietary or generic• name, if any, structure, physio-chemical proportion.• 2.2 Dosage form and its composition.• 2.3 Specifications of active and inactive ingredients.• 2.4. Tests for identification of the active ingredient and method of its assay.• 2.5. Outline of the method of manufacture of the active ingredient.• 2.6 Stability data• 3. ANIMAL PHARMACOLOGY• 3.1. Summary• 3.2. Specific pharmacological actions.• 3.3 General pharmacological actions.• 3.4. Pharmacokinetics, absorption, distribution, metabolism, excretion.• 4. ANIMAL TOXICOLOGY (See Appendix III and IV)• 4.1. Summary• 4.2 Acute Toxicity• 4.3. Long Term Toxicity• 4.4 Reproduction Studies.• 4.5 Local Toxicity• 4.6. Mutagenicity and Carnicogenicity.• 5. HUMAN/CLINICAL PHARMACOLOGY (PHASE I).• 5.1. Summary• 5.2 Specific Pharmacological effects.• 5.3 General Pharmacological effects.• 5.4. Pharmacokinetics, absorption, distribution, metabolism, excretion.

• EXPLANATORY CLINICAL TRIALS (PHASE II).• 6.1. Summary• 604• 6.2 Investigatorwise reports.• 7.. CONFIRMATORY CLINICAL TRIALS (PHASE III)• 7.1. Summary• 7.2 Investigatorwise reports• 8. SPECIAL STUDIES• 8.1. Summary• 8.2 Bioavailability and dissolution studies.• 8.3 Investigatorwise reports.• 9. REGULATORY STATUS IN OTHER COUNTRIES.• 9.1. Countries where –• (a) Marketed• (b) Approved.• (c) Under trial, with phase.• (d) Withdrawn, if any, with reasons.• 9.2. Restrictions on use, if any, in countries where marketed/approved.• 9.3 Free sale certificate from country of origin.• 10.MARKETING INFORMATION.• 10.1. Proposed product monograph• 10.2. Drafts of labels and cartons.• 10.3. Sample of pure drug substance, with testing protocol.• Notes: (1) All items may not be applicable to all drugs, for explanation, see text of• Schedule Y.• (2) For requirements of data to be submitted with application for clinical• trials see text of Schedule Y, Section 1 and also Appendices II and III.

• APPENDIX II• Format for submission of clinical Trial Reports.• ___ Title of the trial• ___ Name of investigator and institution• ___ Objectives of the trial• ___ Design of study: Open, single-blind or double blind, non-comparative or comparative,• parallel group or crossover.• ___ Number of patients, with criteria selection and exclusion, whether written, informed• consent, was obtained.• ___ Treatments given – drugs and dosage forms, dosage regimens, method of allocation of• patients to treatments, method of verifying compliance, if any• ___ Observations made before, during and at the end of treatment, for efficacy and safety, with• methods used.• 606• ___ Results : exclusions and dropouts, if any, with reasons, description of patients with initial• comparability of groups where appropriate, clinical patients with initial comparability of• groups where appropriate, clinical and laboratory observations on efficacy and safety,• adverse drug reactions.• ___ Discussion of results ; relevance to objectives, correlation with other reports/data, if any,• guidance for further study, if necessary.• ___ Summary and conclusion.

• APPENDIX IV• Number of animals for long term Toxicity Studies.• 2 - 6 Weeks 7 - 26 Weeks• Group Rodents (rats) Non-Rodents• (dogs)• Rodents• (Rats)• Non-Rodents• (dogs)• 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

• APPENDIX V• Patient consent form for participation in a Phase I Clinical Trial• The clinical trial involves the study of a new …………. agent …………….. in• volunteers/patients suffering from ……………………………………………………………….• The drug which will be administered to volunteers/patients has been found to be safe in• animal toxicity tests and other experimental data. The volunteers /patients will be required to• undergo, if necessary, all routine examinations including taking of X-ray, ECG, EEG etc. at• intervals. The volunteers/patients may be asked to collect stool and urine, and there may be need• to draw blood or any other body fluid on several occasions to test the effects of concentrations of• the drug. The volunteers/patients are free to withdraw from the trial at any stage.• Authorisation• I have read/been briefed on the above project summary and I voluntarily agree to• participate in the project. I understand that participation in this study may or may not benefit me.• Its general purpose, potential benefits, possible hazards, and inconveniences have been explained• to my satisfaction, I hereby give my consent for this treatment.• Name of the volunteer/patient• Signature or thump impression• of the volunteer/patient.• Signature of Chief Investigator• Date:

• Patient consent form for participation in Phase II and Phase III Clinical Trial: -• I…………………………….. exercising my free power of choice, hereby give my consent• to be included as a subject in the clinical trial of a new drug, namely……………….. for the• treatment of …………………….. I understand that I may be treated with this drug for the• diseases. I am suffering from ………………………I have been informed to my satisfaction, by• the attending physician the purpose of the clinical trial and the nature of drug treatment and

follow• up including the laboratory investigation to monitor and safeguard my body functions.• I am also aware of my right to opt out of the trial at any time during the course of the trial• without having to give the reasons for doing so.• Signature of the attending physician.• Date: …………. Signature of the patient• Date:

• APPENDIX VI• Fixed Dose Combination (FDC) fall into four groups and their data requirements accordingly.• (a) The first group of FDC includes those in which one or more of the active ingredients is• a new drug. Such FDC are treated in the same way as any other new, drug, both the clinical trials• and for marketing permission (See Rule 122-E, item (a).)• (b) The second group of FDC includes those in which active ingredients already• approved/marketed individually are combined for the first time, for a particular claim and where• the ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic• nature (see Rule 122-E, item (c)). For permission to carry out clinical trials with such FDC, a• summary of available pharmacological, toxicological and clinical data on the individual• ingredients should be submitted, with rationale for combining them in the proposed ratio. In• addition, actual toxicity data (LD 50) and pharmacological data should be submitted on the• individual ingredients as well as their combination in the proposed ratio. If the clinical trials have• been carried out with the FDC in other countries, reports of such trials should be submitted. If the• FDC is marketed abroad, the regulatory status in other countries should be stated. (See Appendix ,• item 9).• For marketing permission, the reports of clinical trails carried out with the FDS in India• should be submitted. The nature of trials depending on the claims to be made and the data already• available.• (c) The 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.• For such FDC, the appropriate rationale should be submitted to obtain a permission for the• clinical trials, and the reports of trials should be submitted to obtain a marketing permission. The• nature of trails will depend on the claims to be made and the data already available.• (d) The fourth group of FDC includes those whose individual active ingredients have been• widely used in particular indication for years, their concomitant use is often necessary and no• claim is proposed to be made other than convenience, and a stable acceptable dosage from the• ingredients are unlikely to have significant interaction of a pharmacodynamic or pharmacokinetic• nature.• No additional animal or human data are generally required for these FDC, and marketing• permission may be granted if the FDC has an acceptable rationale.