the practice of regulatory affairs

8/2/2019 The Practice of Regulatory Affairs

1/42

Import & Registration of drugs in India


2/42

Presentation overview


3/42

All medicines for internal or external use of human or animals and all

substances intended to be used for or in the diagnosis, treatment, mitigation

(decreasing) or prevention of any disease or disorder in human beings oranimals, including preparations applied on human body for the purpose of

repelling insects like mosquitoes; and

Such substances (other than food ) intended to affect the structure or any

function of the human body or intended to be used for the destruction or

vermin or insects which cause disease to human beings or animals.

Allsubstances intended for use as components of a drugincluding empty

geletin capsules; and

Such devices intended for internal or external use in the diagnosis, treatment,

mitigation or prevention of disease or disorder in human beings or animals.

DRUG


4/42

LAWS PERTAINING TO IMPORT, MANUFACTURE AND

SALE OF DRUGS IN INDIA

HISTORICAL PERSPECTIVE

In the beginning of the current century Drug Industry was

practically non-existent in India

Pharmaceuticals were being important from abroad.

The first world war changed the situation and not only were

finished and cheap drugs imported in increasing volume, the

demand for indigenous products also was voiced from all sides.

The Government was, therefore, called upon to take notice of the

situation and consider the matter of introducing legislation to

control the Import, manufacture, distribution and sale of drugs

and medicines.

The Drugs and Cosmetics Act, 1940

The Pharmacy Act, 1948

The Drugs and Magic Remedies (Objectionable Advertisement) Act,

1954

The Narcotic Drugs and Psychotropic Substances Act, 1985

The Medicinal and Toilet Preparations (Excise Duties) Act, 1956

The Drugs (Prices Control) Order 1995 (under the Essential

Commodities Act)


5/42

Drug Regulatory Structure In India


6/42

Drugs Controller General of India ( DCGI ) Dr. Surinder Singh

Main duties : New drug approval, Standards of drugs, drugs import, co-ordination

with State FDAs

State FDAs Maharashtra FDA commissioner

Main duties: Manufacturing, sale and Distribution of drugs

National Pharmaceutical PricingAuthority ( NPPA)Chairman

Main Duties: Drug Pricing

Department of Biotechnology - Secretary

Main Departments related to Pharma


7/42

Regulatory Bodies

Directorate General of Health Services (DGHS)

Ministry of Health & Family WelfareDrug Controller General (India) (DCGI)

Directorate General of Foreign Trade (DGFT)

Indian Council of Medical Research (ICMR)

Department of Biotechnology (DBT)Ministry of Environment & Genetic Engineering

Approval Committee (GEAC)


8/42

Ministry of

Chemicals &

Fertilizers

NPPANational

Pharmaceutical PricingAuthority

Pricing

Regulations

Ministry of

Sci & Tech

DBTDepartment ofBiotechnology

Ministry

of Enviro

AdditionalSecretary

State Drug Regulatory Authority

FDA

Mfg. Lic. for New Drug after approval

GEACGenetic Engineering

Approval CommitteeDCGIDrug ControllerGeneral of India

DGHSDirector General ofHealth Services

Health Secretary

Ministry

of Health

CDL/CDTLGov. Drug Testing

Laboratories

Approval of New Drug


9/42

Regulatory Process for Approval of a New Drug in India

Nature of Product

Life Saving Non - Life Saving

Non- Biotech Non- BiotechBiotech

Clinical trial waiver

NDA

Expert

ReviewCDL

Testing specs.

Clinical trial

IND

CT

permission

CDL

testing

Data presentation

GEAC clearance

CDLwaiver

possible


10/42

122 E NEW DRUG DEFINITION

(a) a new substance of chemical, biological or biotechnological origin; in

bulk or prepared dosage form; used for prevention, diagnosis, or treatment

of disease in man or animal; which, except during local clinical trials, has

not been used in the country to any significant extent; and which, except

during local clinical trials, has not been recognized in the country as

effective and safe for the proposed claim;

(b) a drug already approved by the licensing authority mentioned in Rule

21 for certain claims, which is now proposed to be marketed with modified

or new claims, namely, indications, dosage forms (including sustained

release dosage form) and route of administration;

(c) a fixed dose combination of two or more drugs, individually

approved earlier for certain claims, which are now proposed to be combined

for the first time in a fixed ratio, or if the ratio of ingredients in an already

marketed combination is proposed to be changed, with certain claims, viz.

indications, dosage form (including sustained release dosage form) and

route of administration. [See items (b) and (c) of Appendix VI to Schedule Y.]

New

DrugWhat isaNew Drug ?


11/42

Importing Country

India

Form 40

Application for Site

Registration 40

Site RegistrationApplication

Form 40

Fees: $ 1500 for site

+ $ 1000 drug at that site

Exporting Country

D I (Plant Master File DI)

D II (Drug Master File DII )

PowerOfAttorney POA

DCGI

Form 41


12/42

Importing Country

India

Form 8

Application for licence to

import drugs

Import licenceApplication

Form 8

Form 9

Fees Rs. 1000 (20$)

Exporting Country

Form 9

Undertaking to

accompany form 8

DCGI

Form 10


13/42

Schedule Y

Regulation and guidelines for permission to

import and / or manufacture of new drugs forsale or to undertake clinical trials

It has outlined extensive study criteria in line

with the globally accepted formats such as ICH

and US FDA guidelines

REFER TO RULES 122A, 122B, 122D, 122DA,

122DAA and 122E


14/42

Part X-A ofD & C Rules, 1945

122-A Application for permission to import new drug

122-B Application for approval to manufacture newdrug

122-D Permission to import or manufacture FDC

122-DA Permission to conduct clinical trials for New

Drug / Investigational New Drug


15/42

Schedule Y Highlights

No clinical trial should be conducted without thewritten permission from licensing authority.

For drugs not approved / marketed in India,permission is granted to initiate study a phaseearlier to the phase of trials in other countries.

Phase I studies of drug discovered in other

countries are usually not allowed.

Trials in children are usually allowed only afterPhase III in adult is completed.


16/42

Schedule Y Highlights

Written Informed Consent must be obtained inprescribed format from every participant. Theconsent must be signed by patient and Investigatorboth.

Unusual, unexpected or serious ADRs to becommunicated to Licensing Authority and to all

Investigators. Annual Status Reports to be submitted (Ongoing, at

completion / termination)


17/42

Regulatory Documents

Clinical Trial Application (DCGI)

Test License to import study drugs (DCGI)

Export License to export biological samples

(DGFT with NOC from DCGI)


18/42

Clinical Trial Application

Rule 122DA

Application for permission to conduct clinicaltrials for New Drug / Investigational New Drug

should be submitted in Form 44.

Fees payable in cash:Phase I - Rs. 50,000/- Phase II - Rs. 25,000/-

Phase III - Rs. 25,000/-


19/42

Clinical Trial Application

Additional indication / modified dosage form of

an approved drug -Rs. 15,000.00. Approval of a drug one year after its first

approval - Rs. 15,000.00.

Fixed Dose Combination - Rs. 15,000.00.

Modifications related to approved trials e.g.

additional patients / sites - No additional fees


20/42

PROCESSAPPLICATION

FORM 44

-Imp ff

-Imp rm-Mfg ff

-Mfg rm

-CT

NOC FOR CT + Test

Licence forImport

Application Form 46

A (MFG RM)

Approval Form 46

(MFG FF)

Approval Form 45 A

(IMP RM)

Approval Form 45

(IMP FF)


21/42

FEES

Import ff/ Mfg ff/ Import bulk + Mfg ff = Rs 50,000/-

of new drug

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

Secondary applicants after 1 = Rs 15,000/-

year of approval

Import / Mfg FDC = Rs 15,000/-

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


22/42

Application Form 44

FORM 44

(See Rules 122A, 122B, 122D and 122DA)

Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial

I/We.... of .., hereby apply for grant of permission for import and / or clinical trial or forapproval to manufacture of a new drug or fixed dose combination or subsequent permission ofalready approved new drug. The necessary information / data is given below :

1. Particulars of New Drug : Name of the drug : Dosage Form : Composition of the formulation : Test specifications :

Active ingredients :

Inactive ingredients :

Pharmacological classification of the drug :

Indications for which proposed to be used : Manufacturer of the raw material : Patent status :


23/42

FORM 44 Contd

2. Data submitted along with the application

A. Permission to market new drug

1. Chemical and Pharmaceutical information

2. Animal Pharmacology

3. Animal Toxicology

4. Human / Clinical Pharmacology

5. Exploratory Clinical Trials

6. Confirmatory Clinical Trials

7. Bioavailability / dissolution and stability data

8. Regulatory status in othercountries9. Marketing information :

(a) Proposed product monograph

(b) Drafts of labels and cartons

10. Application for test license :


24/42

FORM 44 Contd

D Subsequent approval or approval for new indication new

dosage form :

Number and date of Approval already granted

Justification Data on safety, efficacy and quality

A total fee ofRs has been credited to the

Government under the Head of Account

(receipt enclosed)

Signature

Designation

Date


25/42

FORM 44 Contd

B. Subsequent approval / permission for manufacture ofalready approved new drug

a) Formulation : Bioavailability / bioequivalence

Name of the investigator / centre

Source of raw mat and stability

b) Raw Material

Manufacturing Method QC parameters, specs, stability

Animal toxicity


26/42

FORM 44 Contd

D. Subsequent approval or approval for new indication newdosage form :

Number and date of Approval already granted

Justification

Data on safety, efficacy and quality

A total fee ofRs has been credited to the Government underthe Head of Account (receipt enclosed)

Signature

Designation

Date


27/42

FORM 44 Contd

C. Approval / permission for FDC

Justification

Pcokinetic / Pcodynamic data

Any other data


28/42

Important Considerations - 1

HUMAN CLINICAL PHARMACOLOGY :-

a) Phase I (Human Pharmacology) Safety and Tolerability with the initialadministration of IND MTD, Kinetics and Dynamics

b) Phase II (Therapeutic Exploratory Trials) Effectiveness for a particularindication, small group

c) Phase III (Therapeutic Confirmatory Trials) Therapeutic benefit in large

number of patients

d) Phase IV (Post Marketing Trials) Related to approved indication


29/42

IMPORTANT CONSIDERATIONS

HUMAN CLINICAL PHARMACOLOGY :-

a) for new drug substances discovered in India : Trials are required to be carriedout in india right from phase 1 and required data needs to be submitted.

b) for new drug substances discovered in countries other than India : Phase I datagenerated outside India, permission may be granted to repeat phase 1.

Application for permission to initiate specific phase of clinical trial should alsoaccompany Investigators brochure, proposed protocol, case record form,study subjects informed consent document(s) investigators undertakingand ethics committee clearance, if available

c) Sample size depends on type of study

d) EC application can be in parallel to DCGI application

e) Drugs indicated in life-threatening, serious disease or diseases of specialrelevance to Indian health scenario, toxiciological / clinical data abbreviated,deferred or omitted

f) Administrative/Logistic Amendments notified to DCGI and EC within 30 daysand approval obtained


30/42

Important Considerations - 2

PSUR :-

New drugs should be closely monitored for their clinical safety; submission of PeriodicSafety Update Reports (PSURs) in order to-

report all the relevant new information (patient exposure) summarize the market authorization status in different countries and any

significant variations related to safety; and

indicate whether changes should be made to product information

PSURs shall be submitted every 6 months for the first two years after

approval

For subsequent two years the PSURs need to be submitted

annually

PSURs due for a period must be submitted within 30 calendar days of

the last day of the reporting period.


31/42

IMPORTANT CONSIDERATIONS - 3

BA/BE

i. For drugs approved elsewhere in the world and absorbedsystemically, bioequivalence with the reference formulationshould be carried out.

ii. Evaluation of the effect of food

iii. Dissolution and bioavailability data to be submitted

iv. All bioavailability and bioequivalence studies should beconducted according to the Guidelines for Bioavailability andBioequivalence studies as prescribed (ICMR guidelines)


32/42

TEST LICENCE

Application :

Form 12 application Material Justification Plan

Treasury Challan of Rs 100 for first drug,

followed by Rs 50 for additional drug

Test Licence obtained in FORM 11


33/42

CT Application accompanied by

Proposal Letter

Particulars of New Drug Name ofDrug, dosage form, composition of

formulation, Pharmacological classification,

proposed indication, patent status and

Manufa

cturer

Chemical and Pharmaceutical Data


34/42


Pre-clinical Data (Animal Pharmacology and

Toxicology).

Clinical Data (Phase I, II and III studies).

Regulatory status in other countries

Published Reports


35/42


Protocol.

Investigators Brochure

Proposed Sites / Investigators list

Investigators Consent Letters

EC approvals from sites

Application for the Test License in Form 12with justification.


36/42

Test License to Import Drugs

Drugs and Cosmetics Rules 1945Rule 122 DA

Form 11: License to import drugs for thepurpose of examination, test or analysis

Form 12: Application for License to import drugs

for th

e purpose of examination, test or analysis Test License fees - Rs.15/-

Validity of Test License - 1 year


37/42

Importing Drugs for CT

Can be imported by Sponsor / CRO or

investigator Application to be made by respective party

With DCGI approval for study

Justification of quantity to be imported

Renewal required if imports required aftervalidity of license expires

Customs duty payable

IP temp requirements to be followed

during shipment


38/42

Application to DGFT

Required to export biological samples to a centrallaboratory outside India.

Proposal letter

Letter from Sponsor appointing the central laboratory

Letter from the Sponsor stating that no genetic testingwill be done on biological samples

IEC certificate CT NOC

POA


39/42

Application to DGFT

Letter from the central laboratory stating that

only protocol specific laboratory tests will becarried out

Justification for the quantity of biologicalspecimen to be exported

Application package to DGFT & JDGFT (cc) Permission letter issued by DGFT to Sponsor

(cc to JDGFT local issues Export license)


40/42

Renewal of Export License

Export license expires after 1 years

To be applied again within 1 years time forrenewal, timelines 4 6 weeks

Can be renewed twice after fresh application

should be made.


41/42

Application to DGFT

Appendix 16 - Application form for the grantof Export License - 5 copies.

Appendix-2 - Profile of the Exporter

To be submitted once with first application andto be resubmitted in case of any change in the

information already submittedValidity of Export License is one year


42/42

Timelines forRegulatory Approvals

DCGI - 12 to 16 weeks

DGFT - 4 to 6 weeks after DCGI approval

Test-license - 1 week after DCGI approval