Overcoming Regulatory and Logistical Hurdles When Conducting Clinical Trials in India

Barbara H. Ost Vice-President, QA Compliance and Regulatory Affairs

History of India
Forsters time around 1924 1
Political occupation of India by the British from 1858 to 1947 (Indian Independence Act) System of aloof, condescending sovereignty in which the English bureaucracy did not associate with the persons they ruled in India

Where They Are Today 2

Over the past 15 years, India has been the second fastest-growing country in the world after Chinaaveraging above 6 percent growth per year. Growth accelerated to 7.5 percent last year and will probably hold at the same pace this year. Many observers believe that India could well expand at this higher rate for the next decade

Cities That Are Exploding (From North to South)

Delhi Kolkata (Calcutta) Mumbai (Bombay) Pune Hyderabad Chennai (Madras) Bangalore

Industries: Software, Pharmaceuticals, Automobiles, Steel

India

Todays Challenges
Infrastructure
Roads Airports Power grids

Intellectual Property Enforcement Regulatory/Government Challenges Weather

Cultural Considerations 3
Personal relationship based on mutual respect and confidence Focus on relations Negotiating Traditional greeting namaste (nah-mas-tay) Titles are highly valued Business meals Religion and faith are integral
Hindu, Muslim, Sikhs, Christian, Zoroastrians

Communication Pattern & Use of Language in India 4

courteous, adaptable
Word Base
long, verbose sociable preamble ask for other sides view favorable flexible reaction deal some seemingly modifications made proposed re-packaging agreement usually reached

risk-taking, entrepreneurial

Listening Habits In India 4

We are more experienced than you think

We are willing to listen at length to an eloquent, respectful speaker

Relationships are more important than the deal Suspicious of excolonialists

Key:
Be eloquent, humble and respectful

No I

ro ny

Dont Push Us

Pl ea

se

Cultural Hurdles 3 (Contd.)

The objective of business is success Dichotomy of the businessman It is better to speak what is beneficial than what is true. 5 Expect delays The word no has harsh implications (similar to Japan) Head as the seat of the soul Gesturing Whistling and winking Gift giving Business Dress

Clinical Supplies Challenges

Clinical supplies understanding is growing exponentially Infrastructure Transportation Infrastructure Electricity (Cold Chain) Meeting EU and US regulatory standards Customs/documentation issues Regulatory changes

India Regulatory Info (Contd.)

First in Man (Phase I) Studies Not Allowed for Drugs Discovered Outside India Trial seeking Approvals are classified into Category A or B
Category A those whose protocols are approved by some of the recognized developed countries: USA, UK, Switzerland, Australia, Canada, Germany, South Africa, Japan.

India Regulatory Info (Contd.)

Category A Timing for Approval
Permission will be granted/accepting by submission of the approval of protocols by the country mentioned. Timing: usually 2-4 weeks

India Regulatory Info (Contd.)

Category A Timing for Approval
Permission will be granted/accepting by submission of the approval of protocols by the country mentioned. Timing: usually 2-4 weeks

India Regulatory Info (Contd.)

Category B Requirements: Everyone else
Take more time
Adequacy of the protocol must be verified to protect the subjects. Typical approval time 8-12 weeks Once considered under Category B it cannot shift to Category A.

India Regulatory Info (Contd.)

Requirements for Submission
Name of Company/CRO Authorization letter from the Sponsor Name of Drug Objective of the Study Phase of Study Name of Participating Countries Centers Total number of Patients - Globally

India Regulatory Info (Contd.)

Requirements for Submission (Contd)
Number of Centers/Patients to be included in India Regulatory/IRB Approvals from participating countries Status of study in other countries Serious AE from other countries

India Regulatory Info (Contd.)

Submissions (Contd)
Affidavit from sponsor that study not withdrawn from any country (if once the study is started must notify DCGI at the earliest) Data Submitted
Chemical & Pharmaceutical Data Animal Pharmacological Data Animal Toxicology Data Clinical data phase

India Regulatory Info (Contd.)

Data Submission (Contd)
Rational for selection of the dose Regulatory status of the drug in other countries
if approved for commercial use in other countries with PI Where IND/CTA application if filed

Documents Submitted
Form 44 Form 12 Biological samples to be exported Protocol and informed consent forms

India Regulatory Info (Contd.)

Documents Submitted (Contd)
Case Report forms Investigators Brochure Undertakings by the investigators Ethics committee approvals (if any)

India Regulatory Info (Contd.)

Amendments
3 categories Those which do not require any information or permissions Those which pre-notification is required but need to wait for permissions Those which require prior permissions before implementation.

India Regulatory Info (Contd.)

Amendments
Those which do not require any information or permissions
Administrative and Logistic changes Minor protocol amendments and additional safety assessments in case of institutional ethical committee has already approved the changes

India Regulatory Info (Contd.)

Amendments
Those which pre-notification is required but need to wait for permissions
Additional Investigator Sites Amended Investigators Brochure, amended informed consent

India Regulatory Info (Contd.)

Amendments
Those which require prior permissions before implementation.
Change of Principal Investigator Additional Patients to be recruited Major changes in protocol with respect to study design, dose or treatment options.

India Regulatory Info (Contd.)

Reasons for delays in clearance of application??

India Regulatory Info (Contd.)

Reasons for delays in clearance of application??
Incomplete Applications
Applicant must reapply with necessary fees

India Regulatory Info (Contd.)

Labeling
English Language is Permitted on Labels Similar to EU Annex 13 Required Statements No Specific Local Statements Required Name of Release Site if different than Manufacturer

India Regulatory Info (Contd.)

Schedule Y includes New GCP Guidelines If ICH GCPs Have Been Followed High Quality Data Acceptable to the FDA and EMEA Limited Clinical Laboratories. Increase Costs to Courier Samples to EU or US

India Regulatory Info (Contd.)

Governed by Schedule Y of the Drugs & Cosmetic Rules which are currently being amended 7 Amendment to Schedule Y Allows Parallel Phase Global Clinical Studies Clearance for Clinical Trials is granted by No Objection Certificate (NOC) Prior to NOC Applicant is Required to obtain a Test License (T License) Free of Custom Duty

India Regulatory Info (Contd.)

Application is Form 12 for a Trial License to Import Drug for Clinical Trials (Cof A & $750 US) Require DCGI Approval to Initiate Trials Following Clearance NOC for Clinical Trials 3-6 Months after Filing IND T License 4 Months after Submitting Application Export License for Biological Samples 3-6 Months

India Regulatory Info (Contd.)

Import Information

Import Approval Issued Same Time as CTA Approval Import Approval is Given for a Specific Quantity of Drug Import Permit is Valid for One Year Shipping Invoice Must be Accurate to Import Permit Initiate Shipments on Mondays to Avoid Transit Issues on Weekends

India Regulatory Info (Contd.)

Import Information

Supplies Can Only be Imported to Ports that have a Regulatory Body to Review Pharmaceuticals or Biologics
Mumbai Chennai Delhi Ahmedabad Kolkatta

India Regulatory Info (Contd.)

Shipping Invoice
List Storage Conditions Value for Customs Market Value Statement Clinical Supply. Not for Sale. List Import License Number

Shipping Documentation
Packing Slip Proforma Invoice Copy of Import License

Certificate of Analysis Required with Shipment

India Regulatory Info (Contd.)

Reference Samples
Usually Required After Completion of Clinical Study and Prior to Obtaining Marketing Approval If Required Prior Three Times Release Testing from Same Lot Utilized in Study

Conclusion
India is booming and evolving quickly Infrastructure is Indias greatest challenge (if it were not a problem, Indias growth would be staggering) Be cognizant of the cultural considerations when working with Indian colleagues or business partners Regulatory requirements to get drug in and out of India continue to change Keep up with them and work with your couriers and/or customs brokers to help you succeed with clinical supplies into India

References
1 Gradesaver (2006). About A Passage to India . Available [Online] at: http://www.gradesaver.com/classicnotes/titles/passageindia/about.html 2 Zakaria, F. (1 March 2006). India Rising. Newsweek The New India Cover Story 3 Morison, T, Conaway, W, Borden, G (1994). Kiss, Bow, or Shake Hands How to do Business in Sixty Countries. Adams Media Corporation, Avon, Massachusetts 4 Lewis, D.L. (1999). When Cultures Collide Managing Successfully Across Cultures. Nicholas Brealey Publishing, London, England 5 Augsburger, D.W. (1992). Conflict Mediation Across Cultures. Westminster John Knox Press, Louisville London. 6 Donna McDermott. (10 May 2006) Presentation to 2006 MCSG conference. Albuquerque, NM 7 Central Drugs Standard Control Organization. (21 Dec 2004). http://cdsco.nic.in/html/GCP1.html