A Product Development Services Company From Lab to Market Approval Regulatory Strategy Strategy Implementation Pre-Clinical Assays Global Clinical Trials Global Regulatory Submissions Contact: Patrick Burke at [email_address] 301-528-7000 Amarex Clinical Research Washington DC metro area

A Product Development Services Company

From Lab to Market Approval

Regulatory Strategy

Strategy Implementation

Pre-Clinical Assays

Global Clinical Trials

Global Regulatory Submissions

Contact: Patrick Burke at [email_address]

301-528-7000

Thank you! Goal of these Seminars Information sharing Professional Development Networking

Thank you!

Goal of these Seminars

Information sharing

Professional Development

Networking

Applicable Clinical Trials for Clinical Trial Registration www.clinicaltrials.gov Mukesh Kumar, PhD, RAC Senior Director, Regulatory Affairs Amarex Clinical Research Germantown, MD 20874, USA Tel: 001-240-750-4893 Email: [email_address]

“ Applicability” of the Law Confusion about certain(!) trials Registration before trial initiation Bioequivalence studies (ANDA) IND/IDE studies 505(b)(2) applications Amendments to applications Protocol amendments Information amendments (CMC, Pharm-tox, etc) Foreign clinical trials Enforcement

Confusion about certain(!) trials

Registration before trial initiation

Bioequivalence studies (ANDA)

IND/IDE studies

505(b)(2) applications

Amendments to applications

Protocol amendments

Information amendments (CMC, Pharm-tox, etc)

Foreign clinical trials

Enforcement

History of Clinical Trial Registration FDA Modernization Act 1997 Section 113 instructed the NIH to establish a clinical trial database Serious and life-threatening conditions Only drugs and biologics (not devices) Purpose, eligibility, location and contact First version in Feb 2000 Final Guidance in March 2002 Not mandatory , no penalties for non-compliance Within 21 days of first subject enrollment

FDA Modernization Act 1997

Section 113 instructed the NIH to establish a clinical trial database

Serious and life-threatening conditions

Only drugs and biologics (not devices)

Purpose, eligibility, location and contact

First version in Feb 2000

Final Guidance in March 2002

Not mandatory , no penalties for non-compliance

Within 21 days of first subject enrollment

The Process for Registration Set up an account on Protocol Registration System http://prsinfo.clinicaltrials.gov/ Organization account: Many trials Individual account: individual investigator Enter Trial information http://prsinfo.clinicaltrials.gov/definitions.html Within 21 days of first subject enrollment Update information as applicable

Set up an account on Protocol Registration System http://prsinfo.clinicaltrials.gov/

Organization account: Many trials

Individual account: individual investigator

Enter Trial information

http://prsinfo.clinicaltrials.gov/definitions.html

Within 21 days of first subject enrollment

Update information as applicable

International Committee of Medical Journal Editors (ICMJE) Declared in 2004 that it will not accept publications for non-registered clinical trials Based on discussions with WHO To increase patient access of clinical trial information Establish a world-wide standard for trial registration Lead to Fair Access to Clinical Trials (FACT) Act proposed in the US Congress in June 2005

Declared in 2004 that it will not accept publications for non-registered clinical trials

Based on discussions with WHO

To increase patient access of clinical trial information

Establish a world-wide standard for trial registration

Lead to Fair Access to Clinical Trials (FACT) Act proposed in the US Congress in June 2005

International Committee of Medical Journal Editors (ICMJE) Minimal Registration Dataset Item Comment 1. Unique trial number 2. Trial registration date 3. Secondary IDs 4. Funding source(s) Name of the organization(s) that provided funding for the study. 5. Primary sponsor 6. Secondary sponsor(s) 7. Responsible contact person Public contact person for the trial, for patients interested in participating. 8. Research contact person Person to contact for scientific inquiries about the trial. 9. Title of the study Brief title chosen by the research group (can be omitted if the researchers wish). 10. Official scientific title of the study This title must include the name of the intervention, the condition being studied, and the outcome 11. Research ethics review Has the study at the time of registration received appropriate ethics committee approval (yes/no)?

International Committee of Medical Journal Editors (ICMJE) Minimal Registration Dataset Item Comment 12. Condition The medical condition being studied 13. Intervention(s) A description of the study and comparison/control intervention(s) 14. Key inclusion and exclusion criteria Key patient characteristics that determine eligibility for participation in the study. 15. Study type Randomized vs. non-randomized, type of masking (e.g., double-blind, single-blind), type of controls (e.g., placebo, active), and group assignment, (e.g., parallel, crossover, factorial). 16. Anticipated trial start date Estimated enrollment date of the first participant. 17. Target sample size The total number of subjects the investigators plan to enroll before closing the trial to new participants. 18. Recruitment status Is this information available (yes/no) (If yes, link to information). 19. Primary outcome The primary outcome that the study was designed to evaluate Description should include the time at which the outcome is measured (e.g., blood pressure at 12 months) 20. Key secondary outcomes The secondary outcomes specified in the protocol. Description should include time of measurement (e.g., creatinine clearance at 6 months).

FDA Amendment Act (FDAAA) 2007 All Applicable Clinical trials must be registered by sponsors (responsible party) Expanded data elements Must be done by 26 Dec 2007 Certification of compliance to accompany “Applicable” trial submissions to FDA Submit trial results upon study completion Severe penalties for non-compliance $10,000 plus $10,000/day till the violation is corrected

All Applicable Clinical trials must be registered by sponsors (responsible party)

Expanded data elements

Must be done by 26 Dec 2007

Certification of compliance to accompany “Applicable” trial submissions to FDA

Submit trial results upon study completion

Severe penalties for non-compliance

$10,000 plus $10,000/day till the violation is corrected

The Process for Registration Set up an account on Protocol Registration System http://prsinfo.clinicaltrials.gov/ Organization account: Many trials Individual account: individual investigator Enter Trial information http://prsinfo.clinicaltrials.gov/definitions.html * (Aug 20, 2008) Before IND submission Update information as applicable Enter trial results http://prsinfo.clinicaltrials.gov/results_definitions.html ** (Jan 9, 2009) Within 1 year of completion of trial Extension provided on a case-by-case basis with written request and certification

Set up an account on Protocol Registration System http://prsinfo.clinicaltrials.gov/

Organization account: Many trials

Individual account: individual investigator

Enter Trial information

http://prsinfo.clinicaltrials.gov/definitions.html * (Aug 20, 2008)

Before IND submission

Update information as applicable

Enter trial results

http://prsinfo.clinicaltrials.gov/results_definitions.html **

(Jan 9, 2009)

Within 1 year of completion of trial

Extension provided on a case-by-case basis with written request and certification

Compliance Certification Form FDA 3674 Certify that either not applicable due to No clinical trials No “applicable” clinical trials Applicable Provide Registration Number obtained from Clinicaltrials.gov Declare that the sponsor is Aware of the law the information is accurate there are no false statements

Form FDA 3674

Certify that either

not applicable due to

No clinical trials

No “applicable” clinical trials

Applicable

Provide Registration Number obtained from Clinicaltrials.gov

Declare that the sponsor is

Aware of the law

the information is accurate

there are no false statements

Initial Developments and Confusion Dec 12, 2007: Emergency release of Form FDA 3674 Compliance should take about 45 min March 5, 2008: First draft guidance May 21, 2008 Guidance on reporting results (Basic Results) August 25, 2008: FDA published response to its March notice (IND trials) December 8, 2008: Draft description of “Applicable” clinical trials: Bioequivalence studies Jan 21, 2009: Final Guidance

Dec 12, 2007: Emergency release of Form FDA 3674

Compliance should take about 45 min

March 5, 2008: First draft guidance

May 21, 2008 Guidance on reporting results (Basic Results)

August 25, 2008: FDA published response to its March notice (IND trials)

December 8, 2008: Draft description of “Applicable” clinical trials: Bioequivalence studies

Jan 21, 2009: Final Guidance

Applicable Clinical Trials A clinical trial meeting the following four criteria Using a drug, biologic or device requiring FDA approval for investigation and sale Clinical investigation according to a study protocol Controlled clinical trial Placebo-controlled Dose-comparison Blinded No intervention or active intervention Historical control Other than Phase 1, feasibility, pilot or prototype-testing trial

A clinical trial meeting the following four criteria

Using a drug, biologic or device requiring FDA approval for investigation and sale

Clinical investigation according to a study protocol

Controlled clinical trial

Placebo-controlled

Dose-comparison

Blinded

No intervention or active intervention

Historical control

Other than Phase 1, feasibility, pilot or prototype-testing trial

Current Understanding Covered trials: INDs and new protocol submissions to existing INDs NDAs and efficacy supplements to approved NDAs BLAs and efficacy supplements to approved BLAs Abbreviated new drug applications (ANDAs) Premarket approval applications (PMAs) PMA panel track supplements Humanitarian device exemptions (HDEs) 510(k)s that refer to or include information on a clinical trial

Covered trials:

INDs and new protocol submissions to existing INDs

NDAs and efficacy supplements to approved NDAs

BLAs and efficacy supplements to approved BLAs

Abbreviated new drug applications (ANDAs)

Premarket approval applications (PMAs)

PMA panel track supplements

Humanitarian device exemptions (HDEs)

510(k)s that refer to or include information on a clinical trial

Current Understanding Exempt applications: CMC amendments to INDs, NDAs and BLAs Non-clinical pharmacology/toxicology amendments to INDs, NDAs and BLAs Single Patient INDs ANDA amendments and supplements that contain no in-vivo bioequivalence information ANDA, BLA, and NDA promotional materials IND, BLA and NDA Safety Reports ANDA, BLA, NDA, HDE, and PMA mandatory and voluntary adverse event or medical device reports FDA Meeting requests 510(k)s that contain no clinical data

Exempt applications:

CMC amendments to INDs, NDAs and BLAs

Non-clinical pharmacology/toxicology amendments to INDs, NDAs and BLAs

Single Patient INDs

ANDA amendments and supplements that contain no in-vivo bioequivalence information

ANDA, BLA, and NDA promotional materials

IND, BLA and NDA Safety Reports

ANDA, BLA, NDA, HDE, and PMA mandatory and voluntary adverse event or medical device reports

FDA Meeting requests

510(k)s that contain no clinical data

Foreign Clinical Trials Covered only if: Done under a US IND Drug/device manufactured in the US Have US sites (will have a US IND) Used to support a US marketing approval application Completed after Dec 26, 2007

Covered only if:

Done under a US IND

Drug/device manufactured in the US

Have US sites (will have a US IND)

Used to support a US marketing approval application

Completed after Dec 26, 2007

Foreign Clinical Trials Three options in FDA 3674 A. I certify that the requirements do not apply because the application/submission which this certification accompanies does not reference any clinical trial. B. I certify that the requirements do not apply to any clinical trial referenced in the application/submission which this certification accompanies. C. I certify that the requirements apply to one or more of the clinical trials referenced in the application/submission which this certification accompanies and that those requirements have been met.

Three options in FDA 3674

A. I certify that the requirements do not apply because the application/submission which this certification accompanies does not reference any clinical trial.

B. I certify that the requirements do not apply to any clinical trial referenced in the application/submission which this certification accompanies.

C. I certify that the requirements apply to one or more of the clinical trials referenced in the application/submission which this certification accompanies and that those requirements have been met.

“ Applicability” of the Law Registration before trial initiation Bioequivalence studies (ANDA) IND/IDE studies Foreign clinical trials 505(b)(2) applications Amendments to applications Protocol amendments Information amendments (CMC, Pharm-tox, etc) Enforcement Case by case, for now Avoid by discussing at the meetings

Registration before trial initiation

Bioequivalence studies (ANDA)

IND/IDE studies

Foreign clinical trials

505(b)(2) applications

Amendments to applications

Protocol amendments

Information amendments (CMC, Pharm-tox, etc)

Enforcement

Case by case, for now

Avoid by discussing at the meetings

Best Practices Register trials on Clinicaltrials.gov Easy process: less than an hour to comply Simple one page certification form, easy account set-up Does not need IRB/FDA pre-approval Easy to update, single user, non-technical Similar processes world-wide Free Foreign trials: If you ever want to think about US market… register now

Register trials on Clinicaltrials.gov

Easy process: less than an hour to comply

Simple one page certification form, easy account set-up

Does not need IRB/FDA pre-approval

Easy to update, single user, non-technical

Similar processes world-wide

Free

Foreign trials: If you ever want to think about US market… register now

Thank You! Questions and Comments Mukesh Kumar, PhD, RAC Senior Director, Regulatory Affairs Amarex Clinical Research Germantown, MD 20874, USA Tel: 001-240-750-4893 Email: [email_address]