Sponser Meeting with FDA some facts

There are many meetings which a sponser can have with FDA related to the product being developed and to be approved by FDA. But it can be categorized in to 3 base categories.

Type A: Critical Path (Urgent) meetings – Clinical hold, Safety Issues, Site disqualification, etc (within 30 days)
Type B: Procedural meetings – Pre-IND meeting, EOP2, pre-NDA, etc (within 60 days)
Type C: Miscellaneous meetings – CMC issues, mid-P3, early-review, mid-review, etc ( within 75 days)
Formal meetings are not the only way you communicate with the FDA: comment requests, emails, telecons with the RPMs, etc.

Why meeting FDA?

- Sponsors have the right to request a meeting with the FDA review division
- These meetings are specifically to help prescription drug approvals
–Not granted if FDA perceives that an IND is not being planned
–More for issue resolution while product development than scientific rationale
–Clarification and discussion, not “interrogation”
- Pre-submission meetings (pre-IND, EOP2, pre-NDA) meetings are considered critical by FDA compared to mid-cycle meetings (mid-P3, mid-review, etc)

Time for meeting
1. Developed “final product” idea
–Finished formulation
–Target indication(s) and population(s)
2. CMC information
–Characterization
–Manufacturing and packaging (cGMP)
–Stability studies
3. Basic non-clinical studies (GLP)
–Acute and sub-acute toxicology
–Pharmacology
–In vitro toxicity tests
4. Ready to initiate clinical studies
5. Have sufficient GMP level investigational product
6. The pre-clinical studies demonstrate MTD, NOAEL, major expected adverse events
7. Scientific rationale for mechanism of action is available
8. Clinical development plan is proposed

FCPA Act Anti-bribary provisions

1977 Congress passes FCPA act to stop bribery and restore public confidence in U.S. business systems.
it has 2 sections Anti -Bribery and accounting provision.
Anti-Bribery provison is enforced by DOJ (department of justice) and it helps in Prohibiting corrupt payments (bribes) to foreign government officials, political parties, party officials and candidates in order to obtain or retain business
It has five elements of violation

Recent News - 

SEC Asks Tesco to Retain FCPA Compliance Documents

1- Who comes in its purview :–public companies filing periodic reports with SEC
–Any U.S. citizen, national or resident
- Any corporation, partnership, association, unincorporated organization & sole proprietorship with principal place of business in U.S. or organized in a U.S. state
- If a bribe occured within U.S. then it must use of U.S. mails, interstate telephone, facsimile, wire transfer or interstate or international
- If a bribe occured outside the U.S. then it is not subjected to such requirements
–Foreign companies & nationals if they cause, directly or indirectly through agents, an act in furtherance of a bribe to take place within the U.S.
–U.S. parent corporations if they authorize, direct or control questionable activity of foreign-incorporated subsidiaries
–U.S. citizen & residents employed by or acting on behalf of foreign-incorporated subsidiaries

2- Intent - Payment must be intended to cause foreign official to use his/her influence or misuse his/her position to improperly direct business to payer or some other person.
3-Payment - FCPA violation occurs if there is: A payment or authorization of a payment, An offer to pay or , A promise to pay but there is no minimum value.
4 - Recepients
FCPA applies to:
•Foreign official - Includes officer or employee of a foreign government or public international organization, regardless of rank or position
•Member of a royal family
•Official of state-owned business enterprise?
•Foreign political party or party official
•Candidate for foreign office
5 - Business Purpose
Purpose of payment must be to assist in obtaining or retaining business. However, business need not be with the foreign government, e.g. bribe is made to foreign government official to pressure a private in-country business to award a contract to a U.S. company.

Supplier Qualification Regulations

There are various regulations formulated by different agencies highlight as a whole or part the supplier qualification guidelines. few are below.
ISO 13485 -
–Clause 4.6.2: Assessment of Sub-contractors–ISO 13485:2003 – Clause 7.4.1 mimics previous clause; standard adds explicit reference to “outsourced process” (4.1)

Requirements -
–Clause 7.4.1 - The type and extent of control applied to the supplier… shall be dependent upon the effect of the purchased product on… product realization or the final product.”
–The organization shall evaluate and select suppliers based on their ability to supply product in accordance with…requirements.
–Criteria for selection, evaluation, and re-evaluation shall be established.
–Records of the results of evaluations and any necessary actions arising from the evaluation shall be maintained.

FDA–GMPs : No requirement, but sometimes “unofficially” reviewed during inspection
- 21 CFR 820.50 – Purchasing Controls: “all …product and services…”
- 21 CFR 820.50(a) - Evaluation of suppliers, contractors, and consultants

Allergen Labelling

The various methods of allegen labelling are as follows
- All retail products must have Allergens labelled.
- Restaurant employees must be able to control and discuss allergen presence with customers.
- Common names must be used
- The allergen may appear in bold following the ingredient containing the allergen, on the label
- The allergen and Contains statement must be of equal size and style type.

Sometimes it contains "May Contain" statements to address potential cross contamination. This type of practices should be avoided as .
- It is confusing for consumers and limits product appeal.
- It shows an inadequate allergen control program.

You should include similar allergen control program requirements in the supplier approval program for incoming ingredients as.
- Allergen labeling of incoming ingredients is a necessity for accurate product labeling.
- Allergen testing or Certificates of Analysis for newly approved ingredients is a good way to measure labeling accuracy.

http://www.fda.gov/food/labelingnutrition/FoodAllergensLabeling/GuidanceComplianceRegulatoryInformation/ucm106187.htm

What is FINRA and the guidances

FINRA is Financial Industry Regulatory Authority, Inc., is a private corporation that acts as a self-regulatory organization (SRO) and established in June 2007 . It is the successor to the National Association of Securities Dealers, Inc. (NASD).
FINRA’s mission is to protect America’s investors by making sure the securities industry operates fairly and honestly.

Various guidance by FINRA

•Standards of Commercial Honor and Principles of Trade (FINRA Rule 2010)
•Communications with the Public (NASD Rule 2210)
•Guidelines to Ensure Communications With the Public are Not Misleading (IM- 2210-1)
•Recordkeeping (NASD Rule 2210(b), NASD Rule 3110 and SEC Rule 17a-4)
•Approval and Supervision (NASD Rules 2210(b) and 3010)
•Suitability: Recommendations to Customers (NASD Rule 2310) and Online Communications (Regulatory Notice 01-23)
•Conflicts of Interest (NASD Rule 2711, IM-2210-1 (6)(C) and Regulatory Notices 07-04, 04-18 and 03-44)
•Day Trading Rules (Rules 2270 and 2130)

Top 5 GCP violations

- Protocol non-adherence: Failure to follow the protocol or notify the IRB of problems
- Clinical Records not well documented: They are incomplete, inaccurate or out-of-date. 483 bait
- Informed Consent problems: Incomplete, language issues, back dated, process absent or in question
- Investigational product supply chain accountability: Failure to account for each and every product/pill.
- Adverse Event collection and reporting: from severity determination to reporting errors occur

A clinical trial inspection - general procedure

• Review of the procedures, frequency, scope and process of the sponsor / CRO used to monitor progress
• Reviewing SOPs and Monitoring Plans, interview personnel, and read trip reports
• Review of items to determine that the clinical study / investigation was conducted in accordance with the signed protocol that was submitted to the FDA
• An assessment of protocol deviations or violations from the approved protocol or FDA regulations and how the sponsor / CRO handled them
• An Assessment of training records, SAE reporting, drug accountability,
• Particular attention to both non-compliant sites and the highest enrollers
• Inconsistencies such as protocol deviations, source documents not mirroring CRFs, unclear informed consents, confused Pis
• Is the PI in compliance with the FDA Form 1572
• Making sure the IC process was clear sans coercion
• Do all subjects meet all Inclusion / exclusion criteriaIs the data reasonable and fits the sourse data
• Are all IRB/IEC approvals reasonable / appropriate

to Know more attend the training

GCP violations and Site Mistakes commonly found During a FDA Investigator Site Inspection/Audit

Records FDA inspectors look for - related to Quality system

The FDA’s QSR expects the manufacturer to maintain a series of documents that describe the design and production of the device. QSR allocated the information into four documents.

1. The Design History File (DHF) gives a history of device design. One of the design outputs is the Device Master Record (DMR).
2. The Device Master Record (DMR) contains all the information necessary manufacture, install, service, and maintain the device.
3. The Device History Record (DHR) has the objective evidence to support the device production history.
4. The Quality System Record (QSR) contains information that is not device specific.

A compliant Quality Management System (QMS) should be able to address these questions quickly and easily.

• The list of the records that belong in the Design History File (DHF)?
• Can your team relate the component specifications in the DMR to the Purchasing Data you use to obtain the components?
• What are the records you must keep when you verify the component at receiving?
• Which of these records must go into the DHR?
• What is the list the activities that require a designated individual?
• Do you have quality records that designate the individual and demonstrate training to perform the assigned responsibility?
• How to assure that the designated individual, not somebody else, performed the activity before you released the product for distribution?
• Some information could be in the DMR or the QSR. Does you team know how to make the decision?