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CPG Sec 120.500 Health Fraud - Factors in Considering Regulatory Action

FinalHuman Foods Program Office of Inspections and Investigations03/01/1995
Due DiligenceREMSBioequivalenceManufacturing Process ValidationPharmacology - ToxicologyCMCPharmToxControl of solid-state formRisk Evaluation and Mitigation Strategy

Description

Health Fraud products are articles of unproven effectiveness that are promoted to improve health, well being, or appearance. They can be drugs, devices, foods or cosmetics for human or animal use.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

10
Approved Product

POTIGA (ezogabine) tablets

Tablets

Dosage form for DRUG-X

film-coated immediate-release tablets

dosage form of POTIGA

AED

Antiepileptic Drugs category

Antiepileptic drugs

Commonly studied using add-on or replacement designs

potassium channel opener

POTIGA is a potassium channel opener

Modification C

A pure crystal modification of the compound of formula I characterized by tabular crystals and rapid solubility.

Modification B

A pure crystal modification of the compound of formula I characterized by longish-tabular to columnar crystals.

Modification A

A pure crystal modification of the compound of formula I characterized by specific X-ray reflections and IR bands.

human drug

Subject of DHCP letters

Stakeholders

10
Commissioner for Patents

Addressee for the patent term extension application

Stephanie N. Keefe

FDA Contact for transfer of ownership

Dorothy Demczar

FDA Contact for email correspondence

Art Rosenthal

VPNA representative communicating with FDA

Steven Dinsmore MD

FDA contact for T-Con regarding cardiac safety

A.Rosenthal

VPNA representative contacting FDA

Norm Hershkowitz, MD

FDA contact for T-Con regarding dog study and white blood cell counts; FDA Contact for T-Con Request

Rich Heller

Valeant representative for FDA communications

Courtney Calder

FDA contact for T-Con calls and emails

Melina Griffis

FDA Project Manager contact; FDA contact for emails and pre-NDA questions

Regulatory Context

Regulatory Activities

10
Application for Extension of Patent Term

Request submitted under 35 U.S.C. 156

NEW SUPPLEMENT

Submission of a new supplement for labeling changes and REMS modification

REMS MODIFICATION

Proposed modification to the Risk Evaluation and Mitigation Strategy

Advisory Committee Meeting

The venue where expert advice is provided to FDA; Proceedings involving review of product approval or safety; A meeting where experts review the safety and efficacy of a product.

Proprietary Name Review

Request for review of the name POTIGA

Type C Meeting

Meetings regarding any other aspect of drug development; General meeting regarding development and review of a product.; Type C meetings where the objective is to facilitate early consultation on the use of a biomarker.; FDA sends preliminary responses no later than 5 calendar days before the meeting date; Meeting type with 75 day scheduling goal

IND Safety Report

Safety reports submitted under an Investigational New Drug application.

Pre-NDA Questions

Communication prior to New Drug Application submission

Pre-NDA Mtg

General Correspondence - Pre-NDA Mtg (Type B)

Special Protocol Assessment

repeat-dose toxicity studies that support a carcinogenicity Special Protocol Assessment (SPA)

Document Types

10
U.S. Patent 6,538,151 B1

Patent document containing analytical data for substance modifications

Draft Study Protocols

Protocols submitted for PMR Reference Nos: 1781-2, 1781-3, 1781-4, and 1781-5

PATENT INFORMATION

Time sensitive patent information submitted under sequence 0051

015-Day ADR Report

Adverse Drug Reaction report submission

Container Label

dosage terminology on the container label and carton labeling should be consistent

Communication Plan

statutory element of a REMS

120-Day Safety Update

Safety update sequence 0007

FDA Acknowledgement Letter

Letter confirming transfer of ownership

Letter of Authorization

A document granting written permission to reference information from an NDIN Master File.

CMC Information Amendment

analytical testing site updated and new

Attributes

10
50 mg

Tablet strength

eCTD format

The required electronic format for DMF submissions.

200 mg tablet

CMC Information Amendment for 200 mg tablet

user fee

Fees required for the review of premarket submissions

Type B

Classification of Pre-NDA Meeting

pediatric formulation

Requirement for a separate IND for specific patient population

crystallographic polymorphism

Property of retigabine free-base having multiple crystalline forms

maintenance fee

Fee paid to USPTO to keep patent in force

room temperature

Storage condition for POTIGA

creatinine clearance <50 mL/min

threshold for dosage adjustment in renal impairment

Technical Details

Substances

10
ezogabine

Active ingredient of POTIGA, also known as retigabine; Active ingredient in POTIGA; active ingredient in POTIGA used for partial-onset seizures; Active ingredient in Potiga tablets; USAN Adopted Name Change from Retigabine to Ezogabine; Established name for POTIGA; Active ingredient in POTIGA Tablets; Active ingredient in POTIGA tablets

Lorvigabine

Request for Change of Adopted Name to Lorvigabine

KOTIGA

Earlier proposed proprietary name for retigabine

N-acetyl metabolite

metabolite of retigabine studied in dogs

GKE-841

Referred to as NMDA Receptor Antagonist

Form A

The specific crystalline form used in clinical and formulation studies

dihydrochloride salt

Initial salt form of retigabine found to be unstable

retigabine free-base

The specific chemical form selected for development

retigabine

Active drug substance discussed in development report; FDA Submission Log for Epilepsy; Subject of the FDA submission log; 13-Wk study of N-acetyl metabolite of retigabine in dogs; Active ingredient for epilepsy treatment; Active substance in POTIGA tablets; Alternative name for ezogabine used in early correspondence

acetyl metabolite of ezogabine

NAMR, evaluated as an inhibitor of P-glycoprotein

Testing Methods

10
X-Ray Powder Diffraction

Graph plotted against 2-Theta Scale indicating crystalline modifications; Method used to differentiate crystalline forms

Bioequivalence Study

New BE study results in a major amendment; Failure to demonstrate BE of the test product and reference standard

Urinalysis

Clinical data required for safety evaluation; Safety assessment parameter (UA)

13-Week Dog Study

Pharmacology Toxicology study discussed in Info Amendment

bacterial reverse mutation assay

Preclinical safety testing reported in IND Safety Report

Comparative Oral Bioavailability Study

Study 110-US discussed in T-Con

IR spectroscopy

Analytical technique for identifying solid-state forms

uroflowmetry

Urodynamic measurement technique

electromyography

EMG measurement in urodynamic trial

multichannel cystometry

Urodynamic measurement technique

Processes

10
Crystallization

example of a reprocessing step

batch scale up

Manufacturing process change for commercial image

CMC update

Information Amendment regarding API and Finished Product; Chemistry, Manufacturing, and Controls information update

CMC

chemistry, manufacturing, and controls

28-day oral toxicity study

Preclinical study in dogs reported to FDA

acetylation

metabolic pathway for ezogabine involving NAT2

glucuronidation

primary metabolic pathway for ezogabine

titration

Alternative dosing strategy to improve tolerability.

PROCESSES FOR THEIR PREPARATION

Manufacturing processes for the novel modifications of the substance; Manufacturing methods described in the patent title; Manufacturing methods described in the patent title.

Thermal phase conversion

Method to obtain Modification B from Modification A at temperatures greater than 80°C.

Clinical Concepts

10
partial-onset seizures

Indication for POTIGA treatment; Indicated as adjunctive treatment of partial-onset seizures; indication for POTIGA treatment; Indication for Potiga as adjunctive treatment

Pneumonia

Symptoms used for diagnostic and treatment order options

Neutropenia

Expected toxicity with many MDS drugs

UTI

To assess for UTI, we recommend performing urinalysis

cardiac events

Request for info on cardiac events

QTc Findings

Cardiac safety report for Protocol 103

Suicidality

Analysis of terms requested by FDA

Asystole

Safety finding in case 2008VX000727

urinary crystals

Subject of protocol amendment for study 303

QTc

FDA comments regarding cardiac safety

Identified Hazards

Hazards

2
mutagenicity liability

FDA concurrence on lack of RGB mutagenicity

SAE (death)

Serious adverse event reported in safety reports

Standards & References

External Standards

3
USP Controlled Room Temperature

storage condition standard

German Notarization Act

The legal standard (BeurkG) cited for the notarization process.

X-ray diffractogram

Used to characterize Modification A of the compound

Specifications

4
2-Theta Scale

X-axis measurement for crystalline modification patterns

Stability requirements

FDA email regarding drug substance stability

Heat Flow

Y-axis measurement in W/g used to characterize thermal transitions

Wavenumber

X-axis measurement in CM-1 for infrared absorption bands

Related CFR Sections (4)

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

False or misleading risk presentation
4
Failure to submit under Form FDA-2253
3
Failure to submit promotional materials
2
Omission of material facts
2
False or misleading claims about efficacy and risks
1
False or misleading promotional communication
1
Failure to submit promotional materials at time of initial dissemination
1
False or Misleading Risk Presentation
1
Omission of Material Facts
1
Failure to Submit Under Form FDA-2253
1

Related Warning Letters (7)

See Also (8)