FDA Updates ICH E14 Q&A Modelling in QTc Prolongation Studies

Greg Hileman, Ph.D., Sr. Director and Principle Regulatory Scientist of Cato Research

The International Conference on Harmonization (ICH) last updated its guidance “THE CLINICAL EVALUATION OF QT/QTC INTERVAL PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS (ICH E14 (R3)) in 2005. This month, FDA published the most recent ICH updated list of questions and answers (ICH E14 Q&As ()) related to ICH E14, effectively making it an FDA guidance.  R3 included an updated question on the use of concentration-response modeling in lieu of point estimate and confidence interval calculation at Cmax. Important considerations when using modeling include the possibility of pooling data across multiple studies to explore a wider range of exposures than a single thorough QT prolongation study could explore while maintaining a focus on ECG quality and managing trial heterogeneity.  If data are available to estimate QT effects at sufficiently high multiples of clinically relevant exposures, a separate positive control may not be required.  As always, the focus of the analysis is to exclude a change of 10 ms or more (upper limit of the 90% confidence interval) at relevant concentrations. Significant savings with valid concentration-response modeling may result from predicting results at regimens not studied. A sponsor may be able to avoid certain intrinsic (enzyme induction or inhibition) and extrinsic (DDI) studies by predicting QTc effects.  High quality models may aid in deciding inclusion/exclusion criteria or in predicting dose adjustments needed in phase 3 and 4 studies where such factors are encountered.

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf

”ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3) – questions and answers”

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New FDA Guidances for June 2017

By Michelle Villasmil, Ph.D., RAC (US), Regulatory Scientist at Cato Research

FDA draft and final guidances released from CDER, CBER, and CDRH and Manual of Policies and Procedures (MAPPs) of interest released from CDER in June 2017 are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

 

Special Interest Guidances/Information Date Posted
Product Identifier Requirements Under the Drug Supply Chain Security Act – Compliance Policy Guidance for Industry – Draft Guidance 30 June 2017
Current Good Manufacturing Practice for Medical Gases – Draft Guidance 28 June 2017
Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products – Final Guidance 27 June 2017
Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Draft Guidance 20 June 2017
ANDAs: Pre-Submission Facility Correspondence Associated with Priority Submissions – Draft Guidance 19 June 2017
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Questions and Answers (R3) – Revision 13 June 2017
Form FDA 3674 – Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions – Final Guidance 07 June 2017
Special Interest Manual of Policies & Procedures (CDER) Date Posted
Acceptance Criteria for Residual Solvents 28 June 2017
Prioritization of the Review of Original ANDAs, Amendments, and Supplements 27 June 2017
Review of Bioequivalence Studies with Clinical Endpoints in ANDAs 22 June 2017
NDAs/BLAs: Financial Disclosure  21 June 2017
Upcoming Meetings (* = New)
* July 11, 2017: Meeting of the Oncologic Drugs Advisory Committee
* July 12, 2017: Meeting of the Oncologic Drugs Advisory Committee
* July 13, 2017: Meeting of the Oncologic Drugs Advisory Committee
  July 28, 2017: Vaccines and Related Biological Products Advisory Committee Meeting
* August 2, 2017: Meeting of the Arthritis Advisory Committee Meeting
Last updated: 3 July 2017
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What’s New Health Canada? April – May 2017

By Amelie Rodrigue-Way, Ph.D., RAC (CAN), Associate Director, Regulatory Strategy

 

What’s New in:

Therapeutic Products Directorate:

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/what-new-drug-products-health-canada.html

 

Biologics and Genetic Therapies Directorate:

http://www.hc-sc.gc.ca/dhp-mps/brgtherap/update-miseajour/index-eng.php

 

Medical Devices: https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-devices/what-new.html

 

Natural and Non-prescription Health Products Directorate: https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-prescription/what-new.html

 

 

Health Canada New Guidance Documents (Drugs and Biologics)

 

Health Canada Guidance Type Date Posted
Guidance Document: Master Files (MFs) – Procedures and Administrative Requirements Guidance Document 01 May 2017

 

Updates from Health Canada (Drugs and Biologics)

 

Type of Update and Link Date Posted
Product Monograph Brand Safety Updates 17 May 2017
Notice to Stakeholders: Release of the Product Monograph Template – Schedule D – Biosimilar Biologic Drug 15 May 2017
Updated Master File (MF) Application Fee Form For Human Drugs 01 May 2017
Notice: Release of the Final Guidance Document: Master Files (MFs) – Procedures and Administrative Requirements 28 Apr 2017
Notice Mandatory use of the Electronic Common Technical Document (eCTD) format 24 Apr 2017
Drug Product Database (DPD) Terminology   12 Apr 2017

 

Santé Canada: Quoi de neuf?

 

Par Amélie Rodrigue-Way, Ph.D., RAC (CAN), Directrice associée, Stratégie réglementaire

 

Quoi de neuf :

Direction des produits thérapeutiques

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/update-miseajour/index-fra.php

 

Direction des produits biologiques et thérapies génétiques:

http://www.hc-sc.gc.ca/dhp-mps/brgtherap/update-miseajour/index-fra.php

 

Instruments médicaux: https://www.canada.ca/fr/sante-canada/services/medicaments-produits-sante/instruments-medicaux/quoi-neuf.html

 

Direction des produits de santé naturels et sans ordonnance:

https://www.canada.ca/fr/sante-canada/services/medicaments-produits-sante/naturels-sans-ordonnance/quoi-de-neuf.html

 

Nouvelles lignes directrices de Santé Canada (Médicaments et Produits biologiques)

 

Ligne directrice de Santé Canada Genre Date
Ligne directrice – Fiches maîtresses (FM) – Procédures et exigences administratives Ligne Directrice 01 mai 2017

 

Mises à jour de Santé Canada (Médicaments et Produits biologiques)

 

Genre de mise à jour et lien Date
L’innocuité des monographies de produits pour les médicaments innovateurs 17 mai 2017
Avis à l’intention des intervenants : Publication du Modèle de monographie de produit – Annexe D – Médicament biologique biosimilaire 15 mai 2017
Mise à jour – Formulaire sur les frais pour Fiche maîtresses du médicament (FMM) 01 mai 2017
Avis : Publication de la version finale de la ligne directrice : Fiches maîtresses (FM) – Procédures et exigences administratives 28 avr. 2017
Avis – Utilisation obligatoire du format Electronic Common Technical Document (eCTD) 24 avr. 2017
Base de données sur les produits pharmaceutiques (BDPP) 12 avr. 2017

 

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New FDA Guidances for May 2017

By Sheila Plant, Ph.D., R.A.C., Assistant Director, Regulatory Strategy, US at Cato Research
One revised draft FDA guidance, released from CBER, and two MAPPs, released from CDER, in May 2017, are posted.  In addition, upcoming advisory committee meetings to be held in June and July are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Corrected Draft Guidance May 2017
Special Interest Manual of Policies & Procedures (CDER) Date Posted
CDER FTE Tracking and Table of Organization Review Process 30 May 2017
Good Review Practice: Clinical and Consultative Review of Drugs to Reduce the Risk of Cancer 16 May 2017
Upcoming Meetings (* = New)
* June 20, 2017: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting
* June 21-22, 2017: Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee Meeting
* July 28, 2017: Vaccines and Related Biological Products Advisory Committee Meeting
Last updated: 1 May 2017
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New FDA Guidances for March and April 2017

By Joanne McNelis, Ph.D., Clinical Strategy Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH, and Manual of Policies and Procedures (MAPPs) of interest, released from CDER in March and April are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Extending Expiration Dates of Doxycycline Tablets and Capsules in Strategic Stockpiles – Draft Guidance 24 Apr 2017
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications – Final Guidance 07 Apr 2017
Delayed Graft Function in Kidney Transplant: Developing Drugs for Prevention: Guidance for Industry – Draft Guidance 22 Mar 2017
Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims (Expiration date, updated) – Final Guidance 14 Mar 2017
Special Interest Manual of Policies & Procedures (CDER) Date Posted
Consulting the Controlled Substance Staff on Drug Abuse Potential and Labeling, Drug Scheduling, Dependence Liability and Drug Abuse Risks to the Public Health 06 Mar 2017
Upcoming Meetings (* = New)
* May 17, 2017: Gastroenterology and Urology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* May 17, 2017: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
* May 24, 2017: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
* May 25, 2017: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
2017 Advisory Committee Tentative Meetings
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