Oct 08 2019

New FDA Guidances for September 2019

Special Interest Guidances/Information Date Posted
Patient-Focused Drug Development: Methods to Identify What Is Important to Patients – Draft Guidance 30 Sep 2019
Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act – Final Guidance 27 Sep 2019
Clinical Decision Support Software – Draft Guidance 27 Sep 2019
General Wellness: Policy for Low Risk Devices – Final Guidance 27 Sep 2019
Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices – Final Guidance 27 Sep 2019
Off-The-Shelf Software Use in Medical Devices – Final Guidance 27 Sep 2019
Policy for Device Software Functions and Mobile Medical Applications – Final Guidance 27 Sep 2019
Providing Regulatory Submissions for Medical Devices in Electronic Format – Submissions Under Section 745A(b) of the Federal Food, Drug, and Cosmetic Act – Draft Guidance 26 Sep 2019
Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations – Draft Guidance 24 Sep 2019
Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment – Final Guidance 23 Sep 2019
The Accreditation Scheme for Conformity Assessment (ASCA) Pilot Program – Draft Guidance 23 Sep 2019
Wholesale Distributor Verification Requirement for Saleable Returned Drug Product—Compliance Policy – Final Guidance 23 Sep 2019
Conventional Foley Catheters – Performance Criteria for Safety and Performance Based Pathway – Draft Guidance 20 Sep 2019
Cutaneous Electrodes for Recording Purposes – Performance Criteria for Safety and Performance Based Pathway – Draft Guidance 20 Sep 2019
Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products – Draft Guidance 20 Sep 2019
Orthopedic Non-Spinal Metallic Bone Screws and Washers – Performance Criteria for Safety and Performance Based Pathway – Draft Guidance 20 Sep 2019
Safety and Performance Based Pathway – Final Guidance 20 Sep 2019
Spinal Plating Systems – Performance Criteria for Safety and Performance Based Pathway – Draft Guidance 20 Sep 2019
Safer Technologies Program for Medical Devices – Draft Guidance 19 Sep 2019
Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act – Final Guidance 18 Sep 2019
Format for Traditional and Abbreviated 510(k)s – Final Guidance 13 Sep 2019
Refuse to Accept Policy for 510(k)s – Final Guidance 13 Sep 2019
The Abbreviated 510(k) Program – Final Guidance 13 Sep 2019
The Special 510(k) Program – Final Guidance 13 Sep 2019
Acceptance Review for De Novo Classification Requests – Final Guidance 09 Sep 2019
FDA and Industry Actions on De Novo Classification Requests: Effect on FDA Review Clock and Goals – Final Guidance 09 Sep 2019
User Fees and Refunds for De Novo Classification Requests – Final Guidance 09 Sep 2019
Humanitarian Device Exemption (HDE) Program – Final Guidance 06 Sep 2019
Drugs for Treatment of Partial Onset Seizures: Full Extrapolation of Efficacy from Adults to Pediatric Patients 2 Years of Age and Older – Final Guidance 05 Sep 2019
Humanitarian Use Device (HUD) Designations – Final Guidance 05 Sep 2019
Evaluation of Internal Standard Responses During Chromatographic Bioanalysis: Questions and Answers – Final Guidance 04 Sep 2019
Upcoming Meetings (* = New)
  October 9, 2019: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
  October 16, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* October 29, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement
  October 30, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement
  November 6-7, 2019: General Hospital and Personal Use Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
  November 8, 2019: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
* November 13-14, 2019: Immunology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* November 14, 2019: Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement

Last updated: 04 October 2019

Sep 09 2019

New FDA Guidances for June to August 2019

Special Interest Guidances/Information Date Posted
Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions: Guidance for Industry and Food and Drug Administration Staff – Final 30 August 2019
Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications: Guidance for Industry and Food and Drug Administration Staff – Final 30 August 2019
Guidance for Industry: Policy Related to Cranberry Products with Added Flavorings – Final 30 August 2019
Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products Guidance for Industry – Final 28 August 2019
Male Breast Cancer: Developing Drugs for Treatment: Draft Guidance for Industry – Draft 27 August 2019
CVM GFI #257 (VICH GL57) Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Species: Marker Residue Depletion Studies to Establish Product Withdrawal Periods in Aquatic Species – Final 19 August 2019
Guidance for Industry: Converting Units of Measure for Folate, Niacin, and Vitamins A, D, and E on the Nutrition and Supplement Facts Labels – Final 15 August 2019
Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment Guidance for Industry: Guidance for Industry – Final 14 August 2019
Child-Resistant Packaging Statements in Drug Product Labeling Guidance for Industry – Final 13 August 2019
Gastroparesis: Clinical Evaluation of Drugs for Treatment Guidance for Industry – Draft 13 August 2019
Fabry Disease: Developing Drugs for Treatment Guidance for Industry – Draft 07 August 2019
FDA Deems Certain Tobacco Products Subject to FDA Authority, Sales and Distribution Restrictions, and Health Warning Requirements for Packages and Advertisements: Guidance for Industry – Final 02 August 2019
Testing and Labeling Medical Devices for Safety in the Magnetic Resonance (MR) Environment: Draft Guidance for Industry and Food and Drug Administration Staff – Draft 02 August 2019
“Harmful and Potentially Harmful Constituents” in Tobacco Products as Used in Section 904(e) of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry and FDA Staff – Final 02 August 2019
Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry – Final 01 August 2019
Bacterial Vaginosis: Developing Drugs for Treatment Guidance for Industry – Final 31 July 2019
E8(R1) GENERAL CONSIDERATIONS FOR CLINICAL STUDIES – Draft 31 July 2019
General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products Guidance for Industry – Draft 31 July 2019
Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers – Draft 31 July 2019
Uncomplicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry – Final 31 July 2019
Vulvovaginal Candidiasis: Developing Drugs for Treatment – Final 31 July 2019
Rare Pediatric Disease Priority Review Vouchers: Draft Guidance for Industry – Draft 30 July 2019
Delayed Graft Function in Kidney Transplantation: Developing Drugs for Prevention Guidance for Industry – Final 26 July 2019
Metal Expandable Biliary Stents – Premarket Notification (510(k)) Submissions: Guidance for Industry and Food and Drug Administration Staff – Final 26 July 2019
CVM GFI #181 Blue Bird Medicated Feed Labels – Final 23 July 2019
Providing Regulatory Submissions in Electronic Format–Submission of Manufacturing Establishment Information Guidance for Industry – Draft 23 July 2019
Postmarketing Safety Reporting for Combination Products: Guidance for Industry and FDA Staff – Final 22 July 2019
Submitting Next Generation Sequencing Data to the Division of Antiviral Products Guidance for Industry Technical Specifications Document – Final 18 July 2019
Advanced Prostate Cancer: Developing Gonadotropin-Releasing Hormone Analogues Guidance for Industry: Draft Clinical/Medical – Draft 17 July 2019
Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry – Draft 16 July 2019
Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy Guidance for Industry – Draft 11 July 2019
Live Case Presentations During Investigational Device Exemption (IDE) Clinical Trials: Guidance for Institutional Review Boards, Industry, Clinical Investigators, and Food and Drug Administration Staff – Final 11 July 2019
Population Pharmacokinetics – Draft 11 July 2019
Harmonizing Compendial Standards With Drug Application Approval Using the USP Pending Monograph Process Guidance for Industry – Draft 10 July 2019
Using the Inactive Ingredient Database Guidance for Industry – Draft 10 July 2019
Risk Evaluation and Mitigation Strategies: Modifications and Revisions Guidance for Industry – Final 09 July 2019
Compliance Policy for Certain Compounding of Oral Oxitriptan (5-HTP) Drug Products for Patients With Tetrahydrobiopterin (BH4) Deficiency Immediately in Effect Guidance for Industry – Final 05 July 2019
Center for Devices and Radiological Health (CDRH) Appeals Processes: Guidance for Industry and Food and Drug Administration Staff – Final 02 July 2019
Center for Devices and Radiological Health (CDRH) Appeals Processes: Questions and Answers About 517A: Guidance for Industry and Food and Drug Administration Staff – Final 02 July 2019
Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry – Draft 01 July 2019
Instructions for Use — Patient Labeling for Human Prescription Drug and Biological Products and Drug-Device and Biologic-Device Combination Products — Content and Format Guidance for Industry – Draft 01 July 2019
Epidermolysis Bullosa: Developing Drugs for Treatment of Cutaneous Manifestations; Guidance for Industry – Final 28 June 2019
Marketing Clearance of Diagnostic Ultrasound Systems and Transducers : Guidance for Industry and Food and Drug Administration Staff – Final 27 June 2019
Treatment for Heart Failure: Endpoints for Drug Development Guidance for Industry – Draft 27 June 2019
Clinical Investigations for Prostate Tissue Ablation Devices: Draft Guidance for Industry and Food and Drug Administration Staff – Draft 26 June 2019
E19 OPTIMISATION OF SAFETY DATA COLLECTION – Draft 26 June 2019
M10 BIOANALYTICAL METHOD VALIDATION – Draft 26 June 2019
Draft Guidance for Industry: Reducing Microbial Food Safety Hazards in the Production of Seed for Sprouting – Draft 24 June 2019
Providing Regulatory Submissions in Electronic and Non-Electronic Format—Promotional Labeling and Advertising Materials for Human Prescription Drugs – Final 21 June 2019
Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework Guidance for Industry – Draft 20 June 2019
Guidance for Industry: Determining the Number of Employees for Purposes of the “Small Business” Definition in Parts 117 and 507 – Final 19 June 2019
Guidance for Industry: Declaration of Added Sugars on Honey, Maple Syrup, Other Single-Ingredient Sugars and Syrups, and Certain Cranberry Products – Final 18 June 2019
Mouse Embryo Assay for Assisted Reproduction Technology Devices – Draft 13 June 2019
Testing for Biotin Interference in In Vitro Diagnostic Devices: Draft Draft Guidance for Industry – Draft 13 June 2019
ANDA Submissions — Content and Format of Abbreviated New Drug Applications: Guidance for Industry – Final 12 June 2019
Applications for Premarket Review of New Tobacco Products – Draft 11 June 2019
Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems (ENDS): Guidance for Industry – Final 11 June 2019
Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry – Draft 06 June 2019
Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry – Draft 06 June 2019
Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry – Draft 06 June 2019
Draft Guidance for Industry: Evaluating Alternate Curricula for the Standards for the Growing, Harvesting, Packing, and Holding of Produce for Human Consumption – Draft 03 June 2019
CPG Sec. 651.100 Ethylenediamine Dihydroiodide (EDDI) – Final 01 June 2019
Upcoming Meetings (* = New)
* Vaccines and Related Biological Products Advisory Committee November 8, 2019 Meeting Announcement – 11/08/2019 – 11/08/2019
* November 6-7, 2019: General Hospital and Personal Use Devices Panel of the Medical Devices Advisory Committee Meeting Announcement – 11/06/2019 – 11/07/2019
* October 30, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement – 10/30/2019 – 10/30/2019
* October 16, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement – 10/16/2019 – 10/16/2019
* Vaccines and Related Biological Products Advisory Committee October 9, 2019 Meeting Announcement – 10/09/2019 – 10/09/2019
* September 27, 2019: Meeting of the Pediatric and Drug Safety and Risk Management Committees – 09/27/2019 – 09/27/2019
* September 26, 2019: Meeting of the Pediatric and Drug Safety and Risk Management Advisory Committees – 09/26/2019 – 09/26/2019
* September 18, 2019: Meeting of the Nonprescription Drugs Advisory Committee Meeting Announcement – 09/18/2019 – 09/18/2019
* Allergenic Products Advisory Committee September 13, 2019 Meeting Announcement – 09/13/2019 – 09/13/2019
* September 10, 2019: Patient Engagement Advisory Committee Meeting Announcement – 09/10/2019 – 09/10/2019

Last updated: 09 September 2019

Aug 26 2019

What’s New Health Canada? June and July 2019 Updates

 

What’s New Health Canada?

By Christine Straccini, B.Sc., C.C.R.P., Regulatory Associate

  

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

 

Updates from Health Canada

 

Type of Update and Link Date Posted
Release of the revised Post-Notice of Compliance (NOC) Changes – Quality Guidance 31 July 2019
Release of the revised Notice regarding the Post-Notice of Compliance (NOC) Changes- Notices of Change: Level III Form 31 July 2019
Revisions to the Guidance Document: Management of Drug Submissions and Applications 25 July 2019
Organisation and Document Placement for Canadian Module 1 of the Common Technical Document (CTD) Structure 17 July 2019
Notice: Revisions to the Guidance Document: Administrative Processing of Submissions and Applications Involving Human or Disinfectant Drugs 28 June 2019
Consultation on: Draft Guidance: Canadian Module 1 Technical Implementation Guide for the Electronic Common Technical Document (eCTD) v4.0 Format 26 June 2019
Notice – New regulatory activity types for filing to the Marketed Health Products Directorate (MHPD) 21 June 2019
Notice – Regulatory Enrolment Process (REP) implementation and expansion of the scope for the Common Electronic Submissions Gateway (CESG) 20 June 2019
Update Noticed: Introduction of the Regulatory Enrolment Process (REP) and the Use of the Common Electronic Submission Gateway (CESG) for Medical Devices 07 June 2019
Updated Product Monograph Template – Schedule D and Schedule D Biosimilar Biologic Drug 04 June 2019

 

Santé Canada: Quoi de neuf?

Par Christine Straccini, B.Sc., C.C.R.P., Associée réglementaire

 

Quoi de neuf :

Direction des produits thérapeutiques

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

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

 

Mises à jour de Santé Canada

 

Genre de mise à jour et lien Date
Publication de la version révisée de la Ligne directrice: Changements survenus après l’avis de conformité (AC) : Document sur la qualité  

31 juillet 2019

Révision du Formulaire de déclaration de changements de niveau III de Santé Canada : Changements survenus après l’avis de conformité (AC)  

31 juillet 2019

Révisions à la ligne directrice : Gestion des présentations et des demandes de drogues  

25 juillet 2019

Organisation et emplacement des documents pour le module 1 canadien de la structure Common Technical Document (CTD)  

17 juillet 2019

Avis : Révisions du Ligne Directrice: Traitement administratif des présentations et des demandes concernant les médicaments destinés aux humains ou les désinfectants  

28 juin 2019

Consultation portant sur : L’ébauche de la ligne directrice: Guide de mise en œuvre technique du module 1 canadien pour le format Electronic Common Technical Document (eCTD) v. 4.0  

26 juin 2019

Avis – Nouveaux types d’activité de réglementation à présenter à la Direction des produits de santé commercialisés (DPSC)  

21 juin 2019

Avis – Mise en œuvre du Processus d’inscription réglementaire (PIR) et expansion du portail commun de demandes électroniques (PCDE)  

20 juin 2019

Mise à jour Avis : Implantation du processus d’inscription réglementaire (PIR) et de l’utilisation du portail commun de demandes électroniques (PCDE) pour les instruments médicaux  

07 juin 2019

Mise à jour le Modèle de monographie de produit – Annexe D et Annexe D médicament biologique biosimilaire  

04 juin 2019

 

 

Jul 23 2019

Complicated Drug Product? FDA Releases New Draft Guidance on Instructions for Use to Help Sponsors Communicate Proper Use to the Patient

Complicated Drug Product? FDA Releases New Draft Guidance on Instructions for Use to Help Sponsors Communicate Proper Use to the Patient

By Dieanira Erudaitius, Ph.D, Scientist at Cato Research

This month, July 2019, the United States Food and Drug Administration (FDA) released a new draft guidance to meet Prescription Drug User Fee Act (PDUFA) VI performance goals for patient oriented labeling. This draft guidance provides recommendations on the content and format development for Instructions for Use (IFU) documents submitted under a new drug application (NDA) or a biologics license application (BLA).[ ] The recommendations in this guidance do not apply to labeling for stand-alone medical devices,[1, , ] devices regulated under a BLA, or to labeling intended for healthcare providers.

What is an IFU and who reads it?
An IFU is a document that clearly describes to the patient the proper use of a complicated drug product. A drug product can be a drug, biologic, drug device, or biologic device combination. A complicated drug product can be products having difficult dosing regimens, misleading dosage forms (i.e., capsule must be sprinkled over food not swallowed)[1], special preparation instructions (i.e., thaw 30 minutes before administering), etc.

Because the targeted audience is the patient, the FDA recommends it be written in a patient friendly manner that is easily understood. To develop successful patient-facing documents at all literacy levels, the FDA suggests:

• Avoid using technical language and abbreviations
• Clearly state the actions a patient should take when using the product
• Write in active voice and command language
• Begin sentences or phrases with an action verb whenever possible (e.g., “Mix vial well” rather than “you should mix the vial well”)
• Write the dose designations (amount and volumetric units) clearly by expressing doses in whole numbers to avoid any confusion (e.g., 5 mg instead of 5.0 mg)

TANZEUM[ ], SPRAVATO[ ], TALTZ[ ], PROCRIT[ ], Ripatha[ ], are just a few of the products with FDA approved IFU documents for patients.

Applicants submitting an IFU
Applicants submit the IFU, along with the currently approved prescribing information (PI), to the FDA for review. The FDA will compare the IFU and the PI for scientific accuracy and consistency. The sections of the PI most often included in the IFU are the DOSAGE AND ADMINISTRATION, HOW SUPPLIED/STORAGE AND HANDLING, and PATIENT COUNSELING INFORMATION. The IFU submitted for FDA review must be a true representation of the content and format (same layout, color, etc.) that patients will read.

What is in the guidance?
The guidance gives examples and suggestions on the type of content to include in the IFU. The IFU should contain pertinent information on how the patient properly prepares, administers, handles, stores, and disposes the drug. Typically, this information comes from the PI; however, additional details to ensure safe and effective use of the drug by patients is also recommended to be included. For example, a section may be added to explain the route of administration for drugs where the dosage form may lead to confusion (e.g., oral tablet must dissolve in the mouth instead of being swallowed) or perhaps the drug has a difficult dosing regimen that needs describing. The guidance also discusses formatting tips and tricks for appropriate bolding techniques, utilizing white space and color to enhance document readability, etc.

The IFU must be written clearly to avoid medication errors or improper use of the drug product. IFU documents are required for drug products with complicated or detailed patient use instructions. To ensure appropriate use of the drug product, the IFU must be clearly and informatively written to enhance the patients’ understanding and ensure patient safety and drug efficacy.
Complicated Drug Product? FDA Releases New Draft Guidance on Instructions for Use to Help Sponsors Communicate Proper Use to the Patient

By Dieanira Erudaitius, Ph.D, Scientist at Cato Research

This month, July 2019, the United States Food and Drug Administration (FDA) released a new draft guidance to meet Prescription Drug User Fee Act (PDUFA) VI performance goals for patient oriented labeling. This draft guidance provides recommendations on the content and format development for Instructions for Use (IFU) documents submitted under a new drug application (NDA) or a biologics license application (BLA).[ ] The recommendations in this guidance do not apply to labeling for stand-alone medical devices,[1, , ] devices regulated under a BLA, or to labeling intended for healthcare providers.

What is an IFU and who reads it?
An IFU is a document that clearly describes to the patient the proper use of a complicated drug product. A drug product can be a drug, biologic, drug device, or biologic device combination. A complicated drug product can be products having difficult dosing regimens, misleading dosage forms (i.e., capsule must be sprinkled over food not swallowed)[1], special preparation instructions (i.e., thaw 30 minutes before administering), etc.

Because the targeted audience is the patient, the FDA recommends it be written in a patient friendly manner that is easily understood. To develop successful patient-facing documents at all literacy levels, the FDA suggests:

• Avoid using technical language and abbreviations
• Clearly state the actions a patient should take when using the product
• Write in active voice and command language
• Begin sentences or phrases with an action verb whenever possible (e.g., “Mix vial well” rather than “you should mix the vial well”)
• Write the dose designations (amount and volumetric units) clearly by expressing doses in whole numbers to avoid any confusion (e.g., 5 mg instead of 5.0 mg)

TANZEUM[ ], SPRAVATO[ ], TALTZ[ ], PROCRIT[ ], Ripatha[ ], are just a few of the products with FDA approved IFU documents for patients.

Applicants submitting an IFU
Applicants submit the IFU, along with the currently approved prescribing information (PI), to the FDA for review. The FDA will compare the IFU and the PI for scientific accuracy and consistency. The sections of the PI most often included in the IFU are the DOSAGE AND ADMINISTRATION, HOW SUPPLIED/STORAGE AND HANDLING, and PATIENT COUNSELING INFORMATION. The IFU submitted for FDA review must be a true representation of the content and format (same layout, color, etc.) that patients will read.

What is in the guidance?
The guidance gives examples and suggestions on the type of content to include in the IFU. The IFU should contain pertinent information on how the patient properly prepares, administers, handles, stores, and disposes the drug. Typically, this information comes from the PI; however, additional details to ensure safe and effective use of the drug by patients is also recommended to be included. For example, a section may be added to explain the route of administration for drugs where the dosage form may lead to confusion (e.g., oral tablet must dissolve in the mouth instead of being swallowed) or perhaps the drug has a difficult dosing regimen that needs describing. The guidance also discusses formatting tips and tricks for appropriate bolding techniques, utilizing white space and color to enhance document readability, etc.

The IFU must be written clearly to avoid medication errors or improper use of the drug product. IFU documents are required for drug products with complicated or detailed patient use instructions. To ensure appropriate use of the drug product, the IFU must be clearly and informatively written to enhance the patients’ understanding and ensure patient safety and drug efficacy.

Jun 14 2019

New FDA Guidance’s For May 2019

Special Interest Guidances/Information Date Posted
Formal Dispute Resolution: Sponsor Appeals Above the Division Level Guidance for Industry and Review Staff – Final Guidance 30 May 2019
Section 503A Bulks List Final Rule Questions and Answers; Small Entity Compliance Guide;: Guidance for Industry – Final Guidance 24 May 2019
Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry – Draft Guidance 21 May 2019
Draft Guidance for Industry: The Use of an Alternate Name for Potassium Chloride in Food Labeling – Draft Guidance 17 May 2019
Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry – Final Guidance 09 May 2019
Determining Whether to Submit an ANDA or a 505(b)(2) Application – Final Guidance 09 May 2019
Maximal Usage Trials for Topically Applied Active Ingredients Being Considered for Inclusion in an Over-The -Counter Monograph: Study Elements and Considerations – Final Guidance 09 May 2019
Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations Guidance for Industry: Guidance for Industry – Final Guidance 09 May 2019
Recommendations for Reducing the Risk of Transfusion-Transmitted Babesiosis: Guidance for Industry – Final Guidance 09 May 2019
Classification and Requirements for Laser Illuminated Projectors (LIPs) (Laser Notice No. 57): Guidance for Industry and Food and Drug Administration – Final Guidance 08 May 2019
Clinical Lactation Studies: Considerations for Study Design – Draft Guidance 08 May 2019
Guidance for Industry: Preparation of Food Contact Notifications for Food Contact Substances in Contact with Infant Formula and/or Human Milk – Final Guidance 08 May 2019
Laser Products – Conformance with IEC 60825-1 Ed. 3 and IEC 60601-2-22 Ed. 3.1 (Laser Notice No. 56): Guidance for Industry and Food and Drug Administration Staff – Final Guidance 08 May 2019
Medical X-Ray Imaging Devices Conformance with IEC Standards: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 08 May 2019
Policy Clarification for Certain Fluoroscopic Equipment Requirements: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 08 May 2019
Postapproval Pregnancy Safety Studies Guidance for Industry – Draft Guidance 08 May 2019
Submitting Documents Utilizing Real-World Data and Real-World Evidence to FDA for Drugs and Biologics – Draft Guidance 08 May 2019
Utilizing Animal Studies to Evaluate Organ Preservation Devices: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 08 May 2019
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 07 May 2019
Attention Deficit Hyperactivity Disorder: Developing Stimulant Drugs for Treatment Guidance for Industry – Draft Guidance 03 May 2019
Upcoming Meetings (* = New)
  May 14, 2019: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
  May 30-31, 2019: General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
  June 6, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
  June 11-12, 2019: Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee
  June 19-20, 2019: Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
  June 20, 2019: Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee

 

Last updated: 13 June 2019

May 10 2019

New FDA Guidance’s for April 2019

Special Interest Guidances/Information Date Posted
Characterization of Ultrahigh Molecular Weight Polyethylene (UHMWPE) Used in Orthopedic Devices: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 26 Apr 2019
Recommended Content and Format of Non-Clinical Bench Performance Testing Information in Premarket Submissions: Guidance for Industry and Food and Drug Administration Staff – Final Guidance 26 Apr 2019
Unique Device Identification: Convenience Kits : Guidance for Industry and Food and Drug Administration Staff – Final Guidance 26 Apr 2019
Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biologics with Continuous Outcomes Guidance for Industry – Draft Guidance 24 Apr 2019
Extending Expiration Dates of Doxycycline Tablets and Capsules in Strategic Stockpiles – Final Guidance 24 Apr 2019
Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C Guidance for Industry and FDA Staff – Draft Guidance 24 Apr 2019
Surgical Staplers and Staples for Internal Use – Labeling Recommendations: Draft Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 24 Apr 2019
Compliance Policy for Combination Product Postmarketing Safety Reporting: Immediately in Effect Guidance for Industry and Food and Drug Administration Staff – Final Guidance 21 Apr 2019
Technical Considerations for Non-Clinical Assessment of Medical Devices Containing Nitinol: Draft Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 19 Apr 2019
Technical Performance Assessment of Quantitative Imaging in Device Premarket Submissions: Draft Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 19 Apr 2019
Bispecific Antibody Development Programs Guidance for Industry – Draft Guidance 18 Apr 2019
Draft Guidance for Industry: The Declaration of Allulose and Calories from Allulose on Nutrition and Supplement Facts Labels – Draft Guidance 17 Apr 2019
1988 FDA Guidance for the Format and Content of the Clinical and Statistical Section of an Application – Final Guidance 13 Apr 2019
FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary – Final Guidance 4 Apr 2019
Class II Special Controls Guideline: In Vitro Diagnostic Devices for Bacillus spp. Detection: Guideline for Industry and Food and Drug Administration Staff – Final Guidance 1 Apr 2019
Review and Update of Device Establishment Inspection Processes and Standards: Draft Draft Guidance for Industry – Draft Guidance 29 Mar 2019
CVM GFI #120 Veterinary Feed Directive Regulation Questions and Answers – Draft Guidance 28 Mar 2019
Guidance for Industry: Enforcement Policy for Entities Growing, Harvesting, Packing, or Holding Hops, Wine Grapes, Pulse Crops, and Almonds – Final Guidance 27 Mar 2019
Upcoming Meetings (* = New)
* May 14, 2019: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
* May 30-31, 2019: General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* June 6, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* June 11-12, 2019: Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee
* June 19-20, 2019: Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* June 20, 2019: Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee

 

Last updated: 09 May 2019

Apr 24 2019

New FDA Guidance on Natural History Studies for Rare Diseases

In a recent Ask Cato blog post, I summarized a revised FDA guidance issued in January 2019, Rare Diseases: Common Issues in Drug Development.1 The guidance covers a range of topics, including the use of surrogate biomarkers, nonclinical flexibility, and natural history studies, to assist sponsors in conducting more efficient drug development programs for rare diseases. In March 2019, FDA released its sixth rare disease guidance, Rare Diseases: Natural History Studies for Drug Development,2 which expands on the topic of natural history studies and how they can be used to support the development of drugs and biologics.

Due to the limited information on the natural histories of many rare diseases, natural history studies are particularly important for the development of rare disease therapeutics. Natural history studies provide valuable knowledge of a disease that can aid in the design of clinical trials. Further, they may also provide data to be used as an external control in a clinical trial when a placebo or active-control arm may not be feasible or ethical. Major highlights of the March 2019 guidance are summarized below.

What is a natural history study?

A natural history study is an observational study that follows the course of a disease in individuals to better understand how a disease develops and how it may be treated. Natural history studies aim to identify demographic, genetic, or environmental variables that correlate with the disease’s development and outcomes. Although the natural history of a disease is defined as the course a disease takes in the absence of intervention, natural history studies often include patients receiving the current standard of care, which may alter how the disease naturally progresses.

How can natural history studies be used in drug development?

FDA’s guidance highlights four key ways in which a natural history study may contribute to a drug development program:

  1. Identification of the patient population
  2. Identification or development of clinical outcome assessments
  3. Identification or development of biomarkers
  4. Design of externally controlled studies

While not the primary focus of the guidance, FDA touches briefly on the use of natural history data as an external control in clinical trials. The use of natural history data as an external control is of particular interest to sponsors developing therapies for rare diseases, for which placebo-controlled studies are difficult to complete due to ethical concerns or subject limitations, such as small populations. FDA recognizes that a natural history study may provide an external control group for interventional trials if it is well-designed and conducted. However, natural history studies are subject to certain biases (see Table 1), which can limit their ability to demonstrate effectiveness. To mitigate bias, FDA notes that the treatment effect of the investigational drug should be dramatic.

FDA distinguishes between two types of external controls: nonconcurrent and concurrent (Figure 1). A natural history study completed before an interventional trial is classified as a nonconcurrent external control (also commonly referred to as a historical control).

Figure 1. Types of External Controls

What are the different types of natural history studies?

As noted above, natural history studies can play an important role in the development of rare disease therapies. Depending on the goal of the drug development program, the design of a natural history study can take on several forms.

Natural history studies can be:

  1. Retrospective or prospective; and
  2. Cross-sectional or longitudinal

Retrospective studies are studies in which patient evaluations have already occurred. In contrast, prospective studies are studies in which evaluations occur in the future according to a prespecified data collection plan. In cross-sectional studies, data are collected from patients at a single point in time, which may be set by a stage of illness, date of diagnosis, onset of symptoms, or other criteria. In longitudinal studies, data are collected from the same group of patients over a period of time.

Table 1 compares the characteristics of retrospective studies with those of prospective studies.

Table 1. Comparison of Retrospective and Prospective Studies

Topic Retrospective Prospective
Data collection Data commonly come from existing medical records (e.g., patient charts)

 

Data may have been collected at variable time points or were obtained inconsistently

New data are generated after initiation of the study

 

Studies can follow standard operating procedures, which allows for greater consistency in the information collected

Duration Studies can be performed quickly Studies generally require more time
Medical terminology Medical terminology may have changed over time or have been used inconsistently among health care providers (unclear use of terms may limit interpretability and result in incomplete information) Studies can use up-to-date definitions of medical conditions and treatments
Bias Can be biased through patient selection criteria and through selection of dates of inception and cutoff

 

May be subjected to referral bias (study includes only the most severely affected patients)

 

May be subjected to length-biased sampling (patients who have been in the database the longest may be overrepresented)

Study evaluations occur in the future and are not highly susceptible to bias

 

Due to the limitations of retrospective studies, which may include inconsistent measurement procedures, irregular time intervals, and the unclear use of terms, retrospective natural history studies are more susceptible to bias than prospective natural history studies.  These limitations may prevent such studies from being used as external controls if patient characteristics of an interventional trial cannot be matched with those of the historical control. In contrast, prospective studies allow for the use of standard operating procedures and schedules so that data is collected consistently.

Retrospective and prospective studies may be further classified as either cross-sectional or longitudinal. Table 2 summarizes the advantages of cross-sectional and longitudinal studies.

Table 2. Comparison of Cross-Sectional and Longitudinal Studies

Advantage Cross-Sectional Longitudinal
Faster data collection and analysis?
Less resource intensive?
Provide more comprehensive information about disease onset and progression?
Better suited to distinguish the variety of phenotypes and subgroups of a disease?
Data are more likely to be used an external control group?

 

While data from cross-sectional studies are less likely to be suited to be used as an external control group compared to longitudinal studies, cross-sectional natural history studies may provide valuable information for therapies intended to provide largely immediate benefits in patients experiencing an acute episode or flare of a disease. In general, longitudinal studies provide more comprehensive information about disease onset and progression.

It is important to note that while prospective, longitudinal natural history studies are desirable, the initiation of such studies should not delay a drug development program if interventional testing is ready to proceed for a serious disease with unmet medical need.

What are important considerations for the protocol, study design, data collection, and protection of human subjects in natural history studies?

FDA’s Natural History Studies guidance2 also includes sections on topics related to the protocol, study design, data collection, human subject protection, and interactions with the FDA. Below is a subset of the considerations for natural history studies noted in the guidance:

  • Data that will be used to support a marketing application should be collected according to the data standards for marketing applications. International data standards should also be considered.
  • Data should not be limited to the most severely affected body systems because treatment responses might be more reliably detected by evaluation of a less affected body system.
  • Natural history studies should have a prospectively defined statistical analysis plan.
  • Patients may be identified via disease-specific support groups or patient advocacy groups.
  • Natural history studies can be registered in https://www.ClinicalTrials.gov to increase participation and recruitment.
  • Natural history studies should code data from patient experiences using a vocabulary that is standardized (e.g., Medical Dictionary for Regulatory Activities [MedDRA]).
  • FDA encourages the dissemination of clinical data from a natural history study, as well as the methods and practical aspects of conducting the study, as widely as possible (e.g., through peer-reviewed publications) due to the lack of information available for rare disease.
  • Natural history studies may be subject to 21 CFR Parts 50 and 56 if they meet the definitions of clinical investigation and other applicable definitions under those parts. Regulations under 45 CFR Part 46 (also known as the Common Rule) may also apply.
  • Institutional Review Board (IRB) review is generally required for a natural history study that is subject to the Common Rule.
  • When planning a natural history study, it is important to consider that the data and biospecimens collected may be useful in future secondary research. The study organizer should work with an IRB to determine the best approach to obtain consent for this possibility.
  • FDA discussions do not need to be conducted in the context of a regulatory submission or meeting. Critical Path Innovation meetings may provide advice on drug development issues.

References

1FDA. Rare Diseases: Common Issues in Drug Development. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM629579.pdf; 31 January 2019.

2FDA. Rare Diseases: Natural History Studies for Drug Development. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM634062.pdf; 22 March 2019.

 

 

Apr 10 2019

2019 March FDA Guidances

Special Interest Guidances/Information Date Posted
Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling Good Review Practice – Final Guidance 27 Mar 2019
Standards Development and the Use of Standards in Regulatory Submissions Reviewed in the Center for Biologics Evaluation and Research – Final Guidance 25 Mar 2019
Rare Diseases: Natural History Studies for Drug Development – Draft Guidance 22 Mar 2019
Pediatric HIV Infection: Drug Development for Treatment – Final Guidance 19 Mar 2019
Human Immunodeficiency Virus-1 Infection: Developing Systemic Drug Products for Pre-Exposure Prophylaxis – Final Guidance 19 Mar 2019
Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices) – Final Guidance 15 Mar 2019
A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers – Draft Guidance 14 Mar 2019
Severely Debilitating or Life-Threatening Hematologic Disorders: Nonclinical Development of Pharmaceuticals – Final Guidance 14 Mar 2019
Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products – Final Guidance 14 Mar 2019
Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials – Final Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients – Draft Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies – Draft Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Brain Metastases – Draft Guidance 12 Mar 2019
Nonproprietary Naming of Biological Products – Draft Guidance 07 Mar 2019
Upcoming Meetings (* = New)
* April 25, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* April 26, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* May 8, 2019: Meeting of the Pulmonary-Allergy Drugs Advisory Committee Meeting Announcement

Last updated: 09 April 2019

Mar 22 2019

Does the FDA Esketamine Approval Open the Door for Enrichment Trial Designs in Psychiatry?

By Greg Hileman, Ph.D, Senior Director of Regulatory Affairs and Principle Regulatory Scientist at Cato Research

 

On March 5, the FDA approved Spravato (esketamine) nasal spray, for use in conjunction with an oral antidepressant for treatment-resistant depression. Esketamine is the s-enantiomer of ketamine, approved in the 1970’s as an anesthetic, but used off-label since the 1990’s for treating depression. Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

Of importance to the development of products in the Division of Psychiatric Products (DPP), the efficacy of esketamine was established in one short-term study (two other, similar short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness) and one longer-term maintenance-of-effect trial using a randomized withdrawal study design. In this latter study, patients with a stable response while taking esketamine plus an oral antidepressant were re-randomized, with a portion of the group switched to placebo. Patients remaining on esketamine experienced a statistically significantly longer time to relapse of depressive symptoms than patients switched to placebo.

This approval based on an enriched study design was one of the first for the DPP. Industry and FDA have long debated the utility of enriched study design as providing substantial evidence of efficacy. The key issue identified by FDA statisticians is in controlling type 1 error with stepwise randomization schema and subsequently generalizing results from an enriched population to a general population as key. Various enrichment strategies have been proposed to address the large and growing placebo effect in psychiatry clinical trials. FDA guidance on clinical trial designs encourages the exploration of enrichment and other adaptive study designs in Phase 2, but cautions against relying on such trials for generating pivotal evidence of efficacy.

One can speculate that the approval of esketamine for depression may have political roots, since it allows FDA to exercise enforcement authority over the widespread off-label use of ketamine, now that seriously ill patients have a safe and effective approved product in this space. We are optimistic that the approval of esketamine on the basis of this randomized withdrawal maintenance study may herald a new FDA attitude on the topic supported by incoming Acting Division Director Tiffany Farchione, whose first public appearance in that role was at the 12 February Psychiatric Products Advisory Committee Meeting reviewing esketamine. In her opening remarks, Dr. Farchione explicitly stated that the Division considered the randomized withdrawal study to be “adequate and well controlled” for purposes of providing substantial evidence of effectiveness.

The strength of these remarks bodes well for patients suffering a variety of psychiatric disorders where placebo effects have been attributed to the failure of clinical trial not only in depression, but also in anxiety disorders, schizophrenia and most conditions where structured patient interviews serve as the primary endpoints.

 

 

Mar 20 2019

FDA Approval of New Opioid Drug (DSUVIATM) Stirs Controversy – Is it Necessary or Not?

By Dieanira Erudaitius, Ph.D., Scientist at Cato Research

The United States Food and Drug Administration (FDA) granted approval of the opioid analgesic DSUVIATM on 02 November 2018.[[1]] Its intended use is for adults only where acute pain management has no alternative treatment other than an opioid analgesic.

DSUVIATM is a sublingual tablet containing sufentanil as the active pharmaceutical ingredient (API), a Schedule II controlled substance.[[2]] Sufentanil is an analogue of fentanyl; however, unlike fentanyl that has a potency of 100 times that of morphine, sufentanil is 1,000 times more potent.[[3]] While its potency raises concerns regarding addiction and misuse, advocates for the drug point out that sufentanil is currently already used in the hospital setting where it is intravenously delivered. Intravenous delivery (i.v.) of opioids does provide advantages such as providing immediate relief to the patient; however, it also has risks associated with dosing (e.g., issues have been reported of overdosing the patient).[[4]] DSUVIATM is unique because of its alternative sublingual oral form of delivery [[5]], which advocates argue is more easily controlled for dosing.

Opioids, regardless of the potency, raise concerns because of the risks associated with addiction, abuse, and misuse. Opponents to DSUVIATM’s approval point out that the pill form of the opioid makes it easily divertible. Illicit diversion is not at all uncommon, and is especially a problem for opioids.[3] While the FDA does not have a way to control or prevent this specific type of abuse, the agency did put strong limitations on its use. The FDA required an additional Risk Evaluation and Mitigation Strategy (REMS) from the manufacturer to ensure any risk from accidental exposure is adequately controlled.[[6]] Further, DSUVIATM has been approved for use only in certified, medically-supervised healthcare settings. These settings include emergency rooms (ERs), hospitals, and surgical centers where a certified healthcare provider is to administer the drug.[2]

Many medical experts and advocates in favor of opioid control question whether there was really a need to bring an additional opioid drug to the market. A common argument for the need of a more potent opioid is that oligoanalgesia (the inadequate treatment of pain) does remain a prominent issue in the hospital setting, especially for patients admitted to the ER. Proponents believe that there is not only a need for an opioid strong enough to alleviate such pain but opioids have the potential to be more beneficial than harmful when controlled and monitored appropriately.[[7]] DSUVIATM is targeted at a population where opioid analgesic treatment is required but i.v. administration is not feasible and oral delivery is impractical (e.g., patient can’t swallow).[[8]] Additionally it is argued that the dissolving sublingual tablet is superior to current methods of opioid delivery because the absorption is prolonged resulting in longer analgesia treatment.[8] The Department of Defense (DOD) provided funding support for DSUVIATM with the primary interest of aiding U.S. soldiers wounded in battle. Scott Gottlieb, commissioner of the FDA from 2010 to 2019, supported the approval stating on Twitter that “[w]hile DSUVIATM brings another highly-potent opioid to market it fulfills a limited, unmet medical need.” The unmet need refers to soldiers who often do not have access to intravenous treatment on the battlefield, making an equally potent tablet form necessary for the initial treatment of battlefield injuries.

The indications and usage of DSUVIATM, however, do not explicitly limit use to the soldier population. Like most drugs, it will be left to the discretion of the medical professionals administering the drug, thus increasing the population of patients that may be exposed to such a potent opioid. Critics question whether the FDA should have approved such a drug in the current climate of opioid abuse striking our nation. Dr. Raeford E. Brown, chair of the FDA’s Advisory Committee on Analgesic Drug Products, expressed his concerns in a statement to the FDA arguing that over the past 10 years there has been no historical proof of successful control over any of the marketed opioids nor sufficient data demonstrating their safety.[3]

Scott Gottlieb addressed the controversy around the new opioid approval by explaining that the FDA approves drugs when the benefits outweigh the risks and when there is sufficient evidence for the safety and efficacy for use of the drug in humans.[1] Table 1 lists a brief comparison between the different views (critics vs. advocates) for DSUVIATM.

Table 1. Comparison of views presented by critics and advocates of DSUVIATM.

Topic Critics of DSUVIATM Advocates for DSUVIATM
Method of delivery ·         Increases likelihood of illicit diversion (small pill)

·         Abuse by healthcare individuals is not uncommon

·         Improves dosing control

·         Noninvasive

·         Brings treatment for unmet population of patients unable to take i.v. and oral tablet

Pharmacological potency

(API – sufentanil)

·         1,000 times more potent than morphine

·         Highly addictive

·         Irrelevant because API is currently used intravenously in hospital settings
Opioid crisis and health of the general population ·         Approval increases the risk of abuse, addiction, and misuse (e.g., fentanyl is produced illicitly and contributes to many deaths)

·         No historical proof of FDAs ability to enforce control

·         No post-marketing assessment

·         REMS program for opioids

·         Specific regulation defined for use of DSUVIATM to prevent risks (e.g., only available in hospital setting making accessibility to the general public limited)

·         Usage has limit of 72 hours maximum

 

Meets an unmet need ·         Benefits don’t outweigh the risk, when potent opioids are already on the market ·         Provides management of extreme pain (e.g., soldiers)

·         Years since any new opioid has been brought to the market

 

There has also been talk about AcelRx Pharmaceuticals (the company that developed and commercialized DSUVIATM in the United States) looking for a Canadian partner to obtain approval for the opioid through Health Canada.[[9]] This is alarming considering Canada’s opioid crisis is also on the rise. The Canadian government is specifically concerned with the harm caused by opioids, including fentanyl, and have taken federal action to control opioid substance abuse.[[10]] A number of medical professionals are urging Health Canada to carefully consider such an approval as it brings a large risk to the general public.[9]

In summary, the FDA approved a new form of a potent analgesic opioid for a population of adults requiring strong medication to relieve pain. The question as to whether placing another opioid on the market was necessary is surrounded by a strong controversy. The main concerns are (1) whether the needs of those with acute uncontrolled pain who will benefit from the medication are outweighed by the government’s responsibility to protect the society as a whole and (2) is the REMS for DSUVIATM (or any opioid/drug) adequate to address the potential risks of abuse.

 

L’Approbation d’un nouvel Opioïde (DSUVIATM) par la FDA qui fait controverse – Est-ce que c’est nécessaire?  

Par Dieanira Erudaitius, Ph.D., Scientifique à Cato Research

Le 02 novembre 2018, l’Agence Américaine des Produits Alimentaires et Médicamenteux (ci-après FDA) aux États-Unis a approuvé l’analgésique opioïde DSUVIATM.[[11]] L’utilisation prévue de ce médicament est réservée aux adultes pour lesquels aucun traitement pour la douleur aiguë, autre que les opiacés, n’est disponible.

DSUVIATM est un comprimé sublingual contenant l’ingrédient pharmaceutique actif sufentanil, une substance contrôlée inscrite à l’annexe II de la United States Controlled Substances Act.[[12]] Sufentanil est un analogue de fentanyl; mais contrairement au fentanyl, qui est 100 fois plus puissant que la morphine, sufentanil est 1,000 fois plus puissant.[[13]] Cela soulève d’importantes inquiétudes concernant des problèmes d’abus et de dépendance. Malgré cela, les promoteurs signalent que le sufentanil est déjà utilisé dans le contexte hospitalier avec la distinction que la drogue est administrée par voie intraveineuse. En effet, l’administration intraveineuse des opioïdes peut fournir un soulagement immédiat aux patients, mais aussi augmenter les risques de surdosage.[[14]] DSUVIATM étant administré par voie sublinguale [[15]], les partisans affirment qu’il est plus facile de contrôler le dosage.

Sans égard à leur puissance, les opioïdes peuvent poser de graves problèmes de santé aux patients à cause des risques associés à la dépendance, l’abus, et l’usage inadéquat de la drogue. Les opposants à l’approbation de DSUVIATM informent aussi que la petite taille du comprimé facilite le détournement illicite ce qui n’est pas inhabituel et constitue un grave problème pour cette classe d’agent pharmacologique.[3] La FDA n’a pas la capacité de contrôler ou prévenir ce type d’abus, mais ils ont imposé des conditions d’utilisation strictes. Par conséquent, un programme complémentaire sous le nom « Stratégie d’évaluation et d’atténuation des risques » (REMS, son acronyme en anglais) a été mis en place pour garantir que les risques d’exposition accidentelle sont limités.[[16]] En outre, DSUVIATM at été approuvé uniquement pour l’usage dans les centres médicaux supervisés, ce qui comprend les salles d’urgence, les hôpitaux, et les centres de chirurgie où un professionnel de la santé doit administrer la drogue.[2]

De nombreux experts médicaux et de partisans d’un contrôle plus stricte des opioïdes questionnent la nécessité d‘un autre opioïde sur le marché. Un argument couramment invoqué pour justifier le besoin d’une opioïde puissante est celui de l’  « oligoanalgesia » (le traitement inadéquat de la douleur) qui demeure une priorité des services de santé, notamment pour les patients admis aux urgences. Les promoteurs suggèrent qu’il existe toujours un besoin pour des opioïdes suffisamment fort pour soulager adéquatement la douleur et que les opioïdes peuvent présenter l’avantage d’être plus bénéfiques que néfastes quand ils sont rigoureusement contrôlés et surveillés.[[17]] DSUVIATM est destinée aux patients qui nécessitent une analgésie opioïde mais pour lesquels une administration intraveineuse ou orale n’est pas possible (par exemple, un patient n’arrivant pas à avaler).[[18]] De plus, on fait valoir que la formulation en comprimé sublingual à dissolution rapide de DSUVIATM rend ce produit supérieur à d’autres méthodes d’administration puisque que son absorption prolongée entraine également une analgésie prolongée.[8] Le Département de la Défense a fourni un financement pour appuyer le développement de cette drogue afin d’aider les soldats blessés. Scott Gottlieb, commissaire de la FDA de 2010 à 2019, a plaidé en faveur de l’approbation de DSUVIATM. Il a déclaré sur son compte Twitter qu’ « Alors que DSUVIATM apporte un autre opioïde extrêmement puissant sur le marché, il répond à un besoin médical insatisfait » Ce besoin médical insatisfait concerne le traitement des soldats qui souvent n’ont pas accès au traitement intraveineux. Il est donc nécessaire d’avoir une drogue sous forme de comprimés qui est aussi puissante afin de donner les premiers soins aux soldats sur un champ de bataille.

Cependant, l’indication de DSUVIATM n’est pas expressément limitée aux soldats. Comme pour la plupart des médicaments, la décision de prescrire ce nouvel opioïde, et d’ainsi accroitre la population exposée à un produit particulièrement puissant, demeure à la discrétion du médecin traitant. Les critiques questionnent la décision de la FDA d’approuver un tel médicament dans un climat marqué par les problèmes liés à la dépendance et abus d’opioïdes. Dr. Raeford E. Brown, président du comité consultatif sur les analgésiques de la FDA, a exprimé ses préoccupations dans une déclaration à la FDA dans laquelle il souligne qu’au cours de la dernière décennie, il n’y a aucune démonstration qu’un contrôle adéquat n’ait été exercé sur les opioïdes disponibles sur le marché ou qu’il existe suffisamment de données pour démontrer la sécurité de ces produits.[3]

Scott Gottlieb a répondu à la controverse entourant l’approbation de ce nouvel opioïde en expliquant que la FDA approuve les médicaments si les avantages surpassent les risques et s’il existe des éléments de preuve suffisants pour soutenir l’utilisation, la sécurité, et l’efficacité de la drogue.[1] Une brève comparaison entre les points de vue exprimés par ces deux positions (partisans et détracteurs) est fournie dans le Tableau 1.

Tableau 1. Comparaison entre les deux groups.

Sujet Les Critiques de DSUVIATM Les Promoteurs de DSUVIATM
Le mode d’administration ·         Accroît la probabilité de détournements illicites (une petite pilule)

·         L’abus par les professionnels de la santé n’est pas rare

·         La précision de dosage s’améliorera

·         Non invasive

·         Il offre de traitements aux patients qui sont incapable d’avaler un comprimé et administration intraveineuse n’est pas une solution

La puissance pharmacologique (ingrédient pharmaceutique actif – sufentanil) ·         1,000 fois plus puissant que la morphine

·         Il crée une forte dépendance

·         Non pertinent parce que l’ingrédient pharmaceutique actif est actuellement utilisé à l’hôpital par voie intraveineuse
L’abus d’opioïdes et la santé de la population en général ·         L’approbation augmente considérablement les risques entourant l’abus, d’accoutumance, et de mésusage (par exemple fentanyl est illicitement produite et il contribue aussi à de nombreux décès)

·         Il n’y a aucune preuve historique démontrant la capacité de la FDA à assurer le contrôle

·         Pas d’évaluation postcommercialisation

·         Programme REMS pour des opioïdes

·         L’utilisation de DSUVIATM est restreinte à des instructions strictes afin de réduire les risques (par exemple, offert exclusivement en milieu hospitalier limitant ainsi l’accès au grand public)

·         L’utilisation de DSUVIATM est limitée à une période de 72 heures

Combler un besoin non satisfait ·         Les bénéfices ne sont pas supérieurs aux risques puisque d’autre opioïdes existent déjà sur le marché ·         Fournir une gestion de la douleur extrême (par exemple pour les soldats)

·         Plusieurs années depuis qu’un nouvel opioïde a été mis sur le marché

 

Il a également été rapporté qu’AcelRx Pharmaceuticals (l’entreprise qui a développé et commercialisé DSUVIATM aux États-Unis) est à la recherche d’un partenaire Canadien pour obtenir l’approbation de DSUVIATM par Santé Canada.[[19]] Ceci pourrait être encore plus alarmant pour certains si l’opioïde est approuvé, compte tenu de la crise des opioïdes qui se fait également sentir au Canada. Le gouvernement canadien s’intéresse particulièrement aux dommages causés par les opioïdes, notamment le fentanyl, et le gouvernement fédéral a pris des mesures pour contrôler l’abus de cette substance à l’échelle nationale.[[20]] De nombreux professionnels de la santé incitent Santé Canada à considérer l’approbation de ce médicament avec précaution à cause des risques à la santé publique.[9]

En résumé, la FDA a approuvé un opioïde puissant sous forme de comprimés pour usage chez l’adulte qui a besoin de médicaments analgésiques pour la douleur. La question de savoir si ajouter un autre opioïde sur le marché est absolument nécessaire a suscité une discussion. Les considérations majeures sont: (1) Est-ce que les besoins du patient qui souffre de douleurs violentes dépassent la responsabilité du gouvernement à protéger la société entière et (2) Est-ce que le programme REMS pour DSUVIATM sera adéquat pour faire face aux risques potentiels d’abus?

 

[[1]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on agency’s approval of Dsuvia and the FDA’s future consideration of new opioids”. The U.S. Food & Drug Administration. 02 November 2018.

[[2]] “Full Prescribing Information for Dsuvia” (2018) AcelRx Pharmaceutical, Inc.

[[3]] “For a Public Hearing on Fentanyl and Synthetic Cannabinoids” Statement by Tell, S.R. before the U.S. Sentencing Commission. 05 December 2017.

[[4]] Patanwala, A. E., Keim, S. M., and Erstad, B. L. (2010). Intravenous opioids for severe acute pain in the emergency department. Annals of Pharmacotherapy44(11), 1800-1809.

[[5]] “Dsuvia Direction for Use” (2018) AcelRx Pharmaceutical, Inc.

[[6]] “Approved Risk Evaluation and Mitigation Strategies (REMS)”. The U.S. Food & Drug Administration. 02 November 2018.

[[7]] Motov and Khan (2009). Problems and barriers of pain management in the emergency department: Are we ever going to get better? Journal of Pain Research. 2: 5-11.

[[8]]  “Meeting of the anesthetic and analgesic drug products advisory committee”.  FDA Advisory Committee Briefing Document. 12 October 2018.

[[9]] “Canadian doctors urge caution after FDA approves controversial new opioid pill” CBC News. 07 November 2018.

[[10]] “Responding to Canada’s opioid crisis”. Government of Canada. 18 December 2018.

[[11]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on agency’s approval of Dsuvia and the FDA’s future consideration of new opioids”. The U.S. Food & Drug Administration. 02 November 2018.

[[12]] “Full Prescribing Information for Dsuvia” (2018) AcelRx Pharmaceutical, Inc.

[[13]] “For a Public Hearing on Fentanyl and Synthetic Cannabinoids” Statement by Tell, S.R. before the U.S. Sentencing Commission. 05 December 2017.

[[14]] Patanwala, A. E., Keim, S. M., and Erstad, B. L. (2010). Intravenous opioids for severe acute pain in the emergency department. Annals of Pharmacotherapy44(11), 1800-1809.

[[15]] “Dsuvia Direction for Use” (2018) AcelRx Pharmaceutical, Inc.

[[16]] “Approved Risk Evaluation and Mitigation Strategies (REMS)”. The U.S. Food & Drug Administration. 02 November 2018.

[[17]] Motov and Khan (2009). Problems and barriers of pain management in the emergency department: Are we ever going to get better? Journal of Pain Research. 2: 5-11.

[[18]] “Meeting of the anesthetic and analgesic drug products advisory committee”.  FDA Advisory Committee Briefing Document. 12 October 2018.

[[19]] “Canadian doctors urge caution after FDA approves controversial new opioid pill” CBC News. 07 November 2018.

[[20]] “Responding to Canada’s opioid crisis”. Government of Canada. 18 December 2018.

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