Jun 21

What’s New Health Canada?

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
Cancellation of a Drug Identification Number (DIN) and Notification of Discontinuation of Sales Guidance 12 June 2018
Conduct and Analysis of Comparative Bioavailability Studies & Comparative Bioavailability Standards: Formulations used for Systemic Effects Guidance 16 May 2018
Patented Medicines (Notice of Compliance Regulations) Guidance 11 May 2018

 

Updates from Health Canada (Drugs and Biologics)

 

Type of Update and Link Date Posted
Updated: Patent Register – Frequently Asked Questions 11 May 2018
Consultation for Mandatory Requirements of using Electronic Common Technical Document (eCTD) Format when Submitting Master Files (MFs) 07 May 2018
Notice to Industry: ACSS – New Chemical Entities Work Sharing Trial Phase I 30 April 2018
ICH S3A Questions and Answers: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure – Focus on Microsampling 26 April 2018
ICH M7(R1): Genotoxic Impurities – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 26 April 2018
ICH E18: Genomic Sampling and Management of Genomic Data 26 April 2018
What We Heard – Proposals for prescription drug transparency 25 April 2018
Final Notice – Classification of Dental Plaque-disclosing Products as Drugs 18 April 2018
ICH E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population 04 April 2018
ICH Q11: Questions and Answers: Selection and Justification of Starting Materials for the Manufacture of Drug Substances 04 April 2018
ICH Q3C(R6): Impurities: Guidelines for Residual Solvants 04 April 2018
New Master File Applications Fee Form for Human Drugs for filing on or after April 1st, 2018 16 March 2018
New Drug Submission – Application Fee Form for Human and Disinfectant Drugs for submissions filed on or after April 1st, 2018 16 March 2018

 

  

Santé Canada: Quoi de neuf?

 

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

 

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

 

Ligne directrice de Santé Canada Genre Date
Révision de les Lignes directrices : Conduite et analyse des études de biodisponibilité comparatives et Normes en matière d’études de biodisponibilité comparatives : Formes pharmaceutiques de médicaments à effets systémiques ligne directrice 16 mai 2018
Ligne directrice: Règlement sur les médicaments brevetés (avis de conformité) ligne directrice 11 mai 2018

 

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

 

Genre de mise à jour et lien Date
Mise à jour : Registre des brevets – Foire aux questions 11 mai 2018
Consultation concernant les exigences obligatoires relatives à l’utilisation du format Electronic Common Technical Document (eCTD) pour la présentation des fiches maîtresses (FM) 07 mai 2018
Avis à l’industrie : ACSS – Phase I de l’essai de partage du travail concernant les substances chimiques nouvelles 30 avril 2018
ICH S3A Question et réponse : note explicative sur la toxicocinétique : l’évaluation de l’exposition systémique dans les études de toxicité 26 avril 2018
ICH M7(R1) : Évaluation et contrôle des impuretés réactives de l’ADN (mutagènes) dans les produits pharmaceutiques pour limiter les risques de cancérogénicité 26 avril 2018
ICH E18 L’échantillonnage génomique et la gestion des données génomiques 26 avril 2018
Ce que nous avons entendu – Propositions concernant la transparence relative aux médicaments d’ordonnance 25 avril 2018
Avis final – Classification des produits révélateurs de plaque dentaire en tant que médicaments (drogues) 18 avril 2018
Addenda à la ligne directrice E11(R1) de l’ICH : Recherche clinique sur les produits médicinaux dans la population pédiatrique 05 avril 2018
ICH Q11 : Questions et réponses : Mise au point et fabrication de substances pharmaceutiques (entités chimiques et entité biotechnologiques ou biologiques) 04 avril 2018
ICH Q3C(R6): Impuretés : Directive sur les solvants résiduels 04 avril 2018
Nouveau Formulaire sur les frais pour Fiches maîtresse pour les médicaments à usage humain pour les présentations soumises le 1st avril 2018 ou après 16 mars 2018
Nouveau Formulaire concernant les frais de présentation et de demande de drogue pour les médicaments à usage humain et les désinfectants assimilés à drogues pour les présentations soumises le 1st avril 2018 ou après 16 mars 2018

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Jun 13

2018 Changes in the User Fee Program for Prescription Drugs Under PDUFA VI

By Juliati Rahajeng, Ph.D., Scientist at Cato Research

 

The Food and Drug Administration Reauthorization Act (FDARA) was signed into law by the President on August 18, 2017. The law comprises the reauthorization of the Prescription Drug User Fee Act (PDUFA), which gives the Food and Drug Administration (FDA) the resources to sustain a predictable and efficient review process for human drugs and biologics. The current PDUFA (PDUFA VI), which includes the Fiscal Years 2018-2022, generated a new user fee program that contains some significant changes from the one authorized under the PDUFA V. A new FDA guidance document that describes the new fee structure and the type of fees for which industry is responsible was published in May 2018.1

 

Prior to 1992, the pharmaceutical industry, consumers, and the FDA were frustrated with the FDA’s lengthy and unpredictable review process of New Drug Applications (NDAs) and Biologics License Applications (BLAs). The increasing length of the review process led to the delay for patients in accessing the new drugs and for manufacturers in recovering their development costs. In the late 1980s, the reported median time for review process of an NDA was 29 months.2 During the PDUFA I consideration, a one-month delay in a review process roughly cost a manufacturer an average of $10 million.3 The FDA argued that it needed to hire additional scientists for a more efficient and predictable review process of the incoming and backlogged drug applications.

 

The PDUFA law was passed by Congress in 1992. PDUFA I authorized the FDA to collect fees to accelerate the review process of NDA and BLA without compromising product safety and efficacy.4, 5 Based on PDUFA I, the review of priority applications for new drugs, which demonstrated significant improvement in the treatment, diagnosis, or prevention of a disease, was six months, whereas review of standard applications was 12 months. Since the implementation of PDUFA I, patients have faster access to new drugs and the pharmaceutical industry can expect a predictable review process.

 

PDUFA is reauthorized by Congress every five years. PDUFA II broadened the scope of the user fee program by incorporating activities related to the preclinical and clinical phases of a new drug’s development and by increasing FDA communications with the industry and consumer groups.5 Under PDUFA II, the goal of the standard review is to complete 90% of the NDAs and BLAs within 10 months of receipt.6 PDUFA III widened the scope of activities by incorporating a three-year postapproval period.5 PDUFA IV removed the three-year limitation on postapproval activities and focused on new courses of action regarding the postapproval lifetime of a product.4

 

PDUFA V and PDUFA VI maintained the scope of activities of PDUFA IV.1, 5 Under PDUFA V, FDA was authorized to collect human drug application fees and application supplement requiring clinical data fees, prescription drug establishment fees, and prescription drug product fees.1 However, under PDUFA VI, a new user fee structure was created. PDUFA VI removed the prescription drug product and drug establishment fees and added a human prescription drug program fee, which provides 80% of the total fee revenue for the FDA. Although the establishment fee has been eliminated, the establishment registration and drug listing requirements (described below) are still in effect. The human drug application fee, which provides 20% of the total fee revenue, remains, whereas the supplemental application fee is eliminated.1, 5 Additionally, PDUFA VI removes a provision under which the applicant could apply for a waiver or refund of user fees, in which the fee will exceed the anticipated costs incurred in reviewing submissions (also known as “the fees-exceed-costs waiver”).1

 

Under PDUFA VI, a human drug application for which safety and efficacy clinical data (other than bioavailability or bioequivalence studies) are required for approval is assessed a full application fee, whereas an application not requiring clinical data for approval is assessed one-half of a full fee.1 The application fees are due when the application is submitted. Without the submission of the appropriate fee, a human drug application will be deemed as incomplete and the Health and Human Services Secretary will not accept the application for filing until all fees have been paid. The two exceptions to the application fee are orphan drug-designated applications, and resubmissions of previously filed applications that were reviewed but not approved. A full fee is assessed on a resubmitted application that was rejected for filing or withdrawn before a filing action. If an application is refused for filing or withdrawn without a waiver before filing, 75% of the application fee will be refunded. However, if an application is withdrawn after it is filed, the fee or a portion of the fee may be refunded if no significant work was performed.

 

The FDA provides a waiver or a reduction for one or more user fees assessed under section 736(a) of the Food, Drug, and Cosmetic (FD&C) Act when the waiver or reduction is required to protect the public health, the fee would present a major hurdle to innovation, or the applicant is a small business submitting its first human drug application.1 To receive any waiver, reduction, or refund, an applicant must submit a written request to the Secretary no later than 180 days after the fee is due.

 

A human drug application (or any pending application filed after 01 September 1992) is assessed for the annual prescription drug program fee for each prescription drug product that is identified in the application approved as of 01 October of the fiscal year.1 The prescription drug program fee, which is subjected to the original NDA or BLA holder, is determined by each prescription drug product identified in an NDA or BLA. However, a single approved application of multiple drug products may not be assessed for more than five prescription drug program fees for a fiscal year. A prescription drug product is not subject to a program fee if the product falls under one of the conditions in section 505(j)(7) of the FD&C Act (current generic drug) with a potency defined in terms of per 100 milliliters. A prescription drug product is also not subject to the program fee if the product is

  • the same as another product approved under sections 505(b) or 505(j) of the FD&C Act and that other product is not in the list of discontinued products described in section 505(j)(7) of the FD&C Act.
  • an abbreviated application filed under section 507 of the FD&C Act (a Drug Development Tool such as a biomarker or clinical outcomes assessment), or
  • an abbreviated new drug application (generic) approved prior to the execution of the Drug Price Competition and Patent Term Restoration Act of 1984.

 

Prescription drug products eligible for the program fee are on the list of products detailed in section 505(j)(7)(A) of the FD&C Act (often known as the “Orange Book”), or on the list of products with applications approved under section 351(a) of the Public Health Service Act that is generated and maintained by the Secretary.1 Drugs are added to the Orange Book on the day they are approved and not on the date when the next Orange Book is published. If a drug or a biologic is in the discontinued section of the Orange Book or Biologics List on the date fees are assessed, a drug or a biologic product is not subject to a prescription drug fee program for a fiscal year.

 

The FDA will send a notification to applicants with respect to their prescription drug products in preparation for determining the program fees before the program fees due date.1 Therefore, applicants will have the opportunity to review the notice and inform the Agency of any changes regarding the status of their drug products. Based on the information available to the FDA, it issues invoices for the program fees around the end of September. For each fiscal year, payments for the program fees are due either on or after 01 October, or on the first business day after the authorization of an appropriations Act issuing the collection and obligation of fees for the fiscal year, whichever occurs later.

 

In summary, the FDA is authorized to collect human drug application fees at the time the application is submitted and then annually the prescription drug program fees are collected  after the application is approved for certain prescription drug products under PDUFA VI. In addition, PDUFA VI removed fees for application supplement, establishment fees, and the “fees-exceed-costs waiver” that were previously authorized.1

 

References:

  1. Food and Drug Administration (FDA), Assessing User Fees Under the Prescription Drug User Fee Amendments of 2017: Guidance for Industry. May 2018.
  2. Food and Drug Administration (FDA), Third Annual Performance Report: Prescription Drug User Fee Act of 1991, Fiscal Year 1995 Report to Congress (01 December 1995).
  3. Hilts PJ, “Plan to Speed Approval of Drugs: Makers Would Pay Fees to U.S.” The New York Times. 11 August 1992.
  4. Sections 735 and 736 of the FD&C Act.
  5. Congressional Research Service, Prescription Drug User Fee Act (PDUFA): 2017 Reauthorization as PDUFA VI. 16 March 2018.
  6. Food and Drug Administration (FDA), Prescription Drug User Fee Act II (PDUFA II): Five-Year Plan – Fiscal Year 2000 Update. July 2000.

 

Jun 08

New FDA Guidances for May 2018

By Joanne McNelis, PhD, RAC (US), Scientist at Cato Research
FDA draft and final guidances, released from CDER, CBER, and CDRH, in April are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

 

Special Interest Guidances/Information Date Posted
Development of a Shared System REMS Guidance for Industry – Draft Guidance 31 May 2018
Waivers of the Single, Shared System REMS Requirement; Draft Guidance for Industry – Draft Guidance 31 May 2018
Recommended Content and Format of Complete Test Reports for Non-Clinical Bench Performance Testing in Premarket Submissions – Draft Guidance 31 May 2018
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Core Guideline Guidance for Industry – Draft Guidance 30 May 2018
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Annex – Draft Guidance 30 May 2018
Assessment of Pressor Effects of Drugs Guidance for Industry – Draft Guidance 30 May 2018
Complicated Intra-Abdominal Infections: Developing Drugs for Treatment – Final Guidance 29 May 2018
Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax Guidance for Industry – Final Guidance 23 May 2018
Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an Over-The-Counter Monograph: Study Elements and Considerations – Draft Guidance 22 May 2018
Enforcement Policy — OTC Sunscreen Drug Products Marketed Without an Approved Application – Final Guidance 22 May 2018
Bioanalytical Method Validation Guidance for Industry – Final Guidance 21 May 2018
Acne Vulgaris: Establishing Effectiveness of Drugs Intended for Treatment – Final Guidance 21 May 2018
Establishing Effectiveness for Drugs Intended to Treat Male Hypogonadotropic Hypogonadism Attributed to Nonstructural Disorders Guidance for Industry – Final Guidance 18 May 2018
Cytomegalovirus in Transplantation: Developing Drugs to Treat or Prevent Disease – Draft Guidance 18 May 2018
Pediatric HIV Infection: Drug Development for Treatment – Draft Guidance 11 May 2018
Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act – Final Guidance 10 May 2018
Uncomplicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry – Draft Guidance 09 May 2018
S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies: Focus on Microsampling – Final Guidance 09 May 2018
Waivers, Exceptions, and Exemptions from the Requirements of Section 582 of the Federal Food, Drug, and Cosmetic Act Guidance for Industry – Draft Guidance 08 May 2018
Assessing User Fees Under the Prescription Drug User Fee Amendments of 2017 Guidance for Industry – Final Guidance 02 May 2018
Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry – Draft Guidance 02 May 2018
Upcoming Meetings (* = New)
* June 12, 2018: Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* June 14, 2018: Anesthesiology and Respiratory Therapy Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* June 20, 2018: Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee
* June 22, 2018: Blood Products Advisory Committee Meeting Announcement
* June 26, 2018: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
* July 18-19, 2018: Blood Products Advisory Committee Meeting Announcement
Last updated: 01 June 2018

 

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May 16

New Meeting Opportunities with FDA through the Model-Informed Drug Development (MIDD) Pilot Program

By Joshua Taylor, Ph.D., R.A.C. (US), Regulatory Scientist

 

The Prescription Drug User Fee Act (PDUFA) reauthorization for fiscal years (FYs) 2018 to 2022, known as PDUFA VI, includes language to facilitate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources, referred to as model-informed drug development (MIDD) approaches. MIDD approaches, when successfully applied, can improve clinical trial efficiency, increase the probability of regulatory success, and optimize drug dosing/therapeutic individualization in the absence of dedicated trials.

PDUFA VI mandates that FDA will:

  • develop its regulatory science and review expertise and capacity in MIDD approaches;
  • convene a series of workshops to identify best practices for MIDD;
  • conduct a pilot program (beginning in FY 2018) for MIDD approaches, during which an initial and a follow-up meeting on the same drug development issues will be held with a sponsor;
  • publish draft guidance, or revise relevant existing guidance, on MIDD (by end of FY 2019); and
  • develop or revise, as appropriate, relevant Manuals of Policies and Procedures or Standard Operating Policy and Procedures, and/or review templates and training, to incorporate guidelines for the evaluation of MIDD approaches (by end of FY 2021).

The pilot program for meeting with FDA regarding MIDD approaches was posted to the Federal Register on April 16, 2018, and FDA began accepting meeting requests the next day. Successful applicants to the pilot program will be granted two meetings with FDA (initial and follow-up), separated by 120 days. As described by Raj Madabushi, Ph.D., of CDER’s Office of Clinical Pharmacology, “[u]nder the pilot program, an internal FDA group will review programs with limited clinical data, and where non‑traditional sources of evidentiary support may be helpful. The pilot program aims to advance the use of MIDD as part of the regulatory pathway for drugs, helping both FDA and sponsors to work through issues around developing models, establishing their credibility, and determining how they can be used to address regulatory or drug development issues.”

In an introduction to the pilot program, FDA explains that any drug or biologic company with an active Investigational New Drug (IND) or pre-IND number for the relevant development program is eligible to participate in the pilot program, as are any interested consortia or software/device developers so long as they come in partnership with a drug development company. The pilot program excludes statistical designs that involve complex adaptations, Bayesian models, or other features requiring complex simulations. Because only two to four paired‑meeting requests will be accepted per quarter during the pilot program, FDA will prioritize applications that are related to:

  • Dose selection or estimation (e.g., for dose/dosing regimen selection or refinement)
  • Clinical trial simulation (e.g., based on drug-trial-disease models to inform the duration of a trial, select appropriate response measures, or predict outcomes)
  • Clinical trial simulation (e.g., based on drug-trial-disease models to inform the duration of a trial, select appropriate response measures, or predict outcomes)

Meeting requests are submitted electronically to the relevant application (i.e., IND or pre-IND), and “MIDD Pilot Program Meeting Request for CDER [or CBER, depending on the application]” must be placed in the subject line. FDA will notify applicants during the first week of each quarter whether the meeting request was accepted or denied. If FDA accepts the meeting request through the pilot program, meeting packages must be submitted to FDA no less than 30 days before each of scheduled meetings (initial and follow-up). The expected content of the meeting request and packages is provided in the aforementioned introduction to the pilot program, and FDA will send a meeting summary to the sponsor within 60 days of each meeting.

Importantly, MIDD approaches have the potential to help in all phases of drug development and may allow sponsors to perform smaller or shorter clinical trials or to carry out fewer postmarketing studies. If you think MIDD approaches may help your development program, this new opportunity to work with and get feedback from FDA through the pilot program is well worth your consideration.

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May 07

New FDA Guidances for April 2018

By Joanne McNelis, PhD, RAC (US), Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH, in April are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

 

Special Interest Guidances/Information Date Posted
Multiple Function Device Products: Policy and Considerations – Draft Guidance for Industry and Food and Drug Administration – Draft Guidance 27 Apr 2018
Clinical Trial Imaging Endpoint Process Standards Guidance for Industry – Final Guidance 26 Apr 2018
Severely Debilitating or Life-Threatening Hematologic Disorders: Nonclinical Development of Pharmaceuticals Guidance for Industry – Draft Guidance 23 Apr 2018
Submitting Study Datasets for Vaccines to the Office of Vaccines Research and Review; Guidance for Industry; Technical Specifications Document – Draft Guidance 20 Apr 2018
Opioid Dependence: Developing Depot Buprenorphine Products for Treatment – Draft Guidance 20 Apr 2018
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Questions and Answers Guidance for Industry – Final Guidance 19 Apr 2018
Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products–Quality Considerations – Draft Guidance (revised) 18 Apr 2018
Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination; Draft Guidance for Industry – Draft Guidance 16 Apr 2018
Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria; Draft Guidance for Industry and Food and Drug Administration – Draft Guidance 12 Apr 2018
Special Protocol Assessment Guidance for Industry – Final Guidance 12 Apr 2018
Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination Guidance for Industry – Draft Guidance 12 Apr 2018
E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population – Final Guidance 10 Apr 2018
Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials – Draft Guidance  06 Apr 2018
Atopic Dermatitis: Timing of Pediatric Studies During Development of Systemic Drugs – Draft Guidance 06 Apr 2018
Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation – Final Guidance 04 Apr 2018
Upcoming Meetings (* = New)
  April 19, 2018: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement
  April 23, 2018: Arthritis Advisory Committee Meeting
  April 24-25, 2018: Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
  May 2, 2018: Antimicrobial Drugs Advisory Committee Meeting Announcement
  May 3, 2018: Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Pediatric Advisory Committee Meeting Announcement
  May 10, 2018: Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
* May 11, 2018: Joint Meeting of the Pediatric Advisory Committee and the Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
  May 22, 2018: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
Last updated: 03 May 2018

Apr 25

Exception from Informed Consent in Emergency Research

by Reshma Jagasia, Ph.D., Scientist at Cato Research

by Nicole Tackmann, Ph.D., Clinical Strategy Intern at Cato Research

 

All clinical investigations conducted in the United States are subject to informed consent regulations under federal law (21 CFR Part 50 Subpart B). These regulations define the responsibilities of a clinical investigator to describe to a patient, or to his or her legally authorized representative (LAR), the details of an experimental treatment, including its potential risks and benefits, such that the patient or LAR may make an informed decision as to the patient’s participation in the study.

Under certain circumstances, subjects may not be able to provide consent for an investigational intervention. This inability to consent may arise from the nature of the illness or injury, such as a comatose disease state, or from the need for prompt medical intervention, precluding the time needed in which to inform and obtain consent. Most often, such patients have a life-threatening medical condition that necessitates urgent intervention. For clinical research in which (1) the investigational treatment has the prospect of direct benefit to the patient, (2) the investigational treatment needs to be administered quickly, before informed consent can be obtained, and (3) the prospective identification of individuals eligible for participation is not feasible, FDA recognizes a need for an exception from informed consent (EFIC). The laws governing EFIC are codified in 21 CFR 50.24 and are designed specifically to protect this most vulnerable population of study subjects.

EFIC procedures are not a means for clinical investigators to circumvent the need to inform and to obtain consent from a potential subject or LAR. On the contrary, EFIC procedures define the extra care and efforts that must be expended by the sponsor, clinical investigators, and Institutional Review Boards (IRBs) to protect patients who cannot consent at the time of treatment. Achieving the requirements of EFIC demands significant time, resources, and a concerted effort. The requirements for EFIC can be divided into three categories: investigational plan and consent, community consultation, and public disclosure.

Investigational Plan and Consent

Investigational plans that rely on EFIC must include justification for conducting the study in subjects who cannot consent. Justification for why the investigational intervention may be better than the available standard-of-care treatment must also be presented. These justifications should be specifically stated in the clinical study protocol.

Clinical investigators must also commit to try to contact a subject’s LAR or family member to obtain informed consent within the defined therapeutic window. This therapeutic window, which should be defined in the study protocol, is the time between onset of the event and the administration of the investigational intervention. FDA does not expect attempts to contact a LAR or family member to exhaust the entire therapeutic window. In fact, FDA recognizes that the therapeutic window for emergency research may be very brief or even non-existent.

Subjects in emergency research often do not have a designated LAR. In such cases, a LAR would need to be identified by the clinical investigator. LAR identification laws vary by state; for example, some states clearly define the hierarchy of individuals who may serve as a LAR while others do not address LAR identification at all. In the case of the latter, the IRB should define the hierarchy of who can serve as a LAR, the procedures for contacting a LAR or family member, how much time in the therapeutic window should be dedicated to these procedures, and what to do if two LARs disagree on consent. Attorneys should also review all study plans regarding the contact of LARs.

In the case that a LAR or family member cannot be reached to provide informed consent, the clinical investigator may enroll the patient under emergency research protocols. This emergency enrollment is the “exception” conferred by EFIC procedures. If at any time during the course of the study the subject becomes capable of consent (i.e., the subject is no longer comatose and is of sound mind), informed consent must be sought from the subject for continued participation in the study whether or not informed consent was obtained earlier from a family member or LAR.

The law also requires that any clinical investigation invoking EFIC be overseen by an independent data monitoring committee.

Community Consultations

Because there is no reasonable, prospective manner in which to identify individuals likely to become eligible for participation in an emergency research investigation, sponsors and clinical investigators are required to reach out to communities-at-large from which potential subjects would be drawn to conduct community consultations. “Community” is the geographical area (i.e. city, region) that a clinical site services, but efforts can and should be made to target those members of the community that fit the demographics of the potential patient population. Community consultations should also include community leaders and representatives such as elected officials, local community activists, clergy, school officials, and other interested individuals.

During community consultations, members of the community assemble, and clinical instigators provide information about the proposed clinical trial to be conducted in the community, potential risks and benefits to prospective subjects, and methods, if any, as to how an individual may indicate his/her preference to be excluded from participation. Most significantly, community consultations are a two-way communication, and investigators are required to elicit feedback from the community about the proposed clinical trial.

Information offered in a community consultation should include:

  • Summary of protocol, study design, and description of procedures to be followed, including the identification of any experimental procedures
  • Summary of other available treatment options and their risks and benefits
  • Estimated study duration and individual patient enrollment duration
  • How potential study subjects will be identified
  • Information about the study product, including risks, expected benefits, and potential adverse events
  • Clear statement that informed consent will not be obtained for most subjects
  • The rationale for the need of an exception from informed consent, and copies of the informed consent forms
  • Description of the therapeutic window, and the portion of that window that will be used to contact the subject’s LAR or family member

All plans and materials (posters, presentations, pamphlets, etc.) employed to conduct community consultations must be reviewed by the IRB before community consultations can begin. The IRB will also review the feedback received from the community, which may lead to revisions of the study protocol and supporting documents. The IRB will determine the required amount of community consultation based on the unique circumstances of the study and the community. Typically, the less that is known about the safety and efficacy of an intervention, the greater the amount of community consultation that is required.

Public Disclosure

While community consultation is a two-way form a communication, public disclosure is a one-way transfer of information from the clinical investigator to the public. After community consultation and IRB approval of the study protocol, the investigator must publicly disclose the study before enrollment can begin. Information in public disclosures contain the same information provided in community consultations as well as identification of the sites or institutions that will be participating in the study. Public disclosure is designed to encourage public knowledge about the study.

At the completion of the clinical investigation, the results of the study must be publically disclosed to both the scientific community and the communities in which the study was conducted as part of the EFIC requirements. Reporting results on ClinicalTrials.gov alone is not sufficient to meet these disclosure requirements. Disclosure can be in the form of public service announcements, targeted mailers, press conferences, and information and links on a sponsor and clinic websites.

For more information on the EFIC process, please consult the FDA’s Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (March 2011, Updated April 2013). For more information on LARs, see: “Legally Authorized Representatives in Clinical Trials” Katzen J. J Clin Res Best Pract. 2011; 7(3):1-5.

Apr 13

New FDA Guidances for February and March 2018

By Joanne McNelis, PhD, RAC (US), Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH, in February and March are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.

 

Special Interest Guidances/Information Date Posted
Chronic Obstructive Pulmonary Disease: Use of the St. George’s Respiratory Questionnaire as a PRO Assessment Tool Guidance for Industry – Final Guidance 26 Mar 2018
Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act Guidance for Industry – Draft Guidance 23 Mar 2018
Postmarketing Safety Reporting for Combination Products – Draft Guidance 21 Mar 2018
M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk – Final Guidance 13 Mar 2018
Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act; Draft Guidance for Industry – Draft Guidance 02 Mar 2018
E18 Genomic Sampling and Management of Genomic Data Guidance for Industry – Final Guidance 01 Mar 2018
Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act Guidance for Industry – Draft Guidance 28 Feb 2018
Standardization of Data and Documentation Practices for Product Tracing Guidance for Industry – Draft Guidance 28 Feb 2018
E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) – Final Guidance 28 Feb 2018
Q11 Development and Manufacture of Drug Substances–Questions and Answers (Chemical Entities and Biotechnological/Biological Entities) – Final Guidance 23 Feb 2018
Acceptance of Clinical Data to Support Medical Device Applications and Submissions: Frequently Asked Questions; Guidance for Industry and Food and Drug Administration Staff – Final Guidance 21 Feb 2018
Migraine: Developing Drugs for Acute Treatment – Final Guidance 15 Feb 2018
Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment Guidance for Industry – Final Guidance 15 Feb 2018
Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment – Draft Guidance 15 Feb 2018
Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industy – Draft Guidance 15 Feb 2018
Drugs for Treatment of Partial Onset Seizures: Full Extrapolation of Efficacy from Adults to Pediatric Patients 4 Years of Age and Older – Draft Guidance 15 Feb 2018
Regulatory Classification of Pharmaceutical Co-Crystals – Revised Final Guidance 14 Feb 2018
Bacillus Calmette-Guérin-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry – Final Guidance 12 Feb 2018
Microbiological Data for Systemic Antibacterial Drug Products — Development, Analysis, and Presentation – Final Guidance 07 Feb 2018
Upcoming Meetings (* = New)
* May 2, 2018: Antimicrobial Drugs Advisory Committee Meeting Announcement
* May 3, 2018: Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Pediatric Advisory Committee Meeting Announcement
* May 10, 2018: Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
* May 22, 2018: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
* April 19, 2018: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement
* April 23, 2018: Arthritis Advisory Committee Meeting
* April 24-25, 2018: Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement
Last updated: 05 April 2018

Mar 27

Submitting IND Safety Reports using us-regional DTD v3.3 versus v2.01: What’s the Difference?

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

 

Submitting IND safety reports to an IND in eCTD format is slightly different when using us-regional DTD v3.3 versus v2.01.

Keep in mind that the following aspects remain UNCHANGED for both versions:

  • Each individual IND safety report should be provided in Section 5.3 of the eCTD under its associated study.
  • Each safety report should be referenced in the study’s STF using the ‘IND safety report’ file tag.
  • The eCTD leaf title should include “Safety Report” along with “initial” or “follow-up”, depending on the content of the individual safety report.
  • Leaf titles that clearly relate to the individual cases should be used.
  • Each IND safety report should be submitted as “new” without replacing any previously submitted information.
  • Multiple IND Safety Reports can be submitted in one sequence.

The DIFFERENCES are as follows:

  • When using v2.01:
  • IND Safety Report submissions are grouped by submission-type.
  • Submitted as “amendments” (submission-type) under the IND.
  • Related sequence number will be the sequence number of the IND’s original application (submission-type).

 

  • When using v3.3:
  • IND Safety Report submissions are grouped by submission-type and submission-subtype.
  • Submitted as “IND Safety Reports” (submission-type) and then either as “report” or “amendment” (submission-subtype).
  • First IND safety report submission using v3.3 should use a submission-type of “IND Safety Report” and submission-subtype of “report” in order to start the regulatory activity.
  • All subsequent IND Safety Report submissions can then be submitted as an “amendment” (submission-subtype) to the first “IND Safety Report” (submission-type) in the application.
  • The submission-ID for all IND Safety Report submissions will be the sequence number of the first submission to the “IND Safety Report” regulatory activity with submission-subtype of report”.

 

Questions about using v3.3:

Question:

Can “report” and “amendment” submission-subtypes be used for initial and follow-up IND Safety Reports, respectively?

Answer:

This is possible but then you will need to start a new regulatory activity for each IND Safety Report.  You will not be able to submit multiple IND Safety Reports in one sequence unless they are all either initial or follow-up reports since only one submission-subtype (report or amendment) can be used per sequence.  The same applies for the submission-ID.  You can only include one sequence for the submission-ID so even if you are submitting the same type of report in one sequence they will all need to have the same submission-ID, which may not be the case for follow-up reports.

This can get very cumbersome which is why I contacted the CDER ESUB group to get clarification.  It was explained to me that when using v3.3 or when transitioning to v3.3, it is acceptable to use “report” as the submission-subtype for the first IND Safety Report submission, regardless of whether the report(s) is(are) initial or follow-up. All subsequent initial or follow-up safety report submissions will then be submitted as an “amendment” under the same IND Safety Report regular activity.

Mar 08

Deadline to Begin Submitting Commercial INDs in eCTD Format is May 5, 2018

By Joshua Taylor, Ph.D., R.A.C. (US), Regulatory Scientist

Beginning on May 5, 2018, all commercial Investigational New Drug Applications (INDs) and master files must be submitted in the electronic common technical document (eCTD) format.

Section 745A(a) of the Food, Drug, and Cosmetic Act (FD&C Act) authorizes the United States Food and Drug Administration (FDA) to require that, no sooner than 24 months after issuance of a final guidance document in which the FDA has specified the electronic format for submitting submission types to FDA, such content must be submitted electronically and in the format specified by FDA. On May 5, 2015, FDA published a guidance titled Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 4 published in April 2017) that established timelines of 24 months for electronic submissions of New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), certain Biologics License Applications (BLAs), and master files (May 5, 2017); and of 36 months for electronic submissions of commercial INDs (May, 5 2018).  After internal review and receiving comments from industry, FDA later determined that master files would instead follow the 36-month timeline as well (May 5, 2018).

The first deadline, applicable to marketing applications to FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), arrived last year. Only marketing applications for drugs or combination products submitted under Section 505(b), (i), or (j) of the FD&C Act and marketing applications for biologics and combination products submitted under Section 351(a) or 351(k) of the Public Health Service Act were impacted.

However, the upcoming deadline of May 5, 2018, applicable to commercial INDs and master files, will affect companies at all stages of drug development. It is important to note, however, that the electronic submission requirements do not apply to submissions for blood and blood components and submissions for devices regulated by CBER, but electronic submissions of these types are still accepted.

 

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Common Questions
Common questions regarding electronic submission requirements and corresponding text from Revision 4 of Electronic Submission Requirements Guidance are presented below.

What types of submissions are exempt from electronic submission requirements?

“FDA has exempted all submissions regarding noncommercial INDs from the requirements under section 745A(a). For purposes of this guidance, the term noncommercial products refers to products that are not intended to be distributed commercially and includes investigator-sponsored INDs and expanded access INDs (e.g., emergency use INDs and treatment INDs).”

What format should be used for future submissions if the original application was submitted prior to the electronic requirement deadline?

“[Y]ou must electronically submit any amendments, supplements, and reports, even if the original submission was submitted to FDA prior to implementation of the electronic submission requirements.”

Why is FDA mandating that master files be submitted in electronic format, and what types of master files are affected?

“FDA considers master files to be submissions to an NDA, ANDA, BLA, or IND, and therefore to fall within the scope of requirements set forth in section 745A(a). These include new drug master files (DMFs) (21 CFR 314.420), new biological product files (BPFs) (21 CFR 601.51), and any amendments to or annual reports on previously submitted DMFs or BPFs.”

What is the penalty for noncompliance with electronic submission requirements?

“Submissions that are not submitted electronically and electronic submissions that are not in a format that FDA can process, review, and archive will not be filed or received, unless exempted from the electronic submission requirements.”

Mar 01

Submitting a “Request for Proprietary Name Review” in eCTD format to the FDA

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

Per the April 2016 Guidance for Industry entitled, “Contents of a Complete Submission for the Evaluation of Proprietary Names”, applicants must submit proposed proprietary names to the FDA for review as part of New Drug Applications (NDAs), Abbreviated NDAs (ANDAs) and Biologics License Applications (BLAs).  If such an application is not yet available, it is acceptable to submit the request to an active Investigational New Drug (IND) application provided the product has completed Phase 2 trials.

If submitting electronically in eCTD format, the request is placed in the following sections depending on the US regional DTD version being used:

  • US regional DTD v3.3
    • A “Request for Proprietary Name Review” is placed in “Section 1.18 Proprietary Names”
  • US regional DTD v2.01
    • A “Request for Proprietary Name Review” is placed in “Section 1.12.4 Request for Comments and Advice on an IND”

In both cases, the eCTD leaf title of the document should be clear, concise, and indicative of the document’s content (e.g. “REQUEST FOR PROPRIETARY NAME REVIEW”, “AMENDMENT TO REQUEST FOR PROPRIETARY NAME REVIEW”, or “REQUEST FOR RECONSIDERATION OF PROPRIETARY NAME”).  Moreover, the eCTD location of the request should be included and hyperlinked in the cover letter so the information can be quickly and easily accessed by reviewers.

The FDA will evaluate both safety and promotional aspects of the product’s proposed proprietary name; a tentative acceptance or non-acceptance about the name will be communicated to the applicant within 180 days during the IND phase and 90 days with an NDA or BLA.

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