Aug 16

New FDA Guidances for June and July 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
Recommendations for Reducing the Risk of Transfusion-Transmitted Babesiosis; Draft Guidance for Industry – Draft Guidance 27 July 2018
Peripheral Vascular Atherectomy Devices – Premarket Notification [510(k)] Submissions – Draft Guidance 27 July 2018
Slowly Progressive, Low-Prevalence Rare Diseases with Substrate Deposition That Results from Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies Guidance for Industry – Draft Guidance 26 July 2018
Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments – Draft Guidance 24 July 2018
Inborn Errors of Metabolism That Use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development: Guidance for Industry – Draft Guidance 23 July 2018
E17 General Principles for Planning and Design of Multi-Regional Clinical Trials – Final Guidance 18 July 2018
Use of Electronic Health Record Data in Clinical Investigations Guidance for Industry – Final Guidance 18 July 2018
Labeling for Biosimilar Products Guidance for Industry – Final Guidance 18 July 2018
Field Alert Report Submission: Questions and Answers Guidance for Industry – Draft Guidance 18 July 2018
Metal Expandable Biliary Stents – Premarket Notification (510(k)) Submissions – Draft Guidance 18 July 2018
Innovative Approaches for Nonprescription Drug Products – Draft Guidance 17 July 2018
Q3D(R1) ELEMENTAL IMPURITIES – Draft Guidance 13 July 2018
Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Draft Guidance for Industry – Draft Guidance 11 July 2018
Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Draft Guidance for Industry – Draft Guidance 11 July 2018
Long Term Follow-up After Administration of Human Gene Therapy Products; Draft Guidance for Industry – Draft Guidance 11 July 2018
Human Gene Therapy for Hemophilia; Draft Guidance for Industry – Draft Guidance 11 July 2018
Human Gene Therapy for Rare Diseases; Draft Guidance for Industry – Draft Guidance 11 July 2018
Human Gene Therapy for Retinal Disorders; Draft Guidance for Industry – Draft Guidance 11 July 2018
Smallpox (Variola) Infection: Developing Drugs for Treatment or Prevention – Draft Guidance 10 July 2018
Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components; Guidance for Industry – Final Guidance 09 July 2018
Indications and Usage Section of Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry – Draft Guidance 06 July 2018
ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA – Final Guidance 03 July 2018
Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry – Draft Guidance 28 Jun 2018
Assessing User Fees Under the Biosimilar User Fee Amendments of 2017 Guidance for Industry – Final Guidance 28 Jun 2018
Major Depressive Disorder: Developing Drugs for Treatment – Draft Guidance 20 Jun 2018
Prescription Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products Guidance for Industry – Draft Guidance 20 Jun 2018
Logical Observation Identifiers Names and Codes for In Vitro Diagnostic Tests – Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 15 Jun 2018
Coronary, Peripheral, and Neurovascular Guidewires – Performance Tests and Recommended Labeling – Draft Guidance 15 Jun 2018
Intravascular Catheters, Wires, and Delivery Systems with Lubricious Coatings – Labeling Considerations – Draft Guidance 15 Jun 2018
Epidermolysis Bullosa: Developing Drugs for Treatment of Cutaneous Manifestations; Draft Guidance for Industry – Draft Guidance 15 Jun 2018
S9 Nonclinical Evaluation for Anticancer Pharmaceuticals–Questions and Answers – Final Guidance 15 Jun 2018
Humanitarian Device Exemption (HDE) Program – Draft Guidance 15 Jun 2018
Human Immunodeficiency Virus-1 Infection: Developing Systemic Drug Products for Pre-Exposure Prophylaxis – Draft Guidance 13 Jun 2018
Limited Population Pathway for Antibacterial and Antifungal Drugs Guidance for Industry – Draft Guidance 12 Jun 2018
Patient-Focused Drug Development: Collecting Comprehensive and Representative Input – Draft Guidance 12 Jun 2018
Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers Guidance for Industry – Final Guidance 12 Jun 2018
Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers Guidance for Industry and Review Staff – Final Guidance 12 Jun 2018
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program – Draft Guidance 07 Jun 2018
Prescription Drug User Fee Act Waivers for Fixed-Combination Antiretroviral Drugs for the President’s Emergency Plan for AIDS Relief – Draft Guidance 06 Jun 2018
Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products Guidance for Industry – Draft Guidance 04 Jun 2018
Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials – Draft Guidance 01 Jun 2018
Complicated Urinary Tract Infections: Developing Drugs for Treatment – Final Guidance 01 Jun 2018
Upcoming Meetings (* = New)  
* September 20, 2018: Meeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting Announcement
Last updated: 15 August 2018

Aug 15

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
Notifying Health Canada of Foreign Actions – Guidance Document for Industry – Summary Guidance 12 July 2018

 

Updates from Health Canada (Drugs and Biologics)

 

Type of Update and Link Date Posted
Therapeutic Products Directorate Statistical Report 2017/2018 11 July 2018
Notice: Australia Canada Singapore Switzerland (ACSS) Consortium – Approval of Erleada 13 July 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
Aviser Santé Canada des mesures prises dans les pays étrangers – Document d’orientation à l’intention de l’industrie – Sommaire ligne directrice 12 juillet 2018

 

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

 

Genre de mise à jour et lien Date
Rapport statistique 2017/2018 de la Direction des produits thérapeutiques 11 juillet 2018
Avis : Consortium Australie-Canada-Singapour-Suisse (ACSS)- L’approbation d’Erleada 13 juillet 2018

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Aug 09

Medical Devices: Clinical Trials in South Africa – Part 1

By Nicola Main, Clinical Research Manager I, Clinical Trial Operations – Rest of World Cato Research

 

Medical Device Workshop at MCC – 13/14 July 2017 – Summary for SACRA Members

This workshop provided supporting information and explanation of items contained in the various guidelines regarding medical devices. These guidelines are in the process of being finalized and are posted on the MCC website, either under the Publications / Guidelines tab; or under the Publications / Industry to Comment tab. Most of the discussions related to the licensing of the various local device suppliers, including the application and quality processes. Clinical Trials were discussed very briefly – this information is included first in this summary.

Clinical Trials

General Process

  • Submit in accordance with current clinical trial submission dates
  • Same fees are payable
  • Application will be reviewed by both Clinical Trials Committee and Medical Device Committee before being ratified by MCC (CTC and MD dates don’t line up very well for last 2 submission dates of 2017, this will be sorted out from 2018 onwards)

Medical Device Trial

  • Apply using current CTF1 – mark sections as Not Applicable if truly not applicable to devices(The devices unit are still “piggybacking” onto a number of documents from the medicines section. This is not ideal and these will be revised, but need to be used at the moment due to the focus on getting medical device companies licensed and high-risk products registered)
  • Comply with labelling requirements (9 Dec 2016 Regulations)

Medicine Trial using supporting devices

  • Need to list supporting devices used for a drug trial on the CTF1
  • If not locally sourced devices from licensed company, should be labelled “For clinical trial use only”
  • Supporting devices will be listed on approval letter to facilitate import (still need other import approvals like Department of Radiation for electro-medical devices at this time)

Adverse Event Reporting and Device Recalls

Guideline published and need to comply effective 1 June 2017

Need to report AE to MCC (SAHPRA) if all 3 criteria are met (for registered devices)

  • AE occurred (may also occur in the device operator or other personnel, not limited to the patient)
  • Device / product (of licensed South African manufacturer/distributor) is associated with the AE
  • AE resulted in death or was life-threatening (or is likely to result in death or be life threatening if it occurs again)

(There are 8 sets of exemptions in the guideline which may require reporting even if all 3 criteria are not met)

MCC (SAHPRA) AE reporting timelines vary by event type

  • Serious threat to public health – 48 hours
  • Death/serious deterioration in patient / operator’s health – 10 days
  • May have led to death / serious deterioration in patient / operator’s health – 30 days

Device recalls require consultation with and approval by MCC (SAHPRA)

  • Recall decision is made locally by MCC (SAHPRA) in consultation with local manufacturer/distributor, not by international parent company
  • Various Types and Levels of recall – same as medicines (discussed in same guideline)

Jul 12

FDA Approval of Epidiolex and the Cannabis-Based Drug Pipeline

By: Kristen Biernat, Cato Research

 

The Food and Drug Administration (FDA) granted approval of the cannabis-based drug Epidiolex to GW Research Ltd. (GW) on June 25, 2018.1 The FDA’s approval of Epidiolex represents two major milestones for GW:

First, it is addresses the unmet need for patients with Lennox-Gastaut syndrome and Dravet syndrome, two rare epilepsy disorders. The application received Orphan Drug designation for both indications and Fast-Track Designation for Dravet syndrome. Notably, Epidiolex is the first drug to be approved for the treatment of Dravet syndrome, a genetic disorder that appears during the first year of a child’s life and is associated with severe, fever-related seizures.

Second, it is the first FDA-approved prescription medicine that contains a purified compound derived from marijuana. Epidiolex is an oral solution that contains cannabidiol (CBD), one of over 60 compounds called cannabinoids found in the Cannabis plant.2 Unlike tetrahydrocannabinol (THC), which is also a cannabinoid, CBD does not cause euphoria or a “high”. The exact mechanism by which CBD produces its anticonvulsant effects is still under investigation.3

While Epidiolex is the first FDA-approved drug directly derived from cannabis, it is not the first cannabis-based drug that has been approved in the United States. To better understand how these products relate to each other, three categories may be employed:

  1. Drugs containing cannabinoids derived directly from cannabis
  2. Drugs containing synthetic versions of cannabinoids found in cannabis
  3. Drugs containing compounds that are similar to cannabinoids found in cannabis

As stated above, Epidiolex falls into the first category. However, the commercially available drugs Marinol, Syndros, and Cesamet fall into the second and third categories. Marinol and Syndros contain dronabinol, synthetic THC, and Cesamet contains nabilone, a synthetic analog of THC. All three compounds are indicated in adults for the treatment of nausea and vomiting associated with chemotherapy, while Marinol and Syndros are also indicated for the treatment of anorexia in individuals with AIDS.

The recent Epidiolex decision paves the way for the development of other cannabis-based drugs that fall into all three categories, but in particular, it sets a precedent for the development of drugs derived directly from the cannabis plant. Indeed, GW is also conducting Phase III trials with Sativex for the treatment of multiple sclerosis spasticity. Like Epidiolex, Sativex is an extract of the cannabis plant that contains cannabinoids (THC and CBD in a 1:1 ratio).4

There are also several drugs currently in development that contain synthetic cannabinoids as well as synthetic cannabinoid analogs. Zynerba Pharmaceuticals is conducting Phase II trials with a gel formulation for the transdermal delivery of CBD to treat neuropsychiatric disorders, such as Fragile X Syndrome. A THC pro-drug patch is also undergoing clinical trials for the treatment of Tourette Syndrome. In addition, Corbus Pharmaceuticals is currently conducting Phase II trials with Lenabasum (ajulemic acid), a THC-mimetic drug, for the treatment of rare inflammatory diseases, such as systemic sclerosis, cystic fibrosis, and dermatomyotisis.

Although Epidiolex has been approved by the FDA, it may not be marketed in the U.S. until it is rescheduled by the Drug Enforcement Agency (DEA). The DEA classifies drugs and substances into five schedules based on the drug’s medical use and abuse potential. Schedule I is the most restrictive and consists of drugs with no currently accepted medical use and a high potential for abuse, such as LSD, ecstasy, and cannabis. Schedule V is the least restrictive and consists of drugs with the lowest potential for abuse, such as cough preparations with less than 200 mg of codeine per 100 mL. CBD, a cannabis-derived compound, is currently classified as Schedule I, meaning that it cannot be sold for medical use. Removal of CBD from Schedule I is expected to take place within 90 days of FDA’s approval of Epidiolex, and while it is likely to remain a controlled substance, it is expected to be available for medical use this fall.5 However, removal of Epidiolex from Schedule I does not mean cannabis itself will also be reclassified. Indeed, cannabis was not rescheduled when Cesamet, Marinol, and Syndros, which all contain synthetic versions of THC, were classified as Schedule II, Schedule III, and Schedule II, respectively.6

In summary, the FDA-approval of Epidiolex indicates a promising future for cannabis-based drugs for the treatment of a range of disease states. While there are several products in the cannabis-based drug pipeline, drugs containing compounds derived from the cannabis plant may benefit most from the recent Epidiolex decision.

 

References:

  1. “FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy”. The U.S. Food & Drug Administration. 25 June 2018.
  2. Atakan, Z. (2012) Cannabis, a complex plant: different compound and different effects on individuals”. Therapeutic Advances in Psychopharmacology. 2: 241-254
  3. “Mechanism of Action”. GW Pharmaceuticals.
  4. “Sativex (delta-9-tetrahydrocannibinol and cannabidiol in the EU) (nabiximols in the USA”. GW Pharmaceuticals.
  5. “Biosciences Announce FDA Approval of EPIDIOLEX® (cannabidiol) oral solution – the First Plant-derived Cannabinoid Prescription Medicine”.GW Pharmaceuticals.
  6. “Controlled Substances by DEA Drug Code Number”. 28 March 2018.

 

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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.

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