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Looking for a FDA Breakthrough Therapy Designation (BTD)? Utilizing the Preliminary BTD Advice System Might be USEFUL – or NOT

By Harsh Sancheti, MSPS, MSRS, Ph.D., Medical Writer at Cato Research

Looking for a FDA Breakthrough Therapy Designation (BTD)? Utilizing the Preliminary BTD Advice System Might be USEFUL – or NOT

The Breakthrough Therapy Designation (BTD) process implemented by the US FDA facilitates expedited regulatory review of a drug candidate intended to treat a serious or life-threatening condition.  To be designated BTD, the sponsor must share preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The program has been largely popular with the pharmaceutical/biotech industry since its introduction in July 2012 with the Food and Drug Administration Safety and Innovation Act (FDASIA) approval. By the end of March 31, 2016, the Center for Drug Evaluation and Research (CDER) had received 342 BTD requests (BTDR) of which 111 were designated BTD. Getting a BTD designation is hugely beneficial to the sponsor and according to some estimates can result in approximately 3.5 years less development time than a drug not granted any of the other expedited statuses by the FDA. So why does the FDA want to bring some changes to the BTD process/program? It is because the increasing BTDRs are putting a burden on the FDA and its ability to handle these requests.  Thus, enters FDA’s ‘preliminary BTDR Advice’ system.

Although, there are not many details available from the FDA publicly about the preliminary BTDR Advice system, its primary goal is to allow the FDA to carry out a preliminary review (without using extensive resources) and give nonbinding advice on whether a formal BTDR submission by the sponsor would be appropriate. The FDA advises that, ‘A sponsor can contact the regulatory project manager (RPM) in the division to which the active IND is assigned and request the “Preliminary Breakthrough Therapy Designation Request Advice” template. This template should then be submitted as a formal amendment to the IND and a subsequent teleconference between the sponsor and the review division will be set up by the RPM. The review division will make a recommendation as to whether a request for a BTD is appropriate, may be too preliminary, or does not currently meet the criteria for a BTD. The Agency’s recommendation is advisory and is not to be interpreted to predict the Agency’s decision on the BTD request’.

Additionally, a sample BTDR Advice template found online recommends submission of the   following:

  • Details about the eligibility for a condition being serious and life-threatening along with indication details
  • Candidate drug’s mechanism of action and its relation to existing therapies
  • Describe the currently available therapies
  • Information on the preliminary clinical evidence along with clinical trial details

 

The FDA’s response to a preliminary BTDR Advice:

  • The Division’s preliminary advice is nonbinding and will not preclude you from submitting an official BTDR in the future.
  • Even if you request preliminary BTDR Advice, the Division may not have enough information to determine if a BTDR is appropriate at this time. An official BTDR may be required to make this determination.
  • The Division will schedule a 15 minute teleconference to discuss this information.
  • No written documentation of the advice provided by the Division or minutes of the teleconference will be issued to the sponsor.

The preliminary BTDR Advice system is an interesting initiative by the FDA to perhaps eliminate BTDRs that clearly lack basis for a possible BTD. It must be understood that an official BTD requires a multi-level evaluation by the FDA. The BTDRs are first evaluated by the division who make a recommendation; this is followed by an evaluation by senior FDA officials comprising the CDER Medical Policy Council who make the final decision about granting the designation or not. Clearly, this multi-level review process would be more burdensome for the FDA than the sponsor; additionally, the FDA currently does not charge any fees for BTDR evaluation. Early on, it was estimated that the FDA would get as few as two or three BTDRs per year but the actual requests went up quite steeply by 30- to 40-fold from initial estimates after a guidance on expedited review programs that includes BTD was published by the FDA in 2014. Thus, perhaps trying to streamline the process, especially for sponsors that do not clearly understand the requirements for a BTD would assist the FDA in utilizing its limited resources more efficiently.

But is it more advantageous for the sponsor to submit a ‘preliminary BTDR Advice’ vs. an ‘official BTDR’? Drafting an official BTDR is fairly straightforward and does not require extensive resources. Sponsors submitting an official BTDR would get a definite reply from the FDA (as opposed to a nonbinding reply after submitting a preliminary BTDR Advice). The response to an official BTDR is fairly quick: less than 60 calendar days of FDA receiving the official BTDR. Sponsors are also allowed to resubmit an official BTDR that was initially denied or withdrawn by the FDA. Whereas, sponsors submitting a preliminary BTDR Advice may not even get any FDA advice if the FDA determines that an official BTDR would be required for making any determination. In this scenario, would it be really useful for the sponsor to submit a preliminary BTDR request? This remains to be seen.

 

Posted in BTD, Cato Research, Clinical Trials, FDA, Medical Research, Regulatory Strategy, Regulatory Submissions | Tagged , , , , , , | Comments Off on Looking for a FDA Breakthrough Therapy Designation (BTD)? Utilizing the Preliminary BTD Advice System Might be USEFUL – or NOT

New FDA Guidances for April 2016

By Brant Hamel, Ph.D., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH from February-April 2016, are posted.  In addition, upcoming advisory committee meetings to be held are also listed below with a link to more information.

 

Special Interest Guidances/Information Date Posted
Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products– Draft Guidance 22-Apr-2016
Technical Performance Assessment of Digital Pathology Whole Slide Imaging Devices– Final Guidance 20-Apr-2016
Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information– Draft Guidance 19-Apr-2016
Radiation Biodosimetry Medical Countermeasure Devices– Final Guidance 18-Apr-2016
Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act– Draft Guidance 15-Apr-2016
Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act– Draft Guidance 15-Apr-2016
Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act– Draft Guidance 15-Apr-2016
Data Integrity and Compliance With Current Good Manufacturing Practice– Draft Guidance 14-Apr-2016
Safety Considerations for Product Design to Minimize Medication Errors– Final Guidance 11-Apr-2016
Contents of a Complete Submission for the Evaluation of Proprietary Names– Final Guidance 5-Apr-2016
Labeling for Biosimilar Products– Draft Guidance 31-Mar-2016
General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products– Draft Guidance 24-Mar-2016
Assessment of Radiofrequency-Induced Heating in the Magnetic Resonance (MR) Environment for Multi-Configuration Passive Medical Devices– Final Guidance 22-Mar-2016
Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion– Draft Guidance 15-Mar-2016
Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009 (Corrected Appendix posted on 3/21/16) – Draft Guidance 11-Mar-2016
Questions and Answers Regarding – Recommendations for Donor Screening, Deferral, and Product Management to Reduce the Risk of Transfusion-Transmission of Zika Virus– Final Guidance 11-Mar-2016
Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease, a Patient-Reported Outcome Instrument for the Measurement of Severity of Respiratory Symptoms in Stable Chronic Obstructive Pulmonary Disease: Qualification for Exploratory Use– Draft Guidance 8-Mar-2016
Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271– Final Guidance 8-Mar-2016
Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans– Draft Guidance 8-Mar-2016
Clinical Considerations for Investigational Device Exemptions (IDEs) for Neurological Devices Targeting Disease Progression and Clinical Outcomes– Draft Guidance 7-Mar-2016
Medical Devices and Clinical Trial Design for the Treatment or Improvement in the Appearance of Fungally-Infected Nails– Final Guidance 7-Mar-2016
Environmental Assessment: Questions and Answers Regarding Drugs With Estrogenic, Androgenic, or Thyroid Activity– Final Guidance 4-Mar-2016
Labeling for Permanent Hysteroscopically-Placed Tubal Implants Intended for Sterilization– Draft Guidance 4-Mar-2016
Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products– Final Guidance 3-Mar-2016
Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies– Draft Guidance 1-Mar-2016
Requirements for Transactions with First Responders under Section 582 of the Federal Food, Drug, and Cosmetic Act— Compliance Policy– Final Guidance 29-Feb-2016
Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations– Final Guidance 18-Feb-2016
Immunogenicity-Related Considerations for Low Molecular Weight Heparin– Final Guidance 18-Feb-2016
Recommendations for Donor Screening, Deferral, and Product Management to Reduce the Risk of Transfusion-Transmission of Zika Virus– Final Guidance 16-Feb-2016
Allergic Rhinitis: Developing Drug Products for Treatment– Draft Guidance 12-Feb-2016
Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax– Draft Guidance 12-Feb-2016
Characterization of Ultrahigh Molecular Weight Polyethylene (UHMWPE) Used in Orthopedic Devices– Draft Guidance 12-Feb-2016
Completeness Assessments for Type II API DMFs Under GDUFA – Final Guidance 12-Feb-2016
Nonallergic Rhinitis: Developing Drug Products for Treatment– Draft Guidance 12-Feb-2016
Display Devices for Diagnostic Radiology– Draft Guidance 9-Feb-2016
Recommendations for Premarket Notifications for Lamotrigine and Zonisamide Assays– Final Guidance 9-Feb-2016
Applying Human Factors and Usability Engineering to Medical Devices– Final Guidance 3-Feb-2016
Enforcement Policy on National Health Related Item Code and National Drug Code Numbers Assigned to Devices– Draft Guidance 3-Feb-2016
Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development– Draft Guidance 3-Feb-2016
List of Highest Priority Devices for Human Factors Review– Draft Guidance 3-Feb-2016
Upcoming Meetings (* = New)
* Endocrinologic and Metabolic Drugs Advisory Committee, 24 May, Silver Spring, MD
* Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting, 24 May, Gaithersburg, MD
* Endocrinologic and Metabolic Drugs Advisory Committee, 25 May, Silver Spring, MD
* Circulatory System Devices Panel of the Medical Devices Advisory Committee, 02-3 June, Gaithersburg, MD
* Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, 07 June, Silver Spring, MD
* Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, 08 June, Silver Spring, MD
* Antimicrobial Drugs Advisory Committee, 09 June, Silver Spring, MD
* Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee Meeting, 15-16 September, Silver Spring, MD

* new entry
Last updated: 13 May 2016

Posted in Clinical Trials, Drug Development, FDA, Medical Research, Regulatory Strategy, Regulatory Submissions | Tagged , , , , | Comments Off on New FDA Guidances for April 2016

Jump on the Development Safety Update Report (DSUR) Bandwagon!

By Amelie Rodrigue-Way, Ph.D., RAC (CAN), Clinical Scientist, Cato Research Canada.

If you have an open Investigational New Drug application (IND) then you are all too familiar with the periodic reporting requirements. Many US-based sponsors have opted for the Annual Report format when it comes to their IND (sections 1.13.1 to 1.13.14 of the IND; see http://www.ask-cato.com/2010/09/annual-reports-a-time-for-reflection). If you are one of them and you are conducting or planning to conduct a study in Canada, then this might be a good time to consider changing your annual reporting format.

To conduct a clinical trial in Canada, a Clinical Trial Application (CTA) must be submitted and a No Objection Letter (NOL) must be granted by Health Canada before the trial can begin. During the course of the study, the CTA “annual report” is submitted in the form of the annually updated Investigator’s Brochure. No other annual reporting documentation is required under your active CTA.

Nevertheless, Health Canada adopted the International Conference on Harmonization (ICH) guidance E2F: Development Safety Update Report in June 2012 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e2f-step4-etap4-eng.php). A safety pilot was launched for pharmaceuticals and biologics, and selected sponsors were requested to submit annual DSURs. The safety pilot was successfully completed in 2015, and as of 04 December 2015, DSUR and the DSUR Checklist must be provided upon request, directly to Health Canada’s Office of Submission and Intellectual Property (OSIP). Alternatively, DSURs may be submitted voluntarily by sponsors when important new safety information on a drug needs to be communicated. Health Canada also mentions that a strong rationale/justification for the voluntary filing of the DSUR should be included in the cover letter. The objectives of DSUR review at Health Canada are as follows:

  • Enhance the safety surveillance of drugs in development and protect clinical trial subjects;
  • Analyze important identified and potential risks;
  • Identify potential safety issues at the pre-approval stage;
  • Support, when required, the safety assessment of drugs submitted for market authorization; and
  • Support the life cycle approach to product vigilance.

What does this mean for your CTA? Unlike the IND, which houses several studies and progresses as the drug development process evolves, the CTA is related to a single clinical study. Once the study ends, Health Canada is notified of study completion and the CTA is no longer updated. The DSUR is not submitted as part of your CTA since by definition the DSUR is prepared per active substance and will contain data pertinent to all dosage forms and strengths, all indications, and all patient populations under study with the investigational product during the reporting period. While the new requirement for providing a DSUR upon request has no immediate impact on your CTA, Health Canada may still monitor the updated safety information outside the realm of your active CTA. If requested, you should be able to quickly provide the most current DSUR.

Therefore, when the time will come to prepare your IND annual report, think of your friendly neighbors to the north suggesting to replace your Annual Report with a DSUR, as it also meets the FDA’s requirements for an IND application annual report and has its own section in your Module 1 (Section 1.13.15).

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New FDA Guidances for January 2016

Special Interest Guidances/Information Date Posted
Design Considerations and Pre-market Submission Recommendations for Interoperable Medical Devices– Draft Guidance 26-Jan-2016
Postmarket Management of Cybersecurity in Medical Devices- Draft Guidance 22-Jan-2016
Guidance Agenda: Guidances CDER is Planning 22-Jan-2016
Implanted Blood Access Devices for Hemodialysis– Final Guidance 21-Jan-2016
Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile– Final Guidance 21-Jan-2016
Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products– Final Guidance 14-Jan-2016
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of Hepatitis B Virus from Donor of Human Cells, Tissues, and Cellular and Tissue-Based Products– Draft Guidance 8-Jan-2016
Unique Device Identification: Convenience Kits– Draft Guidance 4-Jan-2016
Upcoming Meetings (* = New)
  Meeting of the Psychopharmacologic Drugs Advisory Committee, 03 February; Silver Spring, MD
* Arthritis Advisory Committee, 03 February; Silver Spring, MD
* Cellular, Tissue, and Gene Therapies Advisory Committee, 16 February; Silver Spring, MD
  Risk Communication Advisory Committee, 16 February; Silver Spring, MD
  Risk Communication Advisory Committee, 17 February; Silver Spring, MD
  Circulatory System Devices Panel of the Medical Devices Advisory Committee, 18 February; Gaithersburg, MD
  Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee, 19 February; Gaithersburg, MD
  Gastroenterology and UrologyDevices Panel of the Medical Devices Advisory Committee, 25-26 February; Gaithersburg, MD
  Vaccines and Related Biological Products Advisory Committee, 04 March; Silver Spring, MD
* Circulatory System Devices Panel of the Medical Devices Advisory Committee, 15-16 March; Gaithersburg, MD
* Meeting of the Psychopharmacologic Drugs Advisory Committee, 29 March; Silver Spring, MD

* new entry
Last updated: 01 Febuary 2016

Posted in Cato Research, Clinical Trials, Drug Development, FDA, Regulatory Strategy, Regulatory Submissions | Tagged , , , , | Comments Off on New FDA Guidances for January 2016