New FDA Guidances for May and June 2016

By Yuka Fukushima, Regulatory Associate & Compliance Specialist at Cato Research
FDA draft and final guidances, released from CDER, CBER, and CDRH from May-June 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
Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information – Final Guidance 6/30/2016
Recurrent Herpes Labialis: Developing Drugs for Treatment and Prevention – Draft Guidance 6/30/2016
Vulvovaginal Candidiasis: Developing Drugs for Treatment – Draft Guidance 6/30/2016
Elemental Impurities in Drug Products – Draft Guidance 6/30/2016
Procedures for Evaluating Appearance Issues and Granting Authorizations for Participation in FDA Advisory Committees – Draft Guidance 6/28/2016
FDA Regional Implementation Specifications for ICH E2B(R3) Reporting to the FDA Adverse Event Reporting System (FAERS) – Technical Specifications Document 6/22/2016
Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices – Final Guidance 6/21/2016
Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies – Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 6/20/2016
Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process – Final Guidance 6/16/2016
Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions – Draft Guidance 6/16/2016
Quality Attribute Considerations for Chewable Tablets – Draft Guidance 6/16/2016
Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment – Draft Guidance 6/13/2016
Dissemination of Patient-Specific Information from Devices by Device Manufacturers – Draft Guidance 6/10/2016
Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act – Final Guidance 6/9/2016
Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry – Final Guidance 6/9/2016
Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance – Final Guidance 6/9/2016
E18 Genomic Sampling and Management of Genomic Data – Draft Guidance 6/2/2016
Individual Patient Expanded Access Applications: Form FDA 3926 – Final Guidance 6/2/2016
Charging for Investigational Drugs Under an IND — Qs & As – Final Guidance 6/2/2016
Expanded Access to Investigational Drugs for Treatment Use — Qs & As – Final Guidance 6/2/2016
FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions – Draft Guidance 6/1/2016
Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs – Draft Guidance 5/31/2016
Implementation of Acceptable Full-Length and Abbreviated Donor History Questionnaires and Accompanying Materials for Use in Screening Donors of Blood and Blood Components – Final Guidance 5/27/2016
Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment – Draft Guidance 5/19/2016
Use of Electronic Health Record Data in Clinical Investigations – Draft Guidance 5/16/2016
Postmarket Surveillance Under Section 522 of the Federal Food, Drug, and Cosmetic Act – Final Guidance 5/16/2016
Considerations for Use of Histopathology and Its Associated Methodologies to Support Biomarker Qualification – Final Guidance 5/13/2016
Infectious Disease Next Generation Sequencing Based Diagnostic Devices: Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers – Draft Guidance 5/13/2016
Technical Considerations for Additive Manufactured Devices – Draft Guidance 5/10/2016
Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment – Draft Guidance 5/3/2016
Special Protocol Assessment – Draft Guidance 5/3/2016
Upcoming Meetings (* = New)
* Arthritis Advisory Committee Meeting – 12 July, Silver Spring, MD
* Arthritis Advisory Committee Meeting – 13 July, Silver Spring, MD
* Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee Meeting – 19 July, Silver Spring, MD
* Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Devices Advisory Committee Meeting – 21-22 July, Gaithersburg, MD
* Cellular, Tissue, and Gene Therapies Advisory Committee Meeting – 26 July, Silver Spring, MD
* Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Devices Advisory Committee Meeting – 10 August, Gaithersburg, MD
* Microbiology Devices Panel of the Medical Devices Advisory Committee Meeting – 16 August, 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
* Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee – 19 October, Silver Spring, MD

* new entry
Last updated: 08 July 2016

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FDA Revises Guidance on Special Protocol Assessments

By Harsh Sancheti, MSPS, MSRS, Ph.D., Medical Writer at Cato Research and
Joanne McNelis, Ph.D., Scientist at Cato Research

 

FDA Revises Guidance on Special Protocol Assessments

What is a Special Protocol Assessment (SPA)?

SPA is a process where a study sponsor and the FDA reach agreement on the critical components of a stability protocol, a pivotal clinical trial, or animal carcinogenicity study to determine if their design and size adequately addresses the specific scientific and regulatory requirements. An FDA agreement on the SPA indicates that the agency agrees with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses). These elements are critical to ensure that the trial conducted under this protocol has the potential to support the regulatory requirements for a future marketing application.

Importantly, the SPA process is beneficial for the sponsor to gain insight into FDA’s thinking and get agreement with the FDA on critical aspects of the protocol; CDER has issued more than 1000 SPA agreements since the program was established in 1997.

 

What is Included in the May 2016 SPA Draft Guidance?

With the aim of improving the quality and appropriateness of SPA requests, and the resulting interaction with sponsors, FDA addressed several key areas of concern in the new draft guidance to reflect alterations in the regulatory landscape and policy since its 2002 predecessor. The new guidance expanded the protocol eligibility for SPA and provided clarification on the overall submission process. Specifically, the topics addressed include:

  • Clarifying which protocols are eligible for SPA
  • Adding animal rule efficacy protocols intended to support approval of drugs and biological products
  • Adding protocols intended to support approval of biosimilar biological products
  • Providing greater detail about the content of an SPA submission
  • Clarifying the process for rescinding an SPA agreement.

 

What Protocols are Eligible for SPA?

The types of protocols that can be reviewed under an SPA are limited, and according to the 2002 guidance include: (1) Carcinogenicity protocols, (2) Final product stability protocols, or (3) Clinical protocols for Phase 3 trials whose data will form the primary basis for an efficacy claim. Perhaps the most significant revision to the May 2016 draft guidance was the expansion of eligibility for SPA. Consistent with new performance goals for SPA, mandated in the Prescription Drug User Fee Amendments of 2012 (PDUFA V) and with the Biosimilar User Fee Act of 2012 (BsUFA), efficacy protocols that meet the animal rule and protocols intended to support approval of biosimilar biological products will also be eligible, in addition to the previously accepted protocols.

 

Increased Details of the SPA Content and Process

The new draft guidance also describes in greater detail the procedures for submitting a request, the content of the request submission, the FDA assessment process, and the obligations the FDA has in responding to sponsors.

 

Before submitting an SPA Request, the FDA strongly suggests that the sponsor meets with the FDA to discuss the trial for its regulatory context. Under PDUFA V and BsUFA goals, a protocol will qualify for SPA only if the sponsor has had an end-of-phase 2/pre-phase 3 meeting or end-of-phase 1 meeting, as appropriate, or Biosimilar Biological Product Development (BPD) Type 2 or Type 3 meeting, respectively. The guidance states that the complete protocol and statistical analysis plan should be submitted along with “a limited number of specific questions about protocol design and scientific and regulatory requirements.” In particular, the FDA calls on sponsors to “identify unusual or potentially problematic aspects of the protocol” in the SPA request.

 

Typically, the agency reviews an SPA relatively quickly and is within 45 days. There are established procedures and timing for requesting an SPA. Both, CDER and CBER recommends submitting the SPA protocol to the Agency at least 90 days prior to the anticipated study starting date. The protocol should be complete, and enough time should be allowed to discuss and resolve any issues before the study begins. It must be noted that SPA will not be provided by the FDA after a study has begun and if they are evaluated by the FDA, it will not qualify for the 45-day time frame FDA review. The SPA protocol should be submitted as a separate amendment to the sponsor’s IND (with additional filing details listed in the 2002 guidance).

 

After completing the SPA review, FDA issues a letter including an assessment of the protocol, agreement or non-agreement with the proposed protocol and answers to the sponsors initiated questions. The FDA will address the critical elements to the protocol design. For example, the FDA may convey their agreement “with the proposed primary endpoint or sample size estimate, but might not include a detailed review of the case report form”. If a no‑agreement letter is issued, FDA will discuss the specific design parameters with which the FDA does not agree. In addition, the May 2016 draft guidance recommends that a Type A or Type 1 meeting be held to discuss outstanding issues.

 

The Benefits and Risks of an SPA

The SPA can be a very valuable process for a sponsor. It can provide additional assurance, above other regulatory guidance, that innovative clinical trial designs and study endpoints are adequate for marketing approval. When used appropriately, it can promote the use of novel approaches to drug development, potentially reducing the associated time and monetary costs. However, it should be noted that an SPA agreement is not binding in all circumstances. FDA’s guidance states, “an agreement may not be changed by the manufacturer or the agency unless through a written agreement of the two entities, or if FDA determines a substantial scientific issue essential to determining the safety or effectiveness of the drug”. The clause of substantial scientific issue is necessary to prevent the approval of drugs that are realized to have safety and efficacy concerns after new scientific information has come to light. In the past, the FDA has come under fire for changing SPA agreements late in clinical development, and for a lack of transparency of this process. Since the impact of rescinding an SPA agreement is so large — potentially setting a sponsor back years in clinical development and costing millions of dollars — the increased level of detail in the new guidance will be welcomed by drug developers. It is hoped by all stakeholders that the increased clarity of the SPA process provided in this draft guidance will foster a more useful interaction between sponsors and the FDA, and reduce the uncertainty and risk of the drug development process.

Comments on the May 2016 Draft Guidance are due by July 5, 2016 here.

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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.

 

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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