Regulatory Intelligence Brief: 2017 FDA Overview

Dec. 12, 2017
All the major changes this year including guidance documents drafted and finalized, new legislation, other areas of interest and some tools to help you explore additional areas not covered herein

Sometimes a year will go by and the regulatory process will seem to move in geologic time (versus real time) and nothing new has happened, that was NOT the case in 2017 which has shaped up to be a very a busy year for the FDA and drug developers. This article will explore all the major changes this year including guidance documents drafted and finalized, new legislation, other areas of interest and some tools to help you explore additional areas not covered herein but might be of interest to you; the impact of these changes is provided for some of the information. First stop, a new CEO for the FDA, or in FDA speak, a new commissioner. 

New Commissioner
The head of the FDA is like a Captain of a ship, the CEO; this person sets the tone for interpretation of regulations, application of regulations and what regulations will be focused on.  Dr. Scott Gottlieb was sworn in as the 23rd Commissioner of Food and Drugs on May 11, 2017 and has been busy every since doing what he can to streamline drug development (from both the Sponsor and FDA perspective), speed up breakthrough therapy reviews, issue more guidance documents and crack down on the opioid addiction epidemic.  Based on his brief output for 2017, 2018 will be another whirlwind year as well.

Guidance Documents
The beginning of 2017 was a busy time for the FDA, there was a flood of guidance documents published in the Federal Register as either draft or final guidance document as it seemed like the FDA wanted to get through as many guidance documents as possible prior to the regime change since a new president usually means a change in the head of the FDA. 

Following is a list of all guidance documents published in 2017 so far, their status followed with all manufacturing guidance documents highlighted.  Want to know where you can check for new guidance documents?  FDA posts them here.  

Search for the guidance document you want here. 

Table X: 2017 Guidance Documents
Generics General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products Guidance for Industry  Final Guidance 11/21/17
User Fees Assessing User Fees Under the Biosimilar User Fee Amendments of 2017 Guidance for Industry   Draft Guidance  11/15/17
International Council for Harmonisation - Safety  S5(R3) Detection of Toxicity to Reproduction   Draft Guidance  11/09/17
Procedural Use of a Drug Master File for Shared System REMS Submissions Guidance for Industry  Draft Guidance 11/08/17
Clinical/Medical Evaluating Drug Effects on the Ability to Operate a Motor Vehicle  Final Guidance  11/08/17
Clinical/ Medical Recurrent Herpes Labialis: Developing Drugs for Treatment and Prevention  Final Guidance  11/06/17
Compliance Recommended Statement for Over-the-Counter Aspirin-Containing Drug Products Labeled With Cardiovascular Related Imagery Guidance for Industry   Final Guidance  11/06/17
Clinical/Antimicrobial Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment Guidance for Industry  Final Guidance  11/06/17
Pharmaceutical Quality/CMC ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence) Guidance for Industry   Draft Guidance  11/03/17
Procedural  Formal Dispute Resolution: Appeals Above the Division Level Guidance for Industy   Final Guidance  11/03/17
Generics - User Fees Controlled Correspondence Related to Generic Drug Development Draft Guidance for Industry  Draft Guidance  11/02/17
International Conference on Harmonisation - Efficacy E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials  Draft Guidance  10/30/17
User Fees Assessing User Fees Under the Generic Drug User Fee Amendments of 2017 Guidance for Industry  Draft Guidance  10/27/17
Clinical/Medical Pediatric Gastroesophageal Reflux Disease: Developing Drugs for Treatment Guidance for Industry  Draft Guidance  10/26/17
Clinical Pharmacology Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications Guidance for Industry   Draft Guidance  10/25/17
Clinical Pharmacology In Vitro Metabolism- and Transporter- Mediated Drug-Drug Interaction Studies Guidance for Industry  Draft Guidance  10/25/17
Generics / User Fees Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA   Draft Guidance  10/13/17
User Fees Assessing User Fees Under the Prescription Drug User Fee Amendments of 2017 Guidance for Industry (PDF - 96KB)  Draft Guidance  10/12/17
Generics Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry   Draft Guidance  10/11/17
Clinical Antimicrobial Respiratory Syncytial Virus Infection: Developing Antiviral Drugs for Prophylaxis and Treatment Guidance for Industry   Draft Guidance  10/11/17
Drug Safety Format and Content of a REMS Document Guidance for Industry   Draft Guidance  10/11/17
Generics - User Fees Requests for Reconsideration at the Division Level Under GDUFA Guidance for Industry  Draft Guidance  10/11/17
Generics/User Fees/ Pharmaceutical Quality/CMC Completeness Assessments for Type II API DMFs Under GDUFA Guidance for Industry   Final Guidance  10/04/17
Generics / User Fees ANDA Submissions – Prior Approval Supplements Under GDUFA   Final Guidance  10/04/17
Generics /User Fees ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin Guidance for Industry   Draft Guidance  10/04/17
Generics - User Fees Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry   Draft Guidance  10/02/17
Generics - User Fees ANDA Submissions - Refuse-to-Receive Standards: : Questions and Answers Guidance for Industry  Draft Guidance   10/02/17
Generics - User Fees  ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA Guidance for Industry  Draft Guidance  10/02/17
Pharmaceutical Quality/CMC Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry   Final Guidance  09/28/17
Pharmacology/ Toxicology Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations Guidance for Industry   Draft Guidance  09/28/17
 Procedural Expedited Programs for Serious Conditions––Drugs and Biologics   Final Guidance  09/22/17
 Biosimilars Statistical Approaches to Evaluate Analytical Similarity   Draft Guidance  09/21/17
Pharmacology/Toxicology Microdose Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations   Draft Guidance  09/12/17
Procedural Identifying Trading Partners Under the Drug Supply Chain Security Act Guidance for Industry   Draft Guidance  08/18/17
Pharmaceutical Quality/Manufacturing Standards (CGMP) Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products   Draft Guidance 08/08/17
Pharmaceutical Quality/CMC CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports   Draft Guidance  08/08/17
Labeling Child-Resistant Packaging Statements in Drug Product Labeling Guidance for Industry   Draft Guidance  08/02/17
Clinical/Antimicrobial Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases   Final Guidance  08/01/17
Over-the-counter Consumer Antiseptic Wash Final Rule Questions and Answers Final  07/25/2017
ICH-Efficacy PDEs for Triethylamine and for Methylisobutylketone Final  07/24/2017
ICH-Quality Q3C Tables and List Rev. 3 Final  07/24/2017
ICH-Quality ICH Q3C Maintenance Procedures for the Guidance for Industry Q3C Impurities: Residual Solvents Final  07/24/2017
ICH-Multidisciplinary M4E(R2): The CTD – Efficacy Final  07/24/2017
Bioequivalence recommendations Diclofenac sodium_204623 Draft  07/11/2017
Bioequivalence recommendations  Brivaracetam_205836  Draft  07/11/2017
Bioequivalence recommendations  Silver sulfadiazine_017381  Draft  07/11/2017
Bioequivalence recommendations  Triamcinolone acetonide_011602  Draft  07/11/2017
Bioequivalence recommendations Cyanocobalamin_021642 Draft  07/11/2017
Bioequivalence recommendations Fluphenazine HCl_089804  Draft  07/11/2017
Bioequivalence recommendations  Dasabuvir Sodium; Ombitasvir; Paritaprevir; Ritonavir_208624  Draft  07/11/2017
Bioequivalence recommendations  Dabigatran Etexilate Mesylate_22512  Draft  07/11/2017
Bioequivalence recommendations  Aspirin; Omeprazole_205103  Draft  07/11/2017
Bioequivalence recommendations  Tenofovir alafenamide fumarate_208464  Draft  07/11/2017
Bioequivalence recommendations  Uridine triacetate_208159  Draft  07/11/2017
Bioequivalence recommendations  Obeticholic Acid_207999  Draft  07/11/2017
Bioequivalence recommendations Brimonidine Tartrate_0.15_21262 Draft 07/11/2017
Bioequivalence recommendations Aspirin_200671 Draft 07/11/2017
Bioequivalence recommendations Glycopyrrolate_207923 Draft 07/11/2017
 Bioequivalence recommendations Dextroamphetamine sulfate_040361 Draft 07/11/2017
 Bioequivalence recommendations Gentamicin sulfate_062307 Draft 07/11/2017 
 Bioequivalence recommendations Triamcinolone acetonide_087356 Draft 07/11/2017
 Bioequivalence recommendations Tiopronin_19569 Draft 07/11/2017
 Bioequivalence recommendations  Clocortolone pivalate_017765 Draft  07/11/2017
Bioequivalence recommendations  Gefitinib_206995 Draft  07/11/2017
Bioequivalence recommendations  Trifluridine; Tipiracil_207981  Draft  07/11/2017
Administrative / Procedural
 Product Identifier Requirements Under the Drug Supply Chain Security Act – Compliance Policy Guidance for Industry  Draft  06/30/2017
Administrative / Procedural  Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 –  Draft  06/20/2017
 ICH-Quality  Q11 Development and Manufacture of Drug Substances—Questions and Answers (regarding the selection and justification of starting materials.  Draft  02/17/2017
 Administrative / Procedural  Requirements for Transactions with First Responders under Section 582 of the Federal Food, Drug, and Cosmetic Act— Compliance Policy Guidance for Industry  Final  02/16/2017
 Administrative / Procedural Dear HealthCare Provider Letters: Improving Communication of Important Safety Information  Final  02/08/2017
 Administrative / Procedural Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers Guidance for Industry & Review Staff  Draft  01/18/2017
 Biosimilarity Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry  Draft  01/17/2017
   2016 Medical Gas Container-Closure Rule Questions and Answers Guidance for Industry  Final  01/17/2017
 Clinical - Medical  Assessment of Abuse Potential of Drugs  Final  01/17/2017
 Compounding, Administrative / Procedural  Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act Final  01/13/2017
Generic Drugs Referencing Approved Drug Products in ANDA Submissions Guidance for Industry Draft 01/13/2017
Generic Drugs Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA: Draft Guidance for Industry Draft 01/13/2017
Compounding, Administrative / Procedural Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry Final 01/13/2017
Compliance, CGMP, Pharmaceutical Quality Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities Final 01/12/2017
Generic Drugs Guidance for Industry 180-Day Exclusivity: Questions and Answers Draft 01/12/2017
Compliance, Pharmaceutical Quality, CGMP Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application Draft 01/12/2017
Clinical - Medical Multiple Endpoints in Clinical Trials Guidance for Industry Draft 01/12/2017
Labeling Nonproprietary Naming of Biological Products Guidance for Industry Final 01/12/2017
Combination Products, CGMP Current Good Manufacturing Practice Requirements for Combination Products Final 1/10/2017
Q&A Annual Reporting by Prescription Drug Wholesale Distributors and Third-Party Logistics Providers: Questions and Answers Guidance for Industry   01/09/2017






Major Legislation/Regulations
What were the major legislation that was passed this year and will find their way to implementation through the passage of regulations or by other means enacted?

On August 18, 2017, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA), with provisions that went into effect October 1, 2017 and remain in effect through September 30, 2022.  FDARA included reauthorization of:

  • Prescription Drug User Fee Act (PDUFA) (Fifth time reauthorized)
  • Generic Drug User Fee Amendments (GDUFA) (first time reauthorized) (ANDA, Drug Master Files,
  • Biosimilar User Fee Act (BsUFA) (first time reauthorized)  
    Table X. Brief Overview of FDARA User Fee Agreement
    User Fee What Does it Provide Impact Analysis
    PDUFA Provides the FDA with new authority to require a pediatric investigation into an adult cancer drug if that drug is directed at a molecular target that is relevant to a pediatric cancer Pediatric trials for oncology products could often be waived until after marketing approval for the adult indication, this was especially true for orphan cancers; FDA can now require a pediatric program.
    PDUFA Providing resources for highly successful, and resource intensive breakthrough therapies program for drugs If you have a Breakthrough program, FDA will have more funding to resource the regulator side
    PDUFA Continuing to leverage the use of “real-world” health data to inform regulatory decision making, including enhancing the capabilities of FDA’s Sentinel System for drug The ability to use real world evidence could potentially help get drugs approved with few Phase 3 patients; this is to “support” approval data, not replace it
    PDUFA Providing new opportunities for early consultation on the use of new surrogate endpoints
    • A request to discuss a surrogate endpoint will be a Type C meeting request
    • At the meeting discuss feasibility of the surrogate as a primary endpoint, any knowledge gaps, and how these gaps should be addressed before surrogate could be used as primary basis for approval.
    • FDA is signaling it is open to discussing new indication and endpoints
     PDUFA  Streamlining combination product review to enhance coordination and transparency between FDA and industry.  Hopefully this will lead to a more streamlined review of combination products and shorter marketing application review times
     PDUFA  Structured Approach to Benefit-Risk Assessment  FDA will publish an implementation plan for benefit-risk assessment so that Sponsors will understand all the elements and factors that need to be taken into consideration
     PDUFA  New Meeting Review Timeline for some Type B and Type C Meetings  
    • Meeting packages will be due earlier for certain Type B meetings (EOP1, EOP2) by Day 20 after meeting request
    • Type C meeting packages will be due by Day 28 after meeting request
    • Sponsors will have a chance to submit comments to the preliminary FDA comments and have FDA review them prior to the actual meeting
    • Will make the meeting process more meaningful to the drug development process
     PDUFA  New Fee Structure  
    • Application fee – will account for 20% of total target revenue
    • Program fee – will account for 80% of total target revenue
    • Supplement and establishment fees are being discontinued; product fee replaced by program fee
    • Program fee applies to the sponsor of a human drug application approved as of October 1 of each fiscal year
    • Each separate product approved under the application will incur a separate fee
    • The total number of fees will be limited to five (5) per application
    • A product is a specific strength or  potency of a drug in its final  dosage form
     GDUFA 75% refund for submissions that have been withdrawn prior to being received  Cost of application will be recoverable if an application needs to be withdrawn
     GDUFA  No more Prior Approval Supplement (PAS) fee  
     GDUFA  Contract Manufacturing Organization (CMO) fee – one-third the Finished Dosage Form (FDF) fee  

    • A CMO is a facility that provides contract manufacturing for ANDA sponsors

    • A CMO does not hold any ANDAs and is not affiliated with any ANDA holder

    Reduced fee currently paid by a CMO
     GDUFA  Generic Drug Applicant Program Fee (the “ANDA Holder Program Fee”)  

    Each person and its affiliates will be assessed an annual fee depending on the number of approved ANDAs in their combined portfolio. There will be three tiers:

    • Large: More than 20 approved ANDAs

    • Medium: Between 6 and 19 approved ANDAs

    • Small: Five or fewer approved ANDAs


    – The fee for each tier will differ:

    • Large: Full fee

    • Medium: 40% of the ‘large’ fee

    • Small: 10% of the ‘large’ fee 
     BsUFA Authorizes FDA to assess and collect fees for biosimilar biological products from October 2017 through September 2022  
    • Fee types
      • Biological Product Development (BDP) program fees (initial, annual, reactivation)
      • Application fee
      • Program fee
    • Changes
      • No supplement, establishment, or product fees
        • Discontinuation of the reduction of BPD fees paid from the application fee
        • New fee:  Program fee
        • Applies to the sponsor of a biosimilar biological product application approved as of October 1 of each fiscal year and does not appear on a discontinued biosimilar list
          • Each separate product approved under the application will incur a separate fee
          • Total number of program fees is limited to five (5) per application
        A biosimilar biological product is a specific strength of a biological product in final dosage form

21st Century Cures Act 
Some could argue that this was signed into law on 2016, not 2017 so it shouldn’t be included here, but just like a tsunami that gets started out at sea (i.e. 2016), the effects of the law hit land in 2017.  Some of the major legislation and acts introduced in this law (and supported by FDARA) include:

  • The Regenerative Medicine Advanced Therapy, or RMAT, that offers a new expedited option for certain eligible biologics products.
  • The Breakthrough Devices program, designed to speed the review of certain innovative medical devices.
  • Reauthorization of the Priority Review Vouchers for pediatric orphan drugs
  • Real World Data
  • Novel Clinical Trial Design
  • Issue patient focused drug development guidance
  • Issue compliance activity reports (whether or not companies have posted on or not)

Want to see the FDA’s progress with the act?  Progress reports can be found here.

OTC Monograph User Fee Program?
A user fee program for nonprescription (over-the-counter or OTC) monograph drugs would be a potential funding mechanism to supplement congressional non user-fee appropriations, and would support timely and efficient FDA review of the efficacy and safety of ingredients included in or proposed for inclusion in a monograph.  This user fee act is currently being negotiated.  For more and current information.

Agreements and Other Items of Interest
Mutual Recognition promises new framework for pharmaceutical inspections for United States and European Union.  The United States and the European Union (EU) completed an exchange of letters to amend the Pharmaceutical Annex to the 1998 U.S.-EU Mutual Recognition Agreement. Under this agreement, U.S. and EU regulators will be able to utilize each other’s good manufacturing practice inspections of pharmaceutical manufacturing facilities. Ultimately, this will enable the FDA and EU to avoid the duplication of drug inspections, lower inspection costs and enable regulators to devote more resources to other parts of the world where there may be greater risk.  

On October 31 2017 it was announced that the FDA will recognize eight European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements including: Austria, Croatia, France, Italy, Malta, Spain, Sweden and the United Kingdom..

The agency is expected to announce additional countries that meet FDA requirements in the first quarter of 2018, and believes that the progress made so far puts them on track to meet their goals of completing all 28 national capability assessments in the European Union (EU) by July 2019.

Tools that Can Help Predict Upcoming Regulations or Stay Updated
Guidance document agenda for 2017

Still using an old guidance document?  See the list of withdrawn guidances.

Novel drug approvals in 2017

First time Generic approvals.

Biologic Approvals

Drug Approval Packages

Meredith Brown-Tuttle, RAC, FRAPS, is the principal consultant for Regulatorium a company specializing in regulatory intelligence, writing and strategy. She is the author of IND Submissions: A Primer, published by Barnett, Regulatory Intelligence 101, published by RAPS, numerous articles and a member of the RAPS Board of editors. She can be reached at [email protected].

About the Author

Meredith Brown-Tuttle | RAC