Regulatory Intelligence Brief: 2017 FDA Overview

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. 

PDUFA/GDUFA/BsUFA
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

   

21^st 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 clinicaltrials.gov 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].