Life Science Compliance Update

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January 09, 2013

FDA Updates PDUFA Goals: NDA’s, BLA’s and REMS

FDA Hearing 2
The Food and Drug Administration (FDA) recently gave three presentations from the Centers for Drug Evaluation and Research (CDER).  The first presentation focused on New Drug Review and a 2012 Update from John K. Jenkins, MD, Director of the Office of New Drugs in CDER.  The presentation was given at an FDA/CMS summit. 

Jenkins first began by addressing how CDER is doing with regards to meeting the Prescription Drug User Fee Act (PDUFA) goals for drug approval.  He also gave an overview of the trends in new drug approvals, investigational new drug (IND) applications, New Molecular Entity (NME) submissions, and NME approvals.  He also discussed the use of expedited pathways; Rare diseases and implementation of PDUFA V/FDASIA “Program” for NME review.

As we previously noted in FDA’s report. the agency is meeting or exceeding nearly all PDUFA goals for application review.  Jenkins noted that the commercial IND pipeline of new drugs under development remains strong and is growing.  Through Nov 30, in Calendar Year (CY) 2012, CDER had received 34 NME applications.  He noted that some are still within the 60‐day filing window, and that FDA usually sees a surge of submissions in December. 

The number of NMEs filed for review is a major rate‐limiting step to the number of NMEs approved.  To date in CY12, CDER has approved 31 NME applications

– CY 12 total to date is one more than the total approved in CY11 and highest total since 2004.  Several NMEs have PDUFA goal dates before end of December.  As a result, the potential exists for the highest number of approvals since the mid‐90’s. 

NME approvals in 2012 include a number of “breakthrough” drugs that provide much needed new treatment options for patients.  Average first cycle approval rates for NME applications in PDUFA IV are at the highest levels since the start of PDUFA; possible reasons include: 

  • Full implementation of 21st Century Review Model
  • Greater experience with use of FDAAA tools (e.g., REMS, PMRs)
  • Targeted therapy with large effect size and increased focus on rare diseases, which improves benefit/risk ratio
  • Fall in “me‐too” submissions for chronic symptomatic diseases where benefit/risk ratio is often less favorable 

The new drug research and development paradigm is shifting rapidly from traditional big pharma to venture capital backed small companies.  Jenkins noted that the “good news is that many small companies are successfully bringing innovative new products to market.” 

He also discussed approvals categorized as those from “emerging” or “non‐emerging” sponsors.  An emerging sponsor is defined as the sponsor listed on the FDA

approval letter who, at the time of approval, was not a holder of an approved application in the Orange Book or RMS/BLA.  Sponsors are still classified as “emerging” even if they have partnership or parent relationships with sponsors currently with an approved product. 

Review “Program” for NME NDAs and Original BLAs 

Jenkins then discussed the review program for NME NDAs and Original BLAs.  He noted that the goal of the program is to  “Improve the efficiency and effectiveness of the first cycle review process and decrease the number of review cycles necessary for approval,ensuring that patients have timely access to safe, effective, and high quality new drugs and biologics.” (PDUFA V Goals Letter). 

The concept of the program is that better planning before application submission, submission of complete applications, improved communication and transparency between applicant and review team during review, and additional review time will improve the efficiency of the first review cycle, which may decrease the number of additional review cycles prior to approval.  Components of the program include: 

  • Pre‐submission meeting strongly encouraged
  • Complete application at time of submission; incomplete subject to RTF
  • 60‐day filing review period “off the clock”
  • 74 Day Letter: Planned review timeline, planned date of internal mid‐cycle meeting, preliminary plans on need for Advisory Committee (AC) meeting, early communication of deficiencies/information requests
  • Mid Cycle Communication
    • Within 2 weeks of internal mid‐cycle meeting
    • Communication of significant issues identified to date/information requests, preliminary thinking on risk management/REMS, proposed dates for late‐cycle meeting, updates on AC plans
    • Discipline review letters
      • Summarize preliminary findings/deficiencies by discipline
      • Late cycle meeting (LCM)
        • Focus on information sharing, planning for AC, and planning for the remainder of review 

Promoting Innovation Through Enhanced Communication Between FDA and Sponsors During Drug Development 

Here, the goal is to promote “timely interactive communication with sponsors during drug development…to help achieve the Agency’s mission to facilitate the conduct of efficient and effective drug development programs….” (PDUFA V Goals Letter).  Components of enhanced communication include: 

  • Dedicated liaison staff in OND to facilitate communication and to develop and deliver training on best practices to FDA staff and sponsors
  • Liaison staff serve as point of contact for general questions (e.g., which division to submit IND to) and secondary point of contact for sponsors encountering communications delays (e.g., >30 days) with review division
  • Provide training on best communication practices to CDER staff involved in IND review by end of FY14
  • Publish draft guidance on best communication practices by end of second quarter of FY15 

An acting team leader will implement this program and additional positions will be added on an ongoing basis.  Information will be posted to FDA’s website along with contact information.  To date, there have been nine (9) requests from external sources on a variety of topics including, Division assignment for IND, BLA review timeline, breakthrough therapy, IND exemption process, status of overdue CMC supplement, etc. 

Breakthrough Therapies FDASIA Section 902 

Jenkins then went into a discussion about the Food and Drug Administration Safety and Innovation Act (FDASIA) and Section 902, which created a “breakthrough therapy” designation designed to expedite the development and review of a drug when it is intended “to treat a serious or life‐threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” 

A drug sponsor may request designation as a breakthrough therapy concurrently with, or any time after submission of an IND.  Within 60 calendar days of receiving such a request, FDA must make a determination as to whether the drug qualifies as a breakthrough therapy.  This new pathway complements existing pathways: Fast Track, Priority Review and Accelerated Approval.  Actions to expedite development and review of a breakthrough therapy application may include: 

  • holding meetings with the sponsor and the review team throughout the development of the drug;
  • providing timely advice to, and interactive communication with the sponsor regarding the development of the drug to ensure that the development program to gather the non‐clinical and clinical data necessary for approval is as efficient as practicable;
  • involving senior managers and experienced review staff, as appropriate, in a collaborative, cross‐disciplinary review;
  • assigning a cross‐disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor and
  • taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment.

Currently, FDA is developing a draft guidance on expedited drug development and review pathways, which will articulate current thinking on Fast Track, Breakthrough (BT), Priority Review, and Accelerated Approval – Information to guide BT submissions and OND contact information will be posted on FDA’s website.  

BT requests are reviewed by CDER’s Medical Policy Council to ensure consistency in application of standards across divisions.  CDER has received 7 BT designation requests to date; two have been granted, one was denied, and 4 are pending within their goal dates. 

CDER Priorities 

The second presentation, given by Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs at CDER, focused on CDER priorities.  He began by noting that two decades ago, the US lacked effective treatments for most life-threatening illnesses, but today, many more treatments are available.  However, patterns of manufacturing, use and access to information have shifted dramatically.  Patients and clinicians want new products sooner that are safer and more effective; products that deliver on the promise of basic science discoveries and increased involvement in process.  They also want accurate and understandable information sooner, especially in post-marketing.       

CDER consists of 3,335 people, 2,608 scientists and professionals:449 MDs; 401 Pharmacologist/Toxicologists; 346 Chemists; and 163 Statisticians.  Its Director is Dr. Janet Woodcock.  Then, Throckmorton went through CDER’s priorities.  First, is FDASIA implementation, including the new Generics and Biologics User Fee Programs (GDUFA and BSUFA).  He noted that implementation will be a large task, with over 150 specific requires: 19 regulations; 24 Guidances; and 14 reports to Congress.  

Throckmorton discussed the focus on patient participation in the drug development process.  FDASIA requires FDA to 

  • Foster participation of FDA Patient Representatives as Special Government Employees in appropriate agency meetings with medical product sponsors and investigators; and,
  • Explore means to provide for identification of potential FDA Patient Representatives who do not have any, or have minimal, financial interest in the medical products industry.               

The Patient-Focused Drug Development under PDUFA V involves a more systematic and expansive approach to obtaining the patient perspective on disease severity or the unmet medical need in a therapeutic area to benefit the drug review process.  This includes 20 meetings over 5 years.  FDA already held a meeting in October 2012 to solicit input on a preliminary list of disease areas and criteria used to select them.               

Throckmorton next discussed FDA’s Sentinel Initiative.  Launched in 2008 in response to FDA Amendments Act (FDAAA) mandate to establish post-market risk identification and analysis tool (the Sentinel System), it currently contains electronic health record (HER) data on over 137 million patient, 3 billion prescriptions.  In 2011, FDA developed a Mini-Sentinel tool developed to rapidly access and query quality-checked data.  FDA queries results available in weeks not months/years.  To date, 290 queries conducted, and the results have facilitated regulatory decision-making.  The program partners with other federal agencies including Medicare and Veteran’s Affairs.             

Drug Shortages 

The next part of his presentation focused on FDA’s response to critical public health issues, such as drug shortages.  Throckmorton noted that FDA has taken a number of steps, including maintaining a database of drugs in shortage and tracking emerging shortages closely.  FDA closely cooperates with other groups tracking shortages and is aided by early notification.  FDA is also: 

  • Encouraging remaining firms to ramp up if others manufacturing.
  • Expediting issues related to addressing shortages (e.g. new manufacturers, increased expiry, increased capacity, new raw material source, changes in specifications).
  • Allowing temporary importation from unapproved sources (e.g., propofol imported in 2010) 

He noted how FDASIA broadened requirements for manufacturers to notify FDA about potential shortages.  FDAISA allows FDA to broaden the scope of reporting to include biological products through regulation.  In addition, there is a requirement for FDA to issue non-compliance letters to manufacturers who fail to comply with the drug shortage notification requirements and to make the letter and the company’s response to the letter available to the public.  Additional FDA activities include: 

  • Increased staff to work on shortages: typical shortage has 25 staff involved
  • Plans to have shortage staff part of Office of Center Director
  • Formed Taskforce to coordinate work on Strategic Plan and other efforts
  • Improved FDA Shortage website
  • Improved FDA Shortage database 


Throckmorton also noted that FDA action is needed to assure that patients continue to have access to opioids, while reducing the epidemic of abuse and misuse. 15,000 overdose deaths in US.  He noted that FDAAA gave the agency new authority to require  additional safety measures by manufacturers (‘REMS’).  He noted the REMS approved in July, 2012 for Extended- Release/Long-Acting opioid drugs, the focus of which is on education for prescribers and patients.  The aim of the REMS is to minimize the burden on the healthcare system and preserve access to opioids.  He also noted that HHS has a report on reducing opioid abuse and there is Mandated Guidance on the development of Abuse-Deterrent formulations due January 2013.

Other CDER Activities 

  • Efforts to improve regulatory science and drug development
  • Efforts to improve the science of safety assessment
  • Data management and informatics of drug assessment
  • Ongoing work to improve manufacturing quality and supply chain
  • Efforts to improve processes related to:
    • Benefit-Risk Assessment
    • Review of Risk Evaluation and Mitigation Strategies (REMS)
    • 21st-Century Review Process         

Review of REMS 

Finally, a third presentation from FDA’s Office of Surveillance and Epidemiology (OSE) gave an overview of recent and future activities regarding REMS.  The presentation was given by Gerald J. Dal Pan, MD, MHS, Director of OSE, CDER, and focused on FDA approved REMS between March 25, 2008 – Sept. 30, 2012.  First, he gave the current number of individual drugs with an approved REMS (individual drugs are defined by different dosage forms or combination products) 

  • 14 Medication Guide only
  • 27 communication plan
  • 27 ETASU
  • Total of 68 individual drugs with REMS*    

There are 4 single shared system (SSS) ETASU REMS.  SSS REMS generally include at least one NDA product and its generic(s), but class-wide SSS REMS include multiple innovators and generics.     

Historically, there have been about 200 REMS approved.  This number is approximate because in the past, REMS were not counted consistently (for example, some REMS contained multiple individual drugs but were counted as one; drugs in a SSS REMS may have been counted individually).  There have been130 released REMS. 

He then went over the REMS Integration Initiative.  In 2011, FDA began an initiative designed to evaluate how the agency has been implementing its REMS authority and to determine how to design REMS that can be better integrated into the existing and evolving healthcare system.  FDA gathered preliminary input from stakeholders, including public meetings held in 2010 to obtain input on issues and challenges associated with the development and implementation of REMS.  They also held a meeting in 2012 to assess how REMS Assessment surveys are working.  The goals of the REMS Integration Initiative are to:  

  • Require a REMS when necessary to ensure that the benefits of a drug outweigh its risks.
  • Approve REMS that can be efficiently implemented.
  • “Measure the effectiveness of REMS and standardize and better integrate REMS into the healthcare system” (PDUFA V, Goal XI (A)) 

Objectives of this initiative include FDA developing: 

  • Criteria for determining when a REMS is required.
  • Strategies for designing REMS, including standardization, so they can be efficiently integrated into the existing and evolving healthcare system.
  • An evidence-based approach to measuring the effectiveness of REMS.     

FDA will also provide opportunities for stakeholders to contribute to the development of standardization and integration initiatives. 

The REMS Integration Steering Committee (RISC) was established to oversee the REMS Integration Initiative.  The RISC will oversee activities of 3 work groups and stakeholder engagement activities.  The RISC consists of the:           

  • REMS Policy Workgroup: Develop principles for how to apply the statutory criteria to determine whether a REMS is necessary
  • REMS Design and Standardization Workgroup: Develop an analytically rigorous approach to design of a REMS
  • REMS Evaluation Workgroup: Develop a consistent and evidence-based approach for assessing the effectiveness of REMS programs and the burden on healthcare delivery systems 

By the end of FY 2013, FDA will:  

  • develop and issue guidance on criteria for requiring a REMS
  • hold one or more public meetings to obtain stakeholder input on standardizing REMS to reduce the burden on the healthcare system
  • initiate one or more public workshops on methodologies for assessing REMS 

Under PDUFA V (FDASIA), FDA will 

  • Use public workshops to gather information and issue draft guidance on methodologies for assessing
    • Whether the REMS is meeting its goals.
    • The impact of REMS on patient access and burden on the healthcare delivery system.
    • With stakeholder input, evaluate appropriate ways to better integrate REMS into the existing and evolving healthcare system

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