Final Summary FDA Liaison Meeting: November 6, 2019

The following is a summary of the PPTA-FDA Liaison Meeting held on November 6, 2019, in Rockville, Maryland. The RPSC met on November 5th to prep for the Liaison meeting and finalize presentations. 

PPTA’s President and CEO, opened the meeting with introductory remarks. PPTA Vice President, Legal Affairs & Global Operations, advised the participants on the meeting guidelines.

Current Priorities

FDA shared their initiatives with PPTA. The initiatives include continuing to serve the public health mission and transition from their acting commissioner to full commissioner. Additionally, their initiatives include pathogen reduction and MSM issues, vaccines, stand up programs for individual therapies (i.e. gene therapy), safety surveillance and artificial intelligence (AI) with large databases, support source plasma facilities and complete inspections in a timely manner and risk-based decision making.

PPTA’s current priorities were presented to FDA. The priorities included Donor Health Projects, CLIA Waiver for digital refractometer, the European Union (EU) and United States (US) Mutual Recognition Agreement (MRA), Donor Health Questionnaire, the pending release of the Safety Reporting Requirements for Human Drug and Biological Product (Safety Rule), continuing activities in China, and pre-licensing timelines.

Donor Health Update

PPTA provided a presentation on the results from the Donor Adverse Event Recording Standard data collection. Donation data collected from three member companies between May 1 and August 31, 2018, showed an adverse event rate of 15.85 per 10,000 donations. The results are expected to be published in 2020. PPTA also stated that the Donor Health Study is underway. Recruitment started on October 8, 2019, and at the time of the meeting, had over 1,700 donors from 14 centers enrolled.

FDA responded by asking for clarification of different topics regarding the IQPP Standard for Recording Donor Adverse Events. FDA also commended PPTA on the use of the Standard and is looking forward to the publications.

Transgender Donor Risk Assessment

PPTA provided a presentation asking the FDA for greater clarity on screening policies for the transgender and non-binary donor population. The presentation shared risk concerns based on current medical literature that focuses on potential cardiac risks from the high-dose medications used for transition and safety data associated with increased risk-based behaviors. One problem in centers’ attempting to obtain information to assist in assessing donor health risk is that the potential donors are aware of the FDA guidance that recommends self-identification only. The hope is that the FDA will provide guidance on gender identification practices during donor screening and deferral criteria will provide more accuracy in ensuring donor and plasma safety.

FDA responded that their advice is to explain to the donor why gender is important for donor health safety, to take the most conservative approach in determining eligibility for non-binary individuals by asking these donors all questions in the Donor History Questionnaire and using the higher hematocrit level. However, FDA responded further that it was helpful to open the conversation focusing on donor health and commented that the current guidance is an over-simplification. FDA added that it is committed to hearing concerns and open to further discussions, including any data on donor health issues.

Value of Behavioral Risk Deferrals with Pathogen Reduction

PPTA provided a presentation as a follow up to the March 2019 FDA Blood Products Advisory Committee meeting welcoming a broader review of the values of behavioral risk deferrals in the face of pathogen reduction. The presentation suggested the time was right to reconsider deferrals based on tattoos and piercings since they have become social norms in the United States. The presentation also suggested a review of other donor management restrictions given the effectiveness of these established practices, and particularly the robustness of the effective virus inactivation / removal steps during current plasma manufacturing processes.

FDA responded that they are committed to review existing policies and changes, especially related to tattoos and piercings. Although there has been no known transmission of HIV, HBV or HCV in blood products since 1987, there are still concerns about donor selection. While plasma inactivation is good, it is not complete with respect to non-enveloped viruses.

PPTA responded that there is evidence that current pathogen reduction works for non-lipid enveloped viruses, such as HEV. A request for a workshop to discuss this topic was made. FDA stated that they will discuss internally and pick a few possible topics for a workshop.

Hepatitis A Epidemic in the U.S.

PPTA presented on the use of in-process testing of plasma for HAV. The emergence of the HAV epidemic in the U.S. has caused some to reconsider that status of HAV as an in-process test and whether donors should be notified given the tests are not diagnostic. The FDA framed the question as:

What is FDA’s current thinking on the management of in-process test results (for HAV NAT and Parvovirus B 19) of plasma intended for further manufacture, with respect to notifying donors and public health agencies and actions on in-date co-components collected for transfusion?

The FDA response was they encourage companies to tell donors of their reactive HAV results from the in-process test. They also recommend complying with state reporting requirements. FDA stated that they are not anticipating any published guidance on this issue. PPTA quizzed as to some procedural aspects, such as informed consent when using a test not labeled for donor screening, FDA advised that it needs to add this topic to its list for more internal discussion and will get back to PPTA in the future.

(UPDATE) PPTA received the following feedback from the FDA on this topic:

“FDA encourages the firm’s responsible physician to voluntarily notify donors of reactive HAV NAT results and counsel them appropriately. Blood establishments and testing laboratories should also comply with state reporting requirements for communicable diseases.

FDA’s current thinking is stated in the 2009 guidance on Parvovirus B19, as follows: “FDA encourages manufacturers of plasma-derived products to employ practices that will reduce the time between product collection and in-process testing to allow for the meaningful notification of blood and plasma collection establishments of positive test results within the dating period of any blood components intended for use in transfusion. FDA encourages retrieval/removal of all in-date co-components collected for transfusion when the results are obtained in a timely fashion.”. Manufacturers should consider applying these principles to in-process testing for HAV.”

Donation Suitability Requirements Under 21 CFR 630.30

FDA discussed the donor suitability requirements under 21 CFR 630.30. FDA highlighted the section of regulation prohibits the use of plasma from an unsuitable donor. FDA stated they are aware of companies performing their own risk assessments in terms of donation suitability without consulting FDA. Companies are using such donations in further manufacturing despite the regulatory prohibition.

Due to this topic being put on the agenda a few days prior to the meeting, PPTA was not prepared to give an answer. PPTA requested to meet with the FDA for future discussion on the issue. As an industry, PPTA wants to ensure compliance. FDA advised that it is interested in hearing how frequent errors in donor screening result in donations being collected from ineligible donors, the risk assessments preformed and disposition of donations and whether the incidents happen equally across the board or more focused, e.g., new centers or geographic differences.

Request for FDA Support for U.S. Regulatory Frameworks for Source Plasma Collection

PPTA provided a presentation to request that the FDA support its own regulatory framework when meeting with regulators and policy-makers from foreign countries. Specifically, since the FDA participates as an observer or is full member on several regional and global working groups and committees, the support would be helpful in improving plasma donation globally, especially in Europe, which is relies on U.S source plasma. PPTA believes it is timely given the current review of Blood legislation in Europe.

FDA responded that it is up to individual countries to have their own policies and regulations, but the FDA is willing to and feels that it already does share what and how the FDA regulates source plasma collection in the U.S.

PPTA Lessons Learned from Recent IG Availability Concern and Update on Current Patient Access Situation

FDA and PPTA discussed the recent IG access issues experienced by patients and providers in the United States. The FDA was interested in PPTA sharing the causes of the access issues. PPTA is unable to provide the cause but did share data that shows PPTA members are expanding their operations globally and that distribution of IG continues to increase annually. PPTA did mention that as a trade association we are limited on what we can know and share, however the FDA may seek company-specific information from the individual companies.

Real-World Evidence: Considerations for Plasma-Derived IgG Therapies

PPTA presented on Real-World Data (RWD) and Real-World Evidence (RWE), stating that RWD is not new for plasma derived therapies in the post approval space. PPTA asked FDA what is the utility of RWD to generate RWE that can be used in regulatory decision making in the pre-approval space for plasma derived therapies.

FDA responded that CBER has access to the Sentinel System and the BEST system for IgG data. PPTA and member companies can also gain access to the Sentinel System by contacting the Reagan-Udall Foundation. The difference is that the Sentinel System, which has been active for 10 years, obtains data from insurance claims data and the BEST system, which has been active for 2 years, obtains data from electronic health records. In terms of observational studies utilized for fulfilment of PMC’s/PMRs for treating rare drug targets, FDA indicated that it was possible to incorporate RWE/RWD into design elements of these studies. FDA encourages member companies to ask for advice regarding RWD and RWE. Additionally, FDA stated that there are no plasma or biological products in the RCT Duplicate study, which is under CDER’s jurisdiction; however, CBER is watching for applicability to biologics. CBER and CDER meet through numerous committees on RWE/RWD and are continually exchanging best practices.


Participants

PPTA Members

Laura O’Brien, Senior Vice President, Global Quality, CSL Behring
Jon Knowles, Senior Director, Laboratory & Regulatory, CSL Plasma
Toby Simon, Senior Medical Director, Plasma and Plasma Safety, CSL Plasma
Angela Dyer, Senior Director, Regulatory Affairs, Emergent BioSolutions
Mark Becker, Corporate Medical Director, Grifols, Inc.
Joan Robertson, Vice President Regulatory Affairs, Grifols, Inc.
Marilyn Rosa-Bray, Chief Medical Officer/VP Quality, Regulatory Compliance & Labs, Grifols. Inc.
Kelly Smith, Director, Regulatory Affairs, Grifols, Inc.
Janis Wilson, Director, Regulatory Affairs for GPO, Grifols, Inc.
Michael Messick, Vice President, Regulatory Affairs & AO, ImmunoTek
Nelli Cherny, Director of Regulatory Affairs, KEDPlasma
Michele Battle, Senior Manager, Regulatory Affairs, Octapharma Plasma
Karen Clifford, Director, Plasma Operations, ProMetic Plasma Resources Inc.
Ron Kraiss, Director, Regulatory Affairs/Technical Specialist, The Interstate Companies
Roger Brinser, Head of Regulatory Affairs, BioLife Plasma Services L.P., Takeda
Janet Hershman, Head of BioLife Medical Affairs, Takeda
Chuck Borders, Head of BioLife Quality, Takeda
Thomas R. Kreil, Associate Professor of Virology, Global Pathogen Safety, Takeda
Barbara Glantschnig, Head of Quality, Plasma Operating Unit, Takeda

FDA

Celia Witten, MD, PhD, CBER Deputy Director
Nicole Verdun, MD, Director
Anne Eder, MD, PhD, Acting Deputy Director
Martin Ruta, PhD, JD, Regulatory Counsel
Jennifer Scharpf, MPH, Associate Director for Policy and Communications
Janet Goldberg, JD, MPH, Regulatory Counsel
Hira Nakhasi, PhD, Director, Division of Emerging & Transfusion Transmitted Diseases (DETTD)
Orieji Illoh, MD, Director, Division of Blood Components and Devices (DBCD)
Emily Storch, MD, DBCD
Rick McBride, Chief, Blood DBCD, Plasma Branch (BPB)
Gerardo Kaplan, Biologist, PhD, DETTD, Laboratory of Emerging Pathogens (LEP)
Hanh Khuu, MD, Medical Officer, DHT
Anne Rowzee, PhD, Associate Director for Policy
Basil Golding, MD, Director, Division of Plasma Protein Therapeutics (DPPT)
Mahmood Farshid, MD, Deputy Director, DPPT
Dorothy Scott, MD, Chief, Plasma Derivatives Branch (PBD)
Steven Anderson, PhD, Director OBE
Pauline Cottrell, Consumer Safety Officer, CSO, Manufacturers Assistance & Technical Training Branch (MATTB)

PPTA Staff

Amy Efantis, President & CEO
Josh Penrod, Senior Vice President, Source & International Affairs
Mary Gustafson, Vice President, Global Regulatory Policy
John Delacourt, Vice President, Legal Affairs & Global Operations
Dominika Misztela, Senior Director, Regulatory Policy Europe
Bill Speir, Senior Director, State Affairs
Larisa Cervenakova, Medical Director
Michelle Fransen, Project Manager, Health Initiatives
Michelle Mason, Coordinator, Global Regulatory Policy/QSEAL Administrator

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