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Vaccines, Blood & Biologics
Submission Type: BLA Submission ID: 125421/0 Office: OBRR
Product: Prothrombin Complex Concentrate (Human)
Applicant: CSL Behring GmbH
Telecon Date/Time: 05-Apr-2013 03:00 PM Initiated by FDA? Yes
Communication Category: 1. Advice
Author: Edward Thompson
Revised: L. Ross Pierce
1. A PMR for this product-indication
2. Addition of a boxed warning for TE events to the draft PI
3. An additional Contraindication in patients with a history of prior TE event, coronary, cerebrovascular, or peripheral vascular disease
4. A PMC plasma-controlled RCT examining the safety and efficacy of a lower dose of Kcentra
Nisha Jain, MD, Chief, OBRR/DH/CRB
L. Ross Pierce, MD, OBRR/DH/CRB
Michael Nguyen, MD, OBE/DE/VSB
Sukhminder Sandhu, MD, OBE/DE/AEB
Wei Hua, MD, OBE/DE/AEB
Thomas Maruna, OBRR/DBA/RPMB
Edward Thompson, OBRR/DBA/RPMB
Robert Goldberg-Alberts M.A., Therapeutic Area Lead Statistician, Acquired Bleeding
Antoinette Mangione MD, PharmD, Global Clinical Therapeutic Head Acquired Bleeding, Sr. Director, Clinical Research and Development
Bruce Hug, MD, PhD, Director, Clinical Research and Development
David Desris, PharmD, Sr. Manager, Regulatory Affairs
Inna Pendrak, MD, Sr. Clinical Safety Director, Global Clinical Safety
Doug Watson, PhD., Director Clinical Epidemiology, Clinical Research & Development
Val G. Romberg, Senior Vice President, Plasma R&D
Three hours prior to the conference, CSL Behring (CSLB) submitted slides for discussion with the FDA by email to summarize the thromboembolic events (TEEs) observed in the RCTs. FDA initiated the conference by noting discrepancies between the data in the slides just submitted by email and the data previously submitted to the BLA on March 19, 2013. CSLB acknowledged the differences in the data and stated that the most recent data they had submitted on March 19 2013 was now “under discussion. FDA pointed out that in the emailed slides, the sponsor was still counting clotted blood in a nasogastric tube in a plasma subject [in bleeding study BE11116_3002], among other errors, and that the sponsor had agreed in the March 19, 2013 BLA amendment that this did not represent an intravascular thrombotic event.
FDA discussed the box warning and disagreed with CSLB’s contention that there was no basis for this. FDA plans to implement a box warning for all Prothrombin Complex Concentrate (PCC) (Human) products. CSLB asked if a boxed warning would be implemented for plasma. FDA indicated that the AABB circular of information for blood products is the equivalent to the package insert. The regulation 21 CFR 201.57 regarding boxed warnings pertains to prescription drug products [and may not necessarily apply to plasma].
FDA discussed the ‘sponsor’s draft package insert discrepancy for the number of TEEs and stated that the revised package insert (PI) to be submitted by Wednesday April 10, 2013 should not pool the data from the two clinical RCTs _3002 and _3003. FDA provided a list of reasons why pooling safety data from the 2 RCTs may not be scientifically justified. The details of the data from the surgery RCT _3003, other than mortality rates, would not be included in the PI, in part because the data were still preliminary when they were submitted prior to the data lock. FDA noted that, although the sponsor had stated that the data from the #_3003 study were “lockable,” the original final safety data submitted for that trial contained errors necessitating resubmission of several data tables some weeks later.
FDA did not agree to limit the definition of adverse reaction to those AEs considered possibly related by the investigator or safety adjudication board (SAB). The sponsor’s argument for not using the FDA definition was based on including all AEs in a table. FDA countered that, including ARs with an incidence of 2.8% or greater (3 subjects or more) produced information useful to clinicians in a table of reasonable size. FDA would be requesting several changes to the Clinical Pharmacology section of the draft PI. There will be other revisions in this section, which will be submitted in the information request today.
For the Post Marketing Requirement (PMR) proposal, FDA clarified that this is version 5 and not version 4. FDA proposed major changes to the protocol in terms of study population. The study will include patients without a history of previous TEE to provide data on the possible TEE risk increase in this population. FDA will send the sponsor the proposed PMR and request a response from CSLB by April 9, 2013. FDA has concerns with the identification of patients on VKA anticoagulants, collection of the TEE and use of historical data in the sponsor’s proposed cohort epidemiologic study..
CLSB discussed the issue of availability of sufficient numbers of patients for the plasma group as the control group and speculated limited use of plasma for this indication after Kcentra is licensed in the U.S.. FDA requested data to support this speculation.
CSLB asked if data collected from clinical studies performed in other countries would be acceptable for review by the FDA. FDA said to submit the proposal for review.
FDA requested clarification on the data submitted on plasma group for the 5001 retrospective chart review study and CLSB had indicated that there was no plan to collect data on this group. [Nevertheless such data were collected by CSLB and submitted to the BLA in response to an information request.]
CSLB discussed the information regarding TEEs and proposed to provide language in the Warnings and Precautions section in lieu of having a contraindication for patients with a history of prior TE event. FDA discussed the CSLB’s Company Core Data Sheet contraindication section and the Canadian Monograph PI. The latter contains a contraindication for patients at risk of TEEs and who have angina pectoris or recent myocardial infarction. FDA noted that it was proposing a less expansive contraindication for patients with a history of TE event or coronary, cerebrovascular, or peripheral vascular disease and this would be included in the FDA revisions to the draft PI which FDA indicated it would send later that evening.
FDA proposed a PMC study with lower dosage which may be as effective as plasma but with potentially greater patient safety. The sponsor said its consultants emphasize clotting factor levels as endpoints. FDA indicated that its thinking was that clinical hemostatic endpoints need to be emphasized over clotting factor levels or INR. This is more along the lines of publications by Dr. Craig Kessler of Georgetown University School of Medicine.
FDA proposed a study to demonstrate the lowest effective dose of the product. If the study showed favorable data, then revisions to the contraindications study would be appropriate. CSLB did not agree to the proposal at this time and required time to consider FDA’s request. FDA indicated that time is short.
FDA stated that the revised PI would be submitted as an information request later today and the proposed PMR would also be sent today (April 5, 2013).