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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Meeting to Discuss Pharmacovigalnce Planning, June 24, 2009 - Laviv

     
  • The product’s safety database was reviewed.   
  • The product shows efficacy with an acceptable safety profile overall.   
  • The follow up periods for the clinical trials (6 months to 1 year) were not       long enough to reveal long term adverse events.  
  • Certain demographic categories were under represented in the clinical trials.  (Non-Caucasians with darker pigmented skin, patients 65 years of age and older and males). 
     
  • The consensus was not to propose that the sponsor conduct a follow-up clinical study on these groups, since it may be difficult to recruit sufficient patients in these demographic groups for a meaningful study.  
  • CDRH require sponsors of dermal filler products to conduct open label post-marketing  studies to look for adverse event profiles in the above groups.  The results, to-date, show low rates of  hypo or hyperpigmentation and keloids in darker skinned individuals.  (Charles Durfor will forward the final reportson these studies for review).
     
  • The  clinical review team suggested that the labeling should emphasize the unknown safety profile in these groups.  
  • CDRH  have required a long-term open label study with one of their products to  collect data on adverse events, longevity of response, and whether the  injected material migrates from the initial injection site.  
  • Bob       Wise raised the concern of possible allergic reactions to the product, as       there were two possible cases in prior UK experience, but no specific       details are available.   
  • Concern       was raised about whether repeated use of the product could lead to adverse       events.  Whereas the clinical trials       involved multiple injections of the product, over a six week period, none       of the trials studied repeat courses of treatment (a second course of 3       sequential injections).  It was       suggested that we ask the sponsor, if, in their prior market experience,       patients returned for additional courses of treatment.  
  • Rachael       Strong provided input on the FDAAA requirements for what is needed to       allow FDA to impose a PMR or REMS, such as having a specific safety       concern that needs to be addressed.        She also noted that it would be a good idea to send our plans to       the CBER Safety Working Group for review before we express concerns or       propose any plans to the sponsor.        It was noted that a PMR or REMS proposal could also be discussed by       the Advisory Committee
  • The       sponsor’s proposed post-marketing study includes a small number of       subjects (100); sufficient detail on the methodology or purpose of the       study was not provided to assess its’ usefulness.   The follow up period (12 months) is too       short to evaluate potential long-term safety events such as overgrowth or       malignant potential.   A larger       post-licensure safety study, with explicit enrollment and follow-up       criteria, may be required to further assess the identified safety concerns       such as pigmentation changes, allergic reactions, or other potential acute       or sub-acute events not identified in the clinical trials.

Possible PMC/PMRs and REMs

  • Require       the sponsor to conduct either an open label study or a registry to       evaluate safety after-licensure in a larger population, including       non-caucasian dark pigmented individuals.        There should be a component of active follow up (e.g., direct       contact with patients or their physician shortly after treatment and/or on       a periodic basis).   
  • Consent       to follow up could be gained as part of the consent for treatment.  
  • Incorporate       questions related to allergic reactions and number of repeat uses of the       product into any post-market studies conducted.  
  • Require       a REMS including restricted distribution of the product only to physicians       who have completed training on administration of the product.  The safety concerns to justify this are       the risks related to occlusion and/or embolization if the product is       injected into a vessel and the unknown risks of malignancy related to       cells procured in the biopsy.

Action items:

  1. OBE       will write a draft summary of safety concerns and potential options for       post-market safety studies to be circulated to the other meeting       participants for comment.   
  2. Charles       Durfor will send:
  • an example of a letter CDRH has used to notify a  sponsor of a specific safety concern  
  • an example of a 100 day letter  
  • final reports of the post-marketing studies  conducted by sponsors marketing dermal filler products.

3.  Convene a second meeting on pharmacovigilance  planning prior to the mid-cycle review meeting to further delineate proposed  requirements and discuss possible need for a REMS.

Participants:
  Craig Zinderman                       Shiowjen  Lee
  Robert Wise
  Rachael Strong
  John Thomas
  Donald Fink
  Lori Tull
  Agnes Lim
  Yao-Yao Zhu
  Bruce Schneider
  Wilson Bryan
  Keith Wonnacott
  Kim Benton
  Raj Puri
  Stephanie Simek
  Celia Witten
Janette Alexander