Draft Panel Questions

1.                  Preclinical animal evaluations (included in this PMA or in the panel package?  Otherwise we should not refer to data that they do not have) have shown that the rate and amount of DMSO can cause vasospasm and vascular wall damage.  Additional preclinical animal evaluations included in the PMA package demonstrated that long term chronic inflammatory responses will occur in response to the presence of the embolization agent.  Patients undergoing staged embolization procedures for Cerebral Arteriovenous Malformations will be exposed repeatedly to the potential for to DMSO -mediated vessel damagesince they will undergo staged procedures over a period of time prior to resection.  If the patient’s AVM is not resected, vessel wall damage due either to repeated-direct DMSO cytotoxicity or to an inflammatory response to the embolic agent could result in angionecrosis with resulting patient morbidity.  Repeat instillation of the product, as would occur in staged embolization procedures, has not been evaluated in animal preclinical models.  Do you believe that the preclinical data in the PMA adequately support the safety of repeated exposure to DMSO as required in the proposed use of the product?  If not, please provide suggestions on the additional preclinical studies that you believe are needed to demonstrate the safety of the repeated exposure to DMSO.-Do you believe additional animal evaluation should be conducted to more completely assess for repeat-DMSO vessel wall exposure and potential adverse effects?  Do you have any recommendations regarding the amount of DMSO a patient should be exposed to over a 24 hour period or the length of time between embolization procedures?

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1.      21 CFR 860.7(d)(1) states that there is a reasonable assurance that a device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks. The clinical study determined that there were slightly more total complications with the subject device than with the control device. Of particular concern were the device-related complications of difficulty in removing the catheter (10 – Onyx, 0 – nBCA), catheter shaft rupture (2 – Onyx, 0 – nBCA) and poor penetration/visualization (5 – Onyx, 0 – nBCA).  In addition, there were more deaths and strokes (both 2 – Onyx, 0 – nBCA) in the treatment group than in the control group.  Please discuss whether the safety data for Onyx Liquid Embolic System provides a reasonable assurance that it is safe for this use with respect to the approved control device.?

Effectiveness Question

 

1.      The device is intended for presurgical embolization and therefore, the material is meant to be removed during surgical resection of the AVM.  Although patients were enrolled in this study based upon the criterion that they were surgical candidates, in some cases, the clinical course of treatment changed so that it was not in few patient’s best interest to such that some subjects did not undergo surgical excision, post-embolization.  With regard to the potential for this product to be used in pediatric patients, and in recognition that there is very limited long-term implantation safety information for the product,  Considering that it is probable that this scenario will also arise under clinical use, if you recommend approval, do you believe a long-term follow-up study for patients not undergoing surgical resection of their AVM should be conducted as a post-approval commitment?

 

2.      21 CFR 860.7(d)(1) states that there is a reasonable assurance that a device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks. Please discuss whether the data in the PMA for Onyx Liquid Embolic System provide a reasonable assurance of safety.

 

3.      21 CFR 860.7(e)(1) states that there is a reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warning against unsafe use, will provide clinically significant results. Please discuss whether the data in the PMA for the Onyx Liquid Embolic System provide a reasonable assurance of effectiveness.

 

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4.      A number of complications were observed related to the placement of the devicein the study that appear to relate to user training.  Of particular concern were the device-related complications of difficulty in removing the catheter (10 – Onyx, 0 – nBCA), catheter shaft rupture (2 – Onyx, 0 – nBCA) and poor penetration/visualization (5 – Onyx, 0 – nBCA).  Please comment on the sponsor’s proposed training plan and whether you believe it is adequate to help ensure proper device placement. (Note:  we should send the training plan in the second mailing, if we have not yet sent it)use.

 

5.      The device is intended for presurgical embolization and therefore, the material is meant to be removed during surgical resection of the AVM.  Although patients were enrolled in this study based upon the criterion that they were surgical candidates, in some cases, the clinical course of treatment changed such that some subjects did not undergo surgical excision, post-embolization.   Considering that it is probable that this scenario will also arise under clinical use, if you recommend approval, do you believe a long-term follow-up study for patients not undergoing surgical resection of their AVM should be conducted as a post-approval commitment?