DRAFT

FDA Questions for Panel Consideration

 

1.      Effectiveness
Under 21 CFR 860.7(e)(1), effectiveness is defined as reasonable assurance, based upon valid scientific evidence, that, in a significant portion of the population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results. 

The PMA for the Synergo system presents clinical data from a single pivotal trial (Study 101.1) and several additional supporting clinical data sources, the review of which present the following challenges in assessing the effectiveness of this combination product:

a.      Significant limitations exist in the design and conduct of Study 101.1, which when considered collectively, potentially impair the ability to interpret the results and increase the uncertainty of the stated conclusions, including:

i.        multiple sources of bias;

ii.      the absence of structured methods for obtaining pathology samples and recording pathology information;

iii.    potential variation in mitomycin C exposure between the study groups; and

iv.    reliance on a small, limited study population to perform the risk/benefit analysis and generalize the study results to the general U.S. population.

b.      The supporting clinical data sources were not designed to provide stand-alone evidence of the safety and effectiveness of the Synergo system for the proposed indication.

 

Considering the design and conduct of Study 101.1 and the supporting clinical data sources, please discuss whether the clinical data in the PMA provide reasonable assurance that the Synergo system is effective.  If not, what additional data or analyses are needed?

 

2.      Safety
Under 21 CFR 860.7(d)(1), safety is defined as reasonable assurance, based upon valid scientific evidence, that the probable benefits to health under conditions of the intended use, when accompanied by adequate directions for use and warnings against unsafe use, outweigh any probable risks. 

As observed in pivotal Study 101.1 and the supporting clinical data sources, treatment with the Synergo system results in an increased rate of adverse rates over mitomycin C alone, particularly posterior bladder wall tissue reaction, pain, and bladder spasms.  These events were generally mild, localized, and transient.  However, limitations in the design and conduct of the pivotal study potentially impair the ability to interpret the safety analysis, including:

a.      the possibility of incomplete safety data from the retrospective completion of case report forms and absence of concomitant medication information; and

b.      reliance on a small, limited study population to perform the risk/benefit analysis and generalize the study results to the general U.S. population.

 

Considering the design and conduct of Study 101.1 and the supporting clinical data sources, please discuss whether the clinical data in the PMA provide reasonable assurance that the product is safe.  If not, what additional data or analyses are needed?

 

3.      Postapproval Study

The firm proposes to conduct a single-arm postapproval study, in which 211 subjects are followed for 12 months.  The objectives of this study are (i) to assess whether the incidences of anticipated adverse events are equivalent (non-inferior) to those observed during the pivotal clinical trial (Study 101.1), and (ii) to document the rates of any unanticipated adverse events.  If the Synergo system is recommended for approval (with or without conditions), please discuss whether the proposed design of this postapproval study is adequate to address all relevant remaining safety and effectiveness issues.  If not, what additional information should be collected?

 

4.      Labeling and Training
The firm provides physician and patient labeling for the Synergo system (i.e., the “Physician’s Instructions Guide” and “Patient Information Guide,” respectively), as well as the approved package insert for mitomycin C.  A physician training program is not proposed.  If the Synergo system is recommended for approval (with or without conditions), please discuss whether the information provided is adequate to assure the safe and effective use of this combination product.   If not, what additional information should be included in these labeling documents?