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by: If your company is planning a submission of a BLA or NDA in the foreseeable future, you should be paying close attention to the changing regulatory environment related to FDA inspections of clinical trials. You will need to be prepared for a comprehensive FDA inspection process which may further delay the approval of your drug. And, if you are outsourcing your clinical studies, you will need to demonstrate how you provided adequate oversight of the CRO for assuring compliance with Good Clinical Practices (GCPs) and FDA regulations. The following paragraphs provide background for FDA’s new inspectional approach. FDA verifies the reliability of clinical data submitted as part of a BLA or NDA through its Bioresearch Monitoring Inspection Program (BIMO). Once a BLA or NDA is considered filed for review by the FDA review team, the responsible BIMO inspectional unit begins planning inspections of clinical study sites. For BLAs and NDAs submitted to Center of Drug Evaluation and Research (CDER), the Division of Scientific Investigations (DSI) schedules inspections of clinical study sites participating in pivotal trials used to substantiate the safety and efficacy of the drug. DSI would select four or five clinical study sites for inspection. If the outcome of the inspections did not uncover serious GCP violations, FDA considered the clinical data from all the clinical sites to be reliable even if more than 250 clinical sites participated in the study. If the outcome of the FDA inspections noted GCP violations at some, but not all of the clinical sites inspected, FDA would exclude the data from the clinical sites where GCP violations occurred and assume that the data was reliable from the remainder of the clinical sites participating in the study. This FDA inspectional approach for verifying the reliability of clinical trial data received criticism during the past five or six years from the US Congress and other interested parties who questioned the adequacy of FDA’s oversight of clinical research. The very public criticism of the FDA for the approval of an antibiotic in 2004 subsequently associated with several patient deaths resulted in a change in FDA policy and the recent comprehensive inspectional approach for clinical trials. New Inspectional Approach According to the March, 2010 presentation by Leslie Ball, Director, DSI, FDA has recently moved to a more robust inspection process. DSI will select four or more clinical study sites but will also schedule inspections at the Study Sponsor and/or CRO¹ responsible for monitoring the clinical study. If GCP violations are noted during the clinical study site inspections or if there is evidence of inadequate monitoring of the study, FDA will schedule more clinical site inspections to determine the extent of GCP violations across all study sites. If the additional inspections uncover further noncompliance, FDA will request the Sponsor to conduct QA audits of a large sample (e.g. > 25%) of the clinical study sites participating in the clinical study. The outcome of these audits will help determine the reliability of the clinical data and whether FDA will accept the data for BLA or NDA approval. How to Prepare With the changes in the FDA inspectional approach, it is in your best interest to start the preparation process early in the clinical trial program. If you plan to outsource the conduct of your clinical studies, you will need to play a more active role in the oversight of the CRO. You will also be expected to perform QA audits of a greater percentage of the clinical study sites participating in the clinical study and/or of the CRO. These QA audits, when performed early in the clinical study, could help identify and correct GCP violations before they negatively impact on reliability of your clinical study data or to the subsequent approval of your BLA or NDA. If you are interested in learning more about how BCG may assist you in this changing regulatory environment, please Contact Michael A. Trapani.
¹ CDER increased the number of Sponsor/ Monitoring Inspections from 25 in 2007 to 73 in 2009. |
