The Problem is not with the FDA….

Anton Lewis Usala, MD

President and CEO

CTMG, Inc.

Recently, a colleague sent me a link to an article about the Venture Capital lobby pressuring the FDA to speed up their review process.

http://www.xconomy.com/national/2011/04/25/vcs-turn-up-the-heat-on-fda-to-get-faster-more-predictable-to-save-u-s-jobs/

This is one of many such pieces to appear online. As the above article points out, Venture Capital has pulled back from investing in start-up biotechnology/pharmaceutical/medical device companies because of the risk that the FDA will delay evaluating their new test article, require additional expensive studies, or endlessly require re-work of the data.

There is plenty of reason for Venture Capital to be hesitant, as they need to get a return on their investment at least some of the time. Given that the number of new drugs approved by the FDA was only 21 last year (http://www.drugs.com/news/fda-s-approval-down-2010-28669.html), and the much cited cost of bringing a new drug to market exceeds $1 billion (NOTE: This figure is hotly debated), it is rational for the Venture Capital community to seek more predictability into what has become an unpredictable, highly expensive investment.

However, in my experience, the FDA is a consistent, steady regulatory body that has a design-reviewed system for conducting its evaluation process. The apparent inconsistencies do not result from the FDA changing its personnel, focus, or systems, but rather with the steady decline in the evaluability of clinical research data.

I believe the reasons for this decline are many, but one cause stands out from all the other peripheral factors—a total lack of design-reviewed, controlled processes linked to required Quality Systems at the point of Physician Investigator data acquisition when conducting clinical trial visits.

All other aspects of drug development require design-reviewed, GxP processes to be administered under layered Quality Systems. The most frequent cause for an FDA 483 for Sponsors is a lack of well described Corrective and Preventative Action (CAPA) Systems. These CAPAs describe what a Sponsor will do IF a variance or out of specification event is detected by their Quality System review of their GxP processes. These processes are required of the Sponsor during their pre-clinical testing, discovery, and manufacturing. However, once a test article enters testing in human clinical trials, neither the code of Federal Regulations nor ICH Good Clinical Practices require design-reviewed procedures or Quality System review at the point of Physician Investigator protocol execution.



It is really quite stunning that this is the only part of the drug development process that has no such requirements. ICH GCPs list what should be done, but as there are no design-reviewed processes nor quality systems to ensure what is intended in a protocol is actually done, each clinical site conducts the study differently.

On an operational level, the lack of these processes and Quality Systems results in the staggeringly poor enrollment metrics at nearly all Investigative Sites. A well designed system is a missing necessity needed to make all the uncontrolled events converge, resulting in robust patient enrollment. Quality Systems, and most importantly CAPA Systems, are required to assure that what is intended in the protocol is in fact done, and done on time. When operational timelines are not met, effective CAPA systems and Quality Review are required to provide on-site solutions.

The FDA utilizes these systems to evaluate data, and reviewers are able to pick up data inconsistencies as a result. Without these systems, it is no wonder that the FDA requires additional testing and credible evidence that new test articles are both safe and effective.

Imagine if the FDA were to receive data sets from Investigative Sites that had validated, design-reviewed processes, administered under layered Quality Systems with CAPAs.

The cost of doing studies in this manner would be significantly cheaper, as fewer investigative sites and fewer patients would be required. The time to market would in many cases be halved.

And for the Venture Capital Investors, that halving of the time to market means sales revenues in half the time.

The problem does not lie with the FDA. The Regulations need to be strengthened to require design-reviewed processes, administered under layered Quality Systems, at the Investigative Sites.