In the Spotlight
US FDA – New Paradigms in Drug Safety Testing
The US Food & Drug Administation’s (FDA) is working to modernize and improve drug safety and efficacy assessment methods by developing and implementing new scientific approaches. Three ongoing FDA programs are described below, and in one case, an additional modification is suggested.
Cardiotoxicity Testing and the CiPA Initiative
Current methods required to assess the potential for new drugs to cause abnormal heart rhythms, or arrhythmias, are time consuming, expensive, and have the potential to flag drug candidates that could actually pose no human risk (FDA, 2017).
FDA’s September 24 webcast, Developing a Mechanistic Model-Based Approach to Assess Cardiac Safety of New Drugs, by Dr. David Strauss, will unveil “a new paradigm for evaluating the cardiac safety of new drugs — the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative.”
CiPA consists of “a suite of mechanistically based in vitro assays coupled to in silico reconstructions of cellular cardiac electrophysiologic activity, with verification of completeness through comparison of predicted and observed responses in human-derived cardiac myocytes.” The CiPA Initiative is an ongoing, international collaboration to validate CiPA for the purpose of updating current regulatory requirements for the proarrhythmia assessment of human drugs.
In March 2017, an FDA advisory committee endorsed the CiPA approach, pending ongoing validation studies. The September webcast will explain the status of the ongoing validation studies, as well as the science behind CiPA and the anticipated impact of regulatory adoption of this approach to proarrhythmia assessment. While CiPA is anticipated as a replacement of the previous proarrythmia guidance, it will not be a replacement for all of the cardiotoxicity testing needed for a new drug.
Microphysiological Systems as Drug Development Tools
The FDA engaged with National Institutes of Health (NIH) and Defense Advanced Research Projects Agency (DARPA) as early as 2011 in the development of cell-based microfluidic devices for regulatory drug safety testing purposes. In 2012, DARPA entered into cooperative agreements with MIT and the Wyss Institute at Harvard “to develop engineering platforms capable of integrating 10 or more organ systems.” Since that time, through their Tissue Chip for Drug Screening Initiative, NIH has funded dozens of awards to various institutions for the development of 3-D human tissue chip/microphysiological systems. FDA’s role, anticipated from the creation of these initiatives, was to evaluate the use of these “chips” in drug safety assessments.
Making the leap to earlier this year, the FDA announced an agreement with Emulate, the company developed to commercialize Wyss Institute’s microfluidic systems, to evaluate their human “organs-on–chips” technology. The first to be evaluated in FDA laboratories is the liver-chip, with the goal of determining how well the liver-chip can predict human liver toxicity for substances under the regulatory jurisdiction of the FDA such as drugs, cosmetics, and dietary supplements.
The primary expectation for “organs-on–chips” are their potential to expedite the preclinical drug development process by reducing time and costs, while possibly even reducing attrition of potentially good drug candidates through the use of more physiologically and human relevant test systems. For more on how recent advances in microphysiological systems are expected to enable a paradigm shift in drug development, see the recent article by Marx, et al. (2016).
FDA’s Drug Development Tools Qualification Programs
To improve the drug development process, FDA created the Critical Path Initiative which includes “the development of a variety of tools, methodologies, and approaches to enhance medical product development.” To facilitate use of these new tools, FDA assesses them for performance, reliability, and applicability to FDA regulatory needs, a process known as “qualification.”
FDA’s Center for Drug Development (CDER) defines drug development tools (DDTs) as follows:
DDTs are methods, materials, or measures that have the potential to facilitate drug development. Examples of DDTs may include, but are not limited to: a biomarker used for clinical trial enrichment, a clinical outcome assessment (COA) used to evaluate treatment benefit, or a disease specific animal model used for efficacy testing under the Animal Rule.
The FDA provides a guidance document, as well as information on several FDA webpages, for their Drug Development Tool (DDT) Qualification Program. Their latest DDT Program news is a change in the process for qualification of drug development tools under the new FD&C Act, Section 507(c). The DDT concept is also used in other FDA divisions as illustrated by the August 10, 2017 release of the final version of guidance for medical device development tools (MDTT), Qualification of Medical Device Development Tools.
CDER’s DDT Qualification Program is currently directed at only 3 categories of DDTs, biomarkers, clinical outcomes assessment, and animal models, and does not include specific consideration for in vitro tests. Thus, the program falls short of fully addressing the need for greater innovation in the drug development process. A DDT Qualification Program for in vitro test methods could facilitate their development and use in accelerating the drug development process. This process complements the ICCVAM validation process, since the FDA may still not adopt/use an ICCVAM-validated method when it does not meet the needs of the FDA. An example of this was their determination of the insufficiency of the mouse local lymph node assay for skin sensitization testing for some types of FDA-regulated products.
A DDT guidance for in vitro tests is not on the latest schedule of New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2017, but such a program could be considered as another approach to accelerate the development of new drugs. The successful development and implementation in vitro systems, such as the liver-chip and CiPA, might facilitate development of guidance for this forth arm of the DDT Qualification Program.