Animal & Veterinary
Leveraging Examples - Part III: CRADAS
by Marilyn Martinez, Ph.D.
FDA Veterinarian Newsletter January/February 2003 Volume XVIII, No 1
This third article on leveraging initiatives at the FDA Center for Veterinary Medicine (CVM) describes two Cooperative Research and Development Agreements (CRADA's) and illustrates the breadth of issues that can be the subject of a CRADA and the activities that go into the development of a CRADA.
WHAT IS A CRADA?
A CRADA is an agreement between one or more FDA Centers/Laboratories and one or more non-Federal parties. The FDA Center/Laboratory provides personnel, services, facilities, equipment, or other resources toward the conduct of specified research or development efforts. Such research must be consistent with the mission of the Center/Laboratory. The CRADA partner contributes one or more of the above and may contribute funding to the project. More detailed information on CRADAs can be obtained at the following websites: http://www.fda.gov/oc/ofacs/partnership/techtran/policyst.htm and http://www.fda.gov/oc/ofacs/partnership/techtran/crada.doc.
Once a CRADA concept is developed, it must go through extensive internal review and approval both within the Center originating the proposal and through the Agency. To be executed, the proposal must be approved by the participating FDA Center Director, FDA's CRADA Review Board, the Commissioner of the FDA, and the non-Federal party. Principal Investigator(s) (PIs) must be designated, serving as the Federal government representative(s) responsible for the scientific and technical conduct of the project.
EXAMPLES OF EXECUTED CRADAS
The remainder of this article will describe two very different examples of executed CRADAs involving CVM:
- Quality of Animal Drug Submissions
- Enhancing Clinical Drug Trial Simulation and Population PK AnalysisSoftware to Improve the Drug Development Process
QUALITY OF ANIMAL DRUG SUBMISSIONS
Research Objective - To provide CVM with information on those areas where sponsors need additional guidance for developing quality submissions and to help CVM identify areas for improvement with regard to its own communication and interactions with the regulated industry.
CRADA Description - CVM and Riviere Consulting entered into a CRADA to identify and address issues regarding the quality of new animal drug applications submitted to the FDA. For a fee, animal drug sponsors can retain Riviere Consulting to provide a pre-submission review of applications in an effort to evaluate the application's compliance with applicable FDA regulations and guidance documents. Riviere Consulting may attend meetings between CVM and the drug sponsor to assist the drug sponsor in understanding CVM's requests and to provide a critique of CVM/Industry interactions as feedback for CVM. Such a critique focuses on the quality of questions CVM asks of the sponsor and the clarity of the observed communications. Thus, the interactions between Riviere Consulting and drug sponsors are intended to serve two important functions:
- Help firms develop a quality submission, thereby enabling CVM to spend more time focusing on the scientific contents of the submission.
By observing the interactions between FDA and both new and established drug companies, Riviere Consulting can provide important neutral party feedback to CVM on the strengths and weakness of these interactions:
- Insight into where additional guidance is needed.
- Ideas regarding how CVM can best communicate this additional guidance to both large and small companies.
- Examples of when CVM failed to adequately communicate with drug sponsors in written and oral communications.
As part of this agreement, Riviere Consulting provides semiannual reports to CVM that help identify causes for poor quality submissions and suggests mechanisms that may help CVM to better meet the needs of its customers. Points addressed in these semiannual reports include:
- A summary of all CRADA activity occurring during the six month reporting period including a list of sponsors who retained the services of Riviere Consulting, any termination of agreements, and a summary of whether advice was followed. It should be noted that due to the time required to develop the necessary client associations, for sponsors to generate submissions, and for Dr. Riviere to provide submission review, there may be minimal information to convey over one or several reporting periods.
- Comments received by Riviere Consulting from the regulated industry pertaining to this CRADA concept.
Observations regarding CVM's availability and willingness to respond to questions or issues relating to New Animal Drug Applications.
- CVM-CRADA partner interactions
- CVM-drug sponsor interactions
- Input received from the drug sponsors regarding where additional information or guidance is needed with regard to CVM's expectations.
- The clarity of CVM's correspondence (teleconferences, meetings, letters).
- The willingness of drug sponsors to communicate with CVM (and any observed or perceived reasons for communication barriers).
- Insights into fundamental reasons CVM receives poor quality submissions. These comments relate to the nature of the problem with submissions and how they can be corrected.
- Technical sections (or components thereof) that have the greatest number of problems.
- Suggestions for CVM actions that could facilitate the development of higher quality submissions.
Through this effort, CVM hopes to optimize the efficiency of the application review process and improve our interactions with the regulated industry.
For additional information with regard to this CRADA, click here and http://www.riviereconsulting.com/.
ENHANCING CLINICAL DRUG TRIAL SIMULATION AND POPULATION PK ANALYSIS SOFTWARE TO IMPROVE THE DRUG DEVELOPMENT PROCESS
Research Objective - To examine the use of in silico methods for addressing complex scientific issues impacting the regulation of animal drug products and to assist in the optimization of clinical study designs.
CRADA Description - Computer-assisted trial design (CATD) is a form of modeling and simulation technology that can be used by a scientific team to develop "virtual clinical trials." It consists of a series of Monte Carlo simulations to approximate a distribution of possible outcomes for a specified set of model conditions, parameter attributes, and assumptions. By repeating the simulations over a range of conditions, the scientific team can test the impact of study design elements and sources of variability or uncertainty on trial outcome. This allows for the optimization both of dosages used in the clinical trial and the conditions under which the trial is executed. It also facilitates the integration of multiple sources of data, thereby expanding the ability to predict the impact of drug or drug use variables.1 Thus, CATD is a tool for maximizing the information derived from existing sources of data and for examining the potential outcomes associated with a range of doses and dosing regimens.
The original CRADA was only between the Center for Drug Evaluation and Research (CDER) and Pharsight. However, great interest in the potential use of this tool was expressed by the Center for Biologics Evaluation and Research (CBER) and CVM. Since the CRADA had already been reviewed and approved by the FDA CRADA Review Board, the addition of CBER and CVM to the existing CRADA did not require additional review. Thus, with the agreement of all parties, CBER and CVM were added to the CRADA partnership.
Within the scope of this CRADA, Pharsight brings scientific software development experience, a base of state-of-the-art scientific software products, and extensive experience drawn from both industry and academia. CDER, CBER, and CVM bring FDA's scientific regulatory expertise and years of experience in the review of drug applications to provide suggestions with regard to potential software modifications for future versions of this software.2