Validated analytical/bioanalytical methods will be required to determine the amount of drug administered to the animals, the amount of circulating drug in the serum/plasma, and the presence of antibodies against the drug (applies only to biopharmaceuticals) in the serum. Depending on your project, you may also need analytical methods for other matrices such as urine, feces, or tissues. Issues can arise during the development of these assays, particularly those dealing with biological matrices due to the complexity in extracting the drug from those matrices. Investment in the development of these assays early in the process can prove beneficial in the long run; for example, these assays may demonstrate that for the bioanalytical samples, special stabilizers need to be added or the samples may need to be processed within a specific timeframe.
Often Sponsors will indicate they have an existing method, so all that is needed is a transfer of the method. However; to meet regulatory requirements, all of the data from the initial lab (electronic and paper) will need to be provided to the second lab, and the second lab must verify that it is following the initial lab’s method exactly. Naturally this makes it very difficult to accomplish a method transfer due to differences in instrumentation, standard procedures, and personal techniques, and additional work is often needed to ensure the method is suitable for use on a GLP study. Most CROs include time to determine feasibility/method development in their proposals which is designed to test the method to see if it works with their instrumentation. This is something well worth the cost and advanced planning as it can avoid many delays in the start of the pivotal safety studies.
Establishment of stability of the formulated material early in the process can aid in planning for the preparation in the longer term studies. Without this information, formulations will need to be prepared daily, which can add a significant amount of cost to your study.
Biohazard Safety Level
The National Institutes of Health (NIH) has published “Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules” to detail the safety practices and containment procedures for research involving recombinant or synthetic nucleic acid molecules, cells, organisms, and viruses containing such molecules. This guideline describes the risk assessment of the agent to be tested and the resultant risk group assignments based on the potential to cause disease in a healthy human population and the available preventative or therapeutic intervention. Based on this risk assessment, an appropriate level of biological and physical containment conditions for the study/experiment is established. Specialized containment equipment, procedures, practices, and laboratory design may be required depending on the Biosafety Level assigned to reduce the potential for exposure of the laboratory staff, public, and the environment. The CRO must appoint an Institutional Biosafety Committee, who must review the information on the agent to be tested, assess the physical/biological containment level, and establish the risk group/containment level for the study conduct. This process requires adequate information on the test article, the known and potential properties of the agent, and a thorough consideration of how the agent is to be manipulated. In addition, costs associated with increased levels of containment, specialized equipment, increased use of personal protective equipment, and additional procedures must be considered. If you are working in this area, your CRO needs to have the capability to conduct these studies accordingly.
Prior to Study Initiation, all protocols that involve a Schedule I (CI) Controlled Substance (CS) as Test or Control Article must have prior approval by the Drug & Chemical Evaluation Section of the Office of Diversion Control at the United States Drug Enforcement Administration (DEA) and the Controlled Substances Staff (CSS) at the FDA to determine the qualifications and competency of each Study Director conducting the study and to review the scientific merits of the protocol. For Schedule I and II CS requests, the CRO must complete DEA Form 222 as set forth in Subpart C of 21CFR 1305.03 and 1311, and several other items must accompany the form regarding the planned nonclinical work. The completion of the forms, estimation of test article requirements, drafting of the protocol(s), Institutional Animal Care and Use Committee (IACUC) review, submission of Form 222 to the DEA and the review process by the DEA and FDA can take several months to complete before the API can even be received by the CRO. Ensuring that these activities are completed well in advance of study scheduling can eliminate costly delays in your nonclinical program.