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It is important to understand regulatory requirements and study challenges to develop and validate the appropriate methods for a bioanalytical study program at the clinical stage.
BioPharm International spoke with Amy Lavelle, associate director, Bioanalytical Lab, PPD Clinical Research, Thermo Fisher Scientific, about the challenges of performing bioanalytical studies and how contract research organizations (CROs) can help mitigate possible regulatory submission problems.
BioPharm: What are the challenges in performing bioanalytical studies?
Lavelle:Common challenges include supply chain issues and the availability of proper quality reagents. As science continues to find new modalities for therapeutics, complex molecular structures and delivery systems pose challenges for the development of specific and robust assays. For example, in the cell and gene therapy space, use of adeno-associated virus (AAV) vectors for drug delivery creates complications for immunogenicity assessment due to the fact that pre-existing antibodies to the viral vector make finding negative controls and appropriate cut points difficult. When evaluating low-level biomarkers, highly sensitive assays are required, as the assay range needs to be relative to expected biological concentrations, which requires appropriate reagents and equipment.
BioPharm: What are some mistakes companies make in performing bioanalytical studies and/or a bioanalytical study program?
Lavelle: The best way to avoid mistakes is to fully understand regulatory requirements and the appropriate guidance to follow when performing bioanalytical studies. It’s also important to allow sufficient time for the laboratory to develop a robust and validated method intended for sample analysis at the clinical stage. The type of lab compliance and assay validation parameters are key factors in ensuring the data are fully supported for the appropriate regulatory submission. Utilizing a CRO that is experienced with and knowledgeable of agency requirements will help prevent the sponsor from facing any submission issues.
BioPharm: What kind of data from bioanalytical studies are included in regulatory filings?
Lavelle: This is dependent on the drug and its mechanism of action, the proposed indication, and the phase of the trial. Additionally, it depends upon the history of the data already available on the drug and similar compounds or if the need for the drug allows for alternatives, as is the case with orphan status.
An investigational new drug (IND) filing application to start human clinical trials is used to determine if the proposed drug is reasonably safe to administer to humans. Regulatory agencies will review preclinical data, such as pharmacology and toxicology information, genotoxicity, drug absorption and metabolism, and toxicity of metabolites. The proposed clinical protocol for the trial as well as manufacturing information for the drug is discussed.
Phase I, II, and III clinical trials are performed based on FDA-approved protocols. In order to manufacture and sell the drug, clinical test data and analysis from Phase I–III are used in a new drug application (NDA) to determine if the drug is safe and effective for its context of use and if there are any risks associated with the drug, and if so, that the benefits outweigh any risks.An abbreviated new drug application (ANDA) also may be filed for generic drugs. These data must demonstrate bioequivalency to the original drug.
BioPharm: How are these data compiled and presented to regulators? Is the process different for FDA versus the European Medicines Agency (EMA)?
Lavelle: For an FDA IND filing, data from animal and in-vitro toxicology and pharmacology studies are compiled with drug manufacturing information and clinical protocols proposed. In addition, available clinical testing or data from foreign countries may be included. A pre-IND meeting with FDA may be conducted to ensure compliance moving forward.
Animal pharmacology/toxicology information includes a summary on pharmacology and drug disposition,pharmacokinetic (PK) bioanalytical data, and mechanism of action (MOA) of the drug; a toxicology summary, including toxicology study design, findings, and data from toxicology and toxicokinetic studies; a full toxicology data tabulation; and toxicology GLP [good laboratory practice] certification.
For an FDA NDA filing, clinical data from human studies (Phase I–III), which include safety and efficacy results, are compiled and also include drug product control, manufacturing, and stability data. For an ANDA, bioequivalence results also are required.
While the United States has one main body governing drug approval, Europe has multiple agencies, including the EMA, the Committee for Medicinal Products for Human Use (CHMP), and various national health agencies. There are also multiple registration processes in Europe, including centralized, decentralized, mutual recognition, and national. There is a two-step process similar to the US, which includes the clinical trial application, approved at the member state level, and the marketing authorization application, which is approved at the member state and/or centralized level.
BioPharm: Are data from bioanalytical studies a factor in post-marketing of approved drugs?
Lavelle: Yes, post-marketing studies are often important for optimizing the drug’s use. For instance, drug-drug interactions, dose response, or safety studies and mortality/morbidity studies. Other post-marketing studies may be requirements set by FDA (post-marketing commitments) to further monitor and characterize the drug’s effects and safety, such as in subpopulations.
BioPharm: What are the benefits of outsourcing bioanalytical studies?
Lavelle: The benefits depend on the needs and resources of the sponsor. These benefits can include, but are not limited to, laboratory resources including technology, expertise, and experience; regulatory knowledge; end-to-end support from trial design to analysis to regulatory submission; dedicated support groups such as quality control, quality assurance, data management, report writing, and statistical analysis; and time/cost savings. Outsourcing frees up internal resources for alternative needs and enables sponsors to work with limited dedicated internal personnel. Capacity and capabilities are often drivers for outsourcing.
BioPharm: How can sponsor companies and CROs work together to gather and present these data to regulators?
Lavelle: CROs can work with sponsors to ensure appropriate regulatory guidance and testing are being followed for data submission, as well as to help to ensure data and reports are compiled in an appropriate format for submission. CRO labs are subject to audits by FDA, and they often have experience in their interactions with regulatory agencies that can benefit the sponsor. Some CROs have regulatory compliance staff to work with the sponsor as they design and execute their trials.
Susan Haigney is managing editor for BioPharm International.
Volume 35, Number 9
When referring to this article, please cite it as S. Haigney, “Robust Bioanalytical Studies Can Aid in Regulatory Submissions,” BioPharm International 35 (9) (2022).