How to Select a CRO for BA/ BE Studies?

Introduction

Contract Research Organization (CRO) plays a vital role as a service provider for the pharmaceutical industries. The market size of the global contract research organization (CRO) services was estimated at USD 38,396.4 million in 2018. By the end of 2026, it is expected to hit USD 90,926.3 million. It should be noted that in terms of the number of generic drugs, 20% of global exports are from India. This makes India the biggest global supplier of generic medicines. It is very much obvious that to get marketing approval for generic drugs on foreign soil, manufacturers from India have to clear all the regulatory parameters. Thus BA/BE studies are of great importance and conducting them needs due planning and experience. Generic companies have the R&D for product development, Manufacturing, and its quality testing. Many of the bigger pharmaceutical firms have of their own clinical and bioanalytical units. They are capable to carry out Phase 1 and BA/BE studies. However because of the desire to produce more compounds in shorter time periods, there comes a point when the internal resources become saturated. Often several smaller firms, virtual companies and generic companies do not have the privilege of performing BA/BE trials with their own dedicated clinical unit or full in-house capability. They may not have clinical and bio-analytical capability. Thus the role of CRO or outsourcing of BA/BE studies comes into the picture. They reduce the cost of BA/BE study, help pharmaceutical companies to file ANDA application and bring new medicines to market quickly.

The typical services outsourced for BA/ BE studies from a pharmaceutical company to a CRO may include Bioanalytical Analysis, Bioanalytical Site Selection and Qualification, Clinical Study Design, Clinical Protocol Development, Clinical Site Selection and Qualification, Clinical Conduct, Clinical Monitoring, Data Management, Pharmacokinetic Analyses, Statistical Analyses, Pharmacokinetic Report Writing, Integrated ICH Report Writing, Project Management, and FDA/Regulatory Consultation.

How to select a CRO?

The first step before outsourcing a study to a CRO is to develop a list of potential CROs that are involved in conducting BA/BE studies. CROs that have good experience in conducting BA/BE studies and can meet the sponsor’s timeline should be given first preference. The list should include the CROs that provide all services and also the ones that provide only clinical or analytical services. CROs that have a proven record of carrying out BA/BE studies with appropriate clinical conduct, laboratory analysis, data management, biostatistics, pharmacokinetics, and medical writing should be given priority. They should be in compliance with Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and other applicable regulatory practices and guidelines.

How to assess the qualification of a CRO?

The sponsor company should assess a CRO on different parameters before finalizing to outsource the project. The parameters include Clinical Capabilities, Bio analytical Capabilities, Pharmacokinetic capabilities, and quality deliverables on time. The sponsor should obtain copies of past FDA inspection reports (483s and Establishment Inspection Reports {EIRs}) through the Freedom of Information (FOI). The client should also request any FDA warning letters (if any) that have been issued against the CRO.

The ability to recruit volunteers for both small and large sample studies is a major assessment criteria for the qualification of any CRO. The CRO should be able to recruit the entire study population at a single center, preferably as a single group.

The client should make sure that the Bioanalytical team is well experienced in analyzing the analyte or metabolite of the drug as appropriate. Client should also check that the facility follows cGLPs and have clean inspection history from regulatory bodies. The Bioanalytical team of the CRO should be able to provide a written validation report.

The CRO should have validated pharmacokinetic and statistical programs in place and should be compliant with 21 CFR Part 11 (especially concerning change control).

The CRO should also provide performance metrics used for monitoring the timelines and financial metrics. The client should request ‘‘references’’ that include those companies which outsourced studies and in return had successful ANDA or NDA approvals.

After evaluating the credentials and performance metrics of each CRO, the sponsor should physically visit the site and audit the clinical, bioanalytical, and pharmacokinetic capabilities of the CRO.

The audit should include the evaluation of the:

• Procedure for the CRO to handle an unexpected and serious adverse event (AE) investigation.
• Training records for the clinical team
• CRO’s capability to synchronize plasma urine deliveries to different bioanalytical facilities
• CRO’s ability to coordinate functional handoffs
• CRO’s clinical project management capabilities
• Validation of the data collection system
• SOPs, CRF and database correction, change control
• Deliverables like CRFs (CRO or sponsor format), transport procedures to the bioanalytical unit, Content of the written clinical report

The client should also asses the capability of the laboratory project management with regards to their coordination with the clinic, pharmacokineticist and the sponsor during the study.

Finally, to support the BA/BE study, the CRO should provide written documentation of the final analytical report that should contain supplementary project-specific validation data.

Thus, in a nutshell, it can be said that factors like the number of years in the business, qualified team of scientific, medical and statistical experts, the ability of CRO to recruit volunteers, sufficient number of beds for in-housing, calibrated laboratory equipment with suitable SOPs, location of the CRO, duration of getting IEC/IRB approval, employee training on SOPs, adherence to GCP and GLP, correct volunteer database, appropriate ambulatory service, clean kitchen facilities with maintained hygiene, recreation rooms for volunteers, working QAU system, facility management, and accurately designed scientific organization charts assess the qualification of a CRO to conduct BA/BE studies.

Conclusion

A generic manufacturer outsources a BA/BE study so that their product can be proved bioequivalent with that of a Reference Listed Drug (RLD). The key elements for success of the BA/BE study between the client and the CRO are transparent Communication at all levels, Sensitivity to the requirement of the project, the Timelines, and Flexibility to recognize and adjust to unexpected events throughout the project timeline. Work culture compatibility between a sponsor and CRO is also a substantial merit, as it leads to a more aligned relationship in future.

REFERENCE

1. Outsourcing Bioavailability and Bioequivalence Studies to Contract Research Organizations, Patrick K. Noonan. Generic Drug Product Development Solid Oral Dosage Forms Chapter 13, Pg No. 299-321.