Pharmaceutical and biopharmaceutical companies have been extensively using contract research organizations (CROs) to meet their challenging needs in R&D and standard work for several decades. A noticeable shift occurred in outsourcing research and clinical work when Big Pharma’s R&D costs skyrocketed. For example, in 2012, approximately 33% of drugs in the pipelines of the top 10 pharmaceutical companies were initially developed elsewhere.

Quality Agreements

Sponsor companies engage CROs either on a transactional basis or on a strategic basis. In either case, stakes are high for pharmaceutical and biopharmaceutical companies to make sure CRO work is successful. Neither selecting a reputable CRO, micromanaging CRO work, nor throwing the work over the fence leads to a successful CRO relationship. Key strategies that can lead to a win-win relationship include a relationship on a solid foundation (CRO selection, quality management, and clarity in expectations), soft factors (building the trust and empowerment), and project management excellence (simplifying the complex, metrics, and continuous improvement). The strategies on win-win relationships were developed and implemented for CROs. The concepts, however, can be applicable to all outsourced contracting work with long-term strategies in mind:

• Transactional vs. strategic relationships – Transactional relationships are favored for short duration and limited scope projects (e.g., verification and validation studies and synthesis of organic compounds). Such a relationship merely augments the sponsor company’s internal resources during the crunch time. Strategic relationships exist when sponsor and CRO actively work together to help each other achieve their respective objectives. Strategic relationships help both parties benefit from long-term commitments on infrastructure, continuous improvement, and innovations.
• FDA guidance – It is necessary to comply with the FDA’s guidance document on quality agreements, which is a major step in an alliance formation. The FDA’s regulations recognize that owners commonly use contract facilities to perform some drug manufacturing activities.
• Three different strategies for successful relationships – The win-win strategies can be grouped into three categories: strategies that can drive a solid foundation, soft factors, and excellence in project management.

Stability Testing 

The stability of clinical trial materials, regardless of the trial phase, must be understood to ensure patient safety. Stability can be affected by the nature of the API, the production process, the choice of excipients, the container and container closure system, and other factors. Stability testing is therefore essential for demonstrating that the formulations administered to patients in any clinical trial will remain unchanged throughout the duration of the trial. The type and length of stability tests typically depend on the phase of development and the nature of the clinical trial (e.g., use of placebo or comparator drug). Below is a list of challenges commonly faced while completing stability testing. 

• Fragmented regulatory guidance – Various guidance documents from the FDA and the European Medicines Agency (EMA) have been published regarding stability testing of clinical trials materials (CTMs). The language regarding duration of testing in these documents tends to be vague, however.
• Duration confusion – For CTMs, at a minimum, real-time data must be collected for a sufficient period to demonstrate shelf life for the product in use, as well as cover the duration for any intended clinical trial. The duration of a clinical phase will vary depending upon the number of subjects required to complete the study, the therapeutic indication and the data read out period.
• Impacts on trial design – The vague guidance regarding stability testing for CTMs can have a number of impacts, including on study designs. For instance, because many companies base their studies on ICH guidelines, especially Q1A(R2) (6), and then make modifications to make protocols more suitable for CTMs, there is often considerable variation in how different companies conduct their studies.
• Potential timeline extension – Any issues identified related to the chemical or physical stability of the drug product could cause a delay to the entire clinical development program. A well designed stability study, initiated early in the program, will facilitate detection of these issues and lessen any impact they may otherwise cause if not understood and resolved quickly. The key challenge is the fact that as candidates progress through the development cycle, typically changes are made to the formulation, manufacturing process, and analytical methodology.
• Method development/validation challenges – Often during early-phase studies, knowledge of both products and methods are limited. When unknown degradation occurs, or a method does not behave as anticipated due to an unforeseen change, this can lead to pressure on the project. There exists a need to explain the change and justify it as safe for ongoing work or understand quickly that it is a change that does have an impact on product safety.

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