Phase 2 to Early Phase 3 Regulatory Opportunities: Return on Investment

CMC and Regulatory Affairs – See the forest and the trees
October 29, 2019

To ensure scientific and commercial success, it is critical to understand the drug development process and the myriad tasks and milestones that are vital to a comprehensive development plan.

Although the primary purpose of a well-designed regulatory strategy is to assure an efficient process for providing new, high quality and effective drugs for patients, it is also essential to effectively maximize the return on investment.

Each step along the path to commercialization is important and an effective chemistry, manufacturing and controls (CMC) strategy and ensuing communication plan plays an integral role in the overall success of a product.

Crucial ROI Considerations on the Path to Product Approval

The shift from Phase 2 clinical (studies to evaluate the effectiveness of the drug for a particular indication in patients) to Phase 3 (expanded trial studies intended to gather the additional information about effectiveness and safety needed to evaluate the overall risk/benefit relationship of the drug) is a major milestone for a drug sponsor.

The value drivers are typically intellectual property, safety and efficacy. The CMC profile is often viewed less important unless there is a major weakness in the products profile. For many small molecules, for example, CMC development principally enables non-clinical and clinical development, and does not drive asset value.

However, by the end of Phase 2, a sponsor company has devoted considerable time, expertise and expense to understanding the science of how the drug works in humans and how to clinically administer the drug product to maximize its medical benefit and minimize its medical risks. But have similar resources been expended to understand the science of how the drug product can be manufactured consistently to yield the desired quality?

For most programs, gone are the days when a manufacturing process that was successful in preparing clinical product for Phases 1 and 2 was also considered good enough to go forward into later-stage clinical trials and even commercial manufacturing.

The aim of pharmaceutical drug development is to design a quality product and manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from development studies and manufacturing experience provide the scientific understanding to support the establishment of the product manufacturing process, specifications, and manufacturing controls.

Today, influenced by and large as a result of amended guidance’s and the evolving regulatory harmonization initiatives, basing manufacturing decisions scientifically on enhanced product knowledge and product performance data over a wider range of material attributes, processing options and process parameters is fast becoming the norm.

Execution is critical at this stage (transition from Phase 2) to ensure that all activities necessary for an eventual marketing approval are being planned for and any identified CMC development impediment is under discussion with the regulatory agencies (see below).

Design of Experiments (DOE) and Statistical Approaches for Data Analysis

The concept of process design and control has gained in popularity as a tool for the process development scientist. A product control space has been traditionally proposed by the sponsor and is subject to regulatory assessment and approval.

However, as the product matures in its life cycle, factors like scale-up, economics and others can require changes in the control scheme for the process. The scientific basis for moving or expanding the product control space is usually developed out of necessity to cope with process shortcomings long after the original process development work is done.

Developing and then filing a process that encapsulates the product control space can provide additional “Process Knowledge Movement” out of this control space then would not be considered as a major change; however, movement out of a rigidly defined process would be considered to be a major change and would normally initiate a regulatory change control course of action.

With the publication of ICH Q8, Q10, Q11 etc. the opportunity now exists to develop an approvable process in advance of commercial launch that anticipates and accommodates continuous improvement. This allows manufacturers to make changes that enhance the process, as necessary, without the need for major regulatory approval, provided that the product control space remains within an approved process, that the agency agrees to what is filed up front in principal.

Use of statistical approaches for designing experimental studies and performing data analysis has re-emerged as a fundamental activity, especially in cases where a low number of clinical batches are produced in clinical development at scale. Many raw materials and process parameters typically impact any given unit operation in a process.

Understanding the impact of each raw material and input parameter on each output parameter is not always practical. A combination of risk assessments and DOE has arisen as the approach of choice to accelerate this task and can be found throughout literature.

To realize the benefits of this approach, the process development and manufacturing team must develop and document the scientific basis for the justification and approval in the Pharmaceutical Development areas of the CMC Module 3. The information used for this work comes in part from appropriately designed experiments that define and test the outer limits or edge of failure of the intended process to understand the effects on the critical quality attributes (CQAs).

At the time of process scale-up or tech transfer, data and information about the process control space, as well as the critical process parameters (CPPs) within which the process control space operate, must be readily available before transferring or scaling the manufacturing operation.

The most important approach to maximize the chance that the Module 3 is received favorably is to strive for clarity, to avoid exaggerations, and to discuss rather than hide negative findings and deficiencies. Avoid claims that cannot be substantiated, and keep in mind the age-old advice that if something is not documented, it is rumor.

As an element of the proposed manufacturing process, the process control space can be described in the section of the application that includes the description of the manufacturing process and process controls (3.2.S.2.2). If appropriate, additional information can be provided in the section of the application that addresses the controls of critical steps and intermediates (3.2.S.2.4).

The manufacturing process development section of the application (3.2.S.2.6) is the appropriate place to summarize and describe process development studies that provide the basis for the design space(s). The relationship of the process control space to the overall control strategy can be discussed in the section of the application that includes the justification of the drug substance specification (3.2.S.4.5).

Your chance to avoid regulatory delays. Seek out regulatory agency advice.

Since the agency in the end controls the drug fate, it can only be a benefit for the sponsor to ensure that the reviewer clearly understands the science behind the manufacturing process and product. This sounds easy, but for some sponsors it also sounds daunting. What if the agency wants much more to be done than is currently planned? What impact would that have on the corporate-established marketing approval date?

Sponsors must recognize that it is not about believing that it knows more about its process and product than the regulatory agency; it is about involving the regulatory agency. Regulatory stringency is lowest at the start of the process development effort and increases as the clinical trials process into later stages, reaching its highest level during commercial manufacturing operations. The best opportunities to explore the edges of the required envelope of the process and product control and develop the scientific support and experience necessary to maximize the predictability and quality of the manufacturing process are therefore available during process development.

Once commercial operations begin, these opportunities are much more limited. Sponsors need a reality check for their regulatory and compliance strategy at this transition from Phase 2 to Phase 3, and the agency can deliver it. Both FDA and EMA see the value of CMC-focused End-of-Phase 2 (EOP2)/Scientific Advice meetings with sponsors. They consider these meetings a critical interaction and especially important.

Sponsors need to encourage communication and teamwork with the regulatory authorities. An investment in process science can pay off in improved manufacturing process control for later clinical stages and ultimately commercial production.

Meetings between the sponsor and the regulatory agency can help provide assurance to sponsors that there will be no major CMC strategic surprises that could significantly delay the marketing applications review and approval provides assurance that a given compound meets requisite technical and quality elements to allow for successful commercialization of the drug and thus serves to increase asset value.

Regulatory correspondence, particularly feedback from regulatory agencies, can guide the CMC to areas of potential concern or areas where mitigation strategies will need to be developed or are underway. Importantly, while reviewing, the sponsor should make linkages to other disciplines, e.g., clinical and safety, that potentially may be impacted and therefore should be addressed in the broader team context.