isk management is one of the cornerstones of effective project management. The generally recognized benefits of effective risk management include improvements to decision-making, increased confidence in projections, and increased probability of achieving project goals. It has been the authors’ experience, however, that risk management activities at the beginning of a therapy’s lifecycle are not always as robust or well-structured as they are later in the drug development lifecycle. This is a problem.

Implementation of Risk Management Activities

Effective risk management involves Subject Matter Experts (SMEs) across a broad range of roles. While the authors do not intend to minimize the essential contributions made by SMEs in statistics, toxicology, or any other area of expertise, the regulatory strategist plays a pivotal role in early drug development that can provide robust benefits for some of the most significant risks that may be realized at this stage. This assertion is informed by the critical nature of a successful regulatory filing for an early-stage biotechnology company and the outsized role that this can play as a value-generating event which can propel a company forward. As the need to accelerate timelines to regulatory filing and approvals could not be more important to small biotech companies, and the primary mechanism to affect this is the company’s regulatory strategy, developing an effective risk mitigation strategy that can prevent potential (and costly) regulatory delays through early and frequent communication between project managers and regulatory strategists provides immense benefit.

Regulatory experts typically have the ability to parse regulatory guidelines that can often appear inscrutable to other clinical development professionals who lack the regulatory expert’s specialized skill set. One of the challenges faced by a regulatory team is the need to translate often dense regulatory language into a more digestible format to help define optimal regulatory strategies for peers in other functional groups. There is a natural, but often overlooked, synergy between project management and regulatory that can help to create clearer presentations that accurately convey the risks and potential outcomes of pursuing different strategies. The core project manager skill set includes the capacity to create clear presentations that summarize complex data sets into useful information that can be easily understood by a wider audience. This same skill is broadly applicable to distilling the information that a regulatory professional must convey. Additionally, these presentations help create robust documentation that can be used as a storyboard to preserve the history of a program, similar to the content of a regulatory strategy plan, and describe why specific decisions were made or a development path followed. These can also be used later in a program’s lifecycle to inform post-mortem/lessons learned conversations or to provide valuable talking points that may be needed as part of a future regulatory inspection. Our project management team designed several decision trees (see Figure 1) in collaboration with the regulatory strategist that allowed the team to present a clear visual representation of how different options would affect the deliverables for submission of a regulatory package. Not only did this process provide direct feedback to the project team that helped to inform their analysis, it also gave the leadership team clarity on the status of the program and allowed them to appropriately plan for changes in funding that were critically needed to advance the program.

Figure 1. BA: Bioanalytical Method; IACUC: Institutional Animal Care and Use Committee; TK: Toxicokinetics.

Risk analysis ideally starts at the inception of any program. The project manager and regulatory strategist should perform a literature search for the therapeutic indication and assess the competitive landscape for the potential market of a new drug candidate. A review of the Summary Basis of Approval (SBA) documentation for other therapies on the market that may be similar to or target the same indication can identify early risks and inform questions to ask regulators during meetings or in other communications. These early steps also help to initiate conversations with other SMEs to further define the overall risk profile and early mitigation steps.

For example, there are existing products in the same space as one of our products in development. So, our team utilized information from their SBAs as a starting point to developing our Regulatory Strategy Plan and to gain a better understanding of potential areas of concern for the FDA. This information was insightful in planning for an FDA meeting where we focused on questions about the proposed first-in-human (FIH) study and other nonclinical aspects of supporting that study. Knowing what shaped previous development pathways for similar drug candidates informed our questions to the agency and our overall development plan for phase 1.

Any documentation from meetings with regulators (e.g., Pre-IND Meeting with the US FDA) should be carefully reviewed with the regulatory strategist to clearly define the expectations of the regulators and ensure that any potential risks are documented, followed, and fully addressed. The regulatory strategist is in a unique position to interpret agency feedback most accurately and formulate the potential steps for satisfactorily addressing it. Ensuring that the risks around a regulatory submission are fully defined and addressed should be a high priority for early-stage biotechnology companies. Receiving a clinical hold letter due to a failure to address regulatory agency feedback might be preventable and should be avoided at all costs since it will effectively halt forward momentum on a program and potentially impact funding opportunities.

The authors watched this example play out when one company did not address a specific issue raised by the US FDA at a pre-IND meeting and in subsequent phone calls. The IND was submitted, but the agency placed the IND on a full clinical hold. The company had to wait approximately 30 days to receive the FDA Clinical Hold Communication and then plan a Type A Meeting. It took another six months to evaluate and address the FDA concerns. In total, it took a year and a half before the phase 1 study could proceed. Considerable additional resources (outside consultants, additional studies, etc.) were needed, and the overall timeline of the development program was lengthened. This was significant: Another product was being developed for the same indication by another company and, as a result, that competitor was able to get to market sooner and establish itself with the target population first.

To keep risk mitigation simple and easy to update, construct a simple risk summary grid (Figure 2). These grids should be initiated at the beginning of a program and continually reviewed and updated. This allows teams to effectively categorize the level of risk, which can be used in conjunction with a risk mitigation log to formulate the appropriate response to address each risk. High Impact/High Probability risks should receive the most detailed and frequent scrutiny until the risk is passed. Low Impact/Low Probability risks may only require occasional or perfunctory review.

Figure 2. Sample Risk Summary Grid.

In another project, our regulatory and project management teams worked hand-in-hand to define the strategy for a long-acting injectable anesthetic. During development of the formulation and nonclinical testing phases, our key opinion leaders identified multiple potential targets for this therapy, all of which would require distinct and unique regulatory strategies. The initial nonclinical strategy was proposed by the company’s leadership team, was strongly influenced by feedback from marketing SMEs, and emphasized obtaining a broad labeling claim. Before initiation of the clinical program, the project manager consulted with our regulatory strategist to confirm that this initial approach aligned with agency expectations. Based on FDA feedback, the regulatory strategist directed the teams to map out the timelines based on the required nonclinical and clinical studies for each indication, and then helped define the risks and potential sticking points for these different strategies and the costs associated with each option. This exercise revealed gaps in the team’s understanding of agency requirements to support specific labeling claims and prompted the scheduling of a Type D Meeting. That meeting greatly clarified the agency’s expectations and allowed the teams to develop more accurate presentations to inform the internal decision-making process and allow the leadership team to move forward with a plan that prioritized patient safety, minimized potential risks, was cost-effective, and represented the most expedient path towards submitting an IND application.

Conclusion

It is important to recognize that the type of risk management described in this article is consistent with the US FDA approach to benefit-risk assessment of new drugs and biologics. In their guidance, the FDA focuses specifically on risks in clinical trials that affect patient safety. Although the topics explored in this article are far broader in scope, it is a fair observation that all activities in clinical research and drug development can potentially affect patient safety. Therefore, it is both reasonable and desirable to extend the concepts of risk mitigation throughout all aspects of the drug development process.