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Key Considerations for Successfully Planning a Submission

Learn the importance of strategy formulation and regulatory engagement for planning a succesful ISS/ISE submission.

Lindsay Lian, senior director of biostats and programming for PPD(R) FSP; Hunter Everton, senior director of biostats and programming; Robert King, executive director of project management; and Craig McIlloney, global vice president of biostats and programming discuss the importance of strategy formulation and regulatory engagement when developing an integrated summary of safety (ISS) and efficacy (ISE).

A submission can be both exciting and daunting. From the initial discovery at a lab to first in-human testing to the completion of phase III program, submission marks the finishing line of a long journey of bringing a new medication to the market. There are many contributing factors to a timely and successful submission, planning being the key in achieving this end goal to improve patients’ health.

Delivering as quickly as possible the integrated summary of safety (ISS) and efficacy (ISE), requires well thought out planning and communication. The top three (3) critical activities to consider when planning the ISS/ISE are:

Data integration strategy

A submission committee should be set-up to decide on the list of studies to be included in the ISS and ISE, if an ISE is warranted, based on the clinical development plan and the proposed new drug label. It is important to remember that an integrated analysis should only be of the combined individual study data that supports the integrated Statistical Analysis Plan e.g., it is not an integration of all individual study data, only the data required for ISS/ISE analysis.

Depending on the nature and length of the clinical development program, there is often a need to include studies that may be in a different data structures compared to the phase III pivotal study or studies. Typical studies could include early phase development (Phase I) and Pharmacokinetic’s trials. All individual study data will need to be integrated and conform to one standard structure for the integration analysis. This could happen at different levels of integration, whether in the collected study results (SDTM) or the integrated analysis (ADaM). To ensure the ideal level of integration, a number of factors need to be considered, including but not limited to; the consistency of inclusion/exclusion criteria, the extent of data/structural alignment, the format of the raw ‘collected’ results and the number of studies in the CDISC SDTM/ADaM format. 

The integrated analysis approach is another key component of the overall submission strategy. A successful submission relies on an analysis approach that establishes the compound safety and efficacy profiles clearly and supports the label claims adequately. It requires a multi-disciplinary team that includes clinical, statistical, regulatory affairs, medical writing  and more. It is recommended to seek regulatory agency feedback during the submission committee engagements.

MedDRA and WHODrug coding must be considered with all integrations, as all study data included in the integration needs to be re-coded using the same coding dictionaries to allow items to be reported using the integration analysis.

Timing of producing the ISS and ISE

The timing of producing the ISS and ISE can be tricky. 

It would be beneficial to have the ISS and ISE ready soon after the last phase III pivotal study database lock to expedite the submission and get the new medication to the market as soon as possible. In order to achieve that, the ISS and ISE activities would need to happen in parallel to the individual pivotal study analysis. This approach bears the risks that: 1) the submission may be a no-go if the pivotal study results turn out to be sub-optimal, therefore ISS/ISE efforts wasted; and 2) changes performed to the individual study analysis may have direct impact on the ISS/ISE analysis and vice versa, which results in extra development, coordination and communication effort in order to achieve consistency across the individual study(ies) and the integration.

Alternatively, waiting until the phase III pivotal study results are known to begin the ISS/ISE activities would minimize the incurrence of the extra effort therefore reducing costs and result in a much more streamlined integrated reporting process.  This approach does increase the overall submission timeline which can delay the timing of the regulatory approval though ensures a more consistent integrated analysis.

Careful consideration needs to take place to decide on the right timing of the ISS and ISE activities for each submission, balancing each company and drug development program’s unique situation. 

Resourcing plans

Once the integration strategy is set and ISS/ISE timelines are determined, a team with the right experience level and the right size becomes key to a successful execution of the strategies. 

When it comes to an ISS/ISE, the team shouldt not only possess the compound knowledge, therapeutic experience, statistical and programming technical expertise, but also have a deep understanding of regulatory requirements and know how these vary from country to country. 

Time is of the essence typically when it comes to submissions. The larger a team is, normally the faster things can be done. However, at what point does a team become too big to function efficiently?

Throughout the ISS/ISE production period, especially when it is happening in parallel to individual study reporting effort, often there are times when rapid resourcing ramp up becomes necessary to accommodate new or changed analysis across the program. How can the team effectively deal with the peaks and troughs of the resourcing needs to avoid unnecessary delay of the overall submission timelines?

Once the submission goes out of the door, what resourcing needs are required to stay prepared for the period between the filing and regulatory approval? 

Some regulatory agencies may require rapid responses to review questions throughout the review period, how should the team set up the resources plan in anticipating such situations, e.g., ad hocs?

There is no one answer to these questions; rather, various scenarios should be worked through with the submission team to determine the best course of actions for the company’s needs.

PPD has the right level of expertise, experience, and capacity to support submissions across the globe with all regulatory agencies. From the strategy formulation, regulatory engagement, developing integrated ISS/ISE analysis, compiling and delivering submission compliant CDISC packages, to responding to regulatory review comments, PPD can support every step along the way leading to a successful submission.

Our global staff have extensive experience dealing with health authorities (HA), either working closely with a client or taking on the full ownership to delivery. Our statistical scientists are well equipped in meeting with different regulatory authorities about the acceptability of certain study designs and analysis methodologies and particularly in support of discussions involving novel designs (e.g., adaptive designs). Our programming experts are well versed in CDISC standards and most recent industry developments.

Our technology infrastructure ensures all deliverables are created in an auditable and efficient manner. We have the processes and tools in place that ensures each study is audit ready throughout the study lifecycle.

With more than 200 CDISC submissions successfully filed, PPD Biostatistics and Programming is the right partner to support a company’s integrated analysis and agency reporting needs.

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