5 potential surprises that may jeopardize your marketing application timeline

For many pharmaceutical and biotech companies, the submission of a marketing application – such as a New Drug Application (NDA), Biologics License Application (BLA) and Marketing Authorization Application (MAA) – is a huge milestone in the regulatory process, second only to market approval.

In today’s highly competitive markets, timelines are under tremendous pressure. Having a dedicated submission leader who can create and implement clear processes for communication, decision making, data analyses and resource allocation is essential for NDA or BLA success. However, even when you have the right resources and leadership in place, unexpected surprises can put your submission timeline in jeopardy.  For both small-to-mid-sized biopharma companies submitting their first NDA, BLA or MAA and experienced companies seeking to streamline their next submission, recognizing and anticipating these surprises can help minimize rework and costly delays– so you can speed your therapy to patients, faster. Here are some unforeseen issues that we have seen in our experience supporting hundreds of marketing applications.

For marketing applications to the US FDA, the interest and expectations for standardized data are increasing. FDA data standards apply to clinical and certain non-clinical studies. Data standards apply to studies initiated prior to, and after December 16, 2016. The Study Data Standardization Plan (SDSP), also referred to as the “eData Plan”, is a crucial document that describes the sponsor’s plan for submitting data for legacy studies (initiated prior to December 16, 2016) and for non-legacy studies.

Some sponsors submit their SDSP at the time of the pre-NDA meeting. The FDA review of the SDSP can yield surprises, such as requests to take different approaches to standardize data. The best practice would be to submit the SDSP prior to the pre-NDA meeting, so that FDA feedback-based expectations, which may be FDA Division and/or indication-specific, are confirmed as early as possible, allowing the sponsor a better opportunity to ensure they are meeting FDA expectations at the time of marketing application submission.

It is well understood that drug abuse liability assessments are important for drugs and biologics for neurologic and psychiatric indications. The January 2017 FDA Guidance, Assessment of Abuse Potential of Drugs, clarifies that abuse potential may require evaluation if the new drug (or any major metabolite) is active within the CNS. This Guidance further provides that a CNS activity determination may require:

• Chemistry studies (drug structure and ability to pass blood brain barrier)
• Receptor binding studies with the drug and major metabolites at CNS sites
• Second messenger system studies (if available) to identify functionality at binding sites
• Pharmacokinetic studies showing the drug’s relative distribution to and penetration of the brain
• Pharmacodynamic studies showing ability of the drug to induce general behavioral changes in animals and humans indicative of CNS activity

Note that the above list addresses much more than the drug passing the blood brain barrier, and may involve chemistry, non-clinical and clinical studies. A failure to make a comprehensive evaluation of CNS activity (at intended therapeutic doses or their equivalent doses in animals), and a lack of discussion and interaction on this topic with FDA, during development, can result in costly surprises to sponsors.

Depending upon the clinical development plan for a drug or biologic, and in particular the duration of the Phase 3 program, significant time may elapse between the End of Phase 2 (EOP2) Meeting and the pre-NDA or pre-BLA meeting. It is important for sponsors to consider that feedback received at the EOP2 Meeting, represents FDA positions at that time, and FDA thinking and expectations may have evolved by the time of the pre-NDA meeting.

For example, expectations for total safety exposure of the drug or biologic, for a particular indication, may increase. An increase in expectations for total safety exposure can be an unwelcome surprise for a sponsor, requiring either that Phase 3 study designs be adjusted to extend their open label extension periods or that additional Phase 3 studies be conducted to augment the safety database.

The statistical analysis protocols (SAPs) for integrated analyses of efficacy (ISE) and/or safety (ISS) are often submitted with the briefing package for the pre-NDA meeting. If the pre-NDA meeting is held too close to the intended submission date for the marketing application, the sponsor is at risk to receive requests from FDA to modify the SAPs, without adequate time to comply.

The impact of SAP modifications may be that additional statistical programming is required, and that the timelines for programming, the production and review of statistical outputs, and the authoring of clinical summary documents, and draft labeling documents, are all extended.

Therefore, sponsors should consider preparing and submitting their SAPs for the ISE and ISS for feedback sufficiently in advance, to avoid putting the planned submission date for the marketing application at risk.

No sponsor welcomes surprises during the pre-NDA or pre-BLA meeting interactions, in particular those that require extensive unplanned work to accommodate. With good planning and sufficient dialog, the following potential surprises may be avoided or mitigated:

• Requests for additional patient safety narratives
• Requests for more Case Report Forms (CRFs) that originally planned
• Requests for graphical patient profiles not previously planned
• Requests for more extensive safety adjudication records than originally planned
• Requests for Phase 1 biostatistical data packages

By addressing these and other topics proactively, sponsors may reduce the risk of unwelcome surprises and their negative impact to the submission timeline.