Having a set of operating standards defined through Quality Documents (QDs) is the only route to compliance and performance. QDs are defined as documents such as Policies, SOPs, Work Instructions (WINs), Manuals, Charters and Memo to File. A set of Pharmacovigilance (PV) specific QDs will ensure the consistency of process, the building of operational and strategic activities around compliance to regulatory obligations, and will also provide for the ability to extract metrics that measure the adherence to a set of clear standards. For a small biotech company at the early stages of Clinical Development, the sudden awakening that specific PV QDs and resources are needed can be quite daunting. There are some fundamentals which can help such companies to start on the right foot.
In the Beginning was the SOP on SOPs…
In order to build a robust set of QDs, a Company Quality System architecture must first be defined. This includes what type of documents are recognized as Quality Documents and what differentiates them (Policies versus SOPs versus WINs for example). It also includes a template for QDs, the Change Control process to follow to create or revise a QD, an impact assessment analysis of the proposed changes, and the QD review and approval process. This “Mother of All SOPs” is essential to any Quality Assurance (QA) organization. There are other key QA SOPs that should predate any functional SOP drafting: a Deviation Management/CAPAs SOP, and an Audit SOP, which will include audits of Contract Service Providers (CSPs). It is only when at least these 3 fundamental documents are established that the rest of the QDs can be developed for PV and other functions. If your company is not there yet, drop whatever you are doing now and have a serious discussion with your QA department.
Which PV SOPs come first for Clinical Development PV?
A few key SOPs should be targeted as a strict minimum start when creating a premarketing PV structure:
A Clinical Trial Handling of SAEs SOP, all inclusive from initial notification to case processing/triaging/coding to expedited reporting;
A Safety Management Plan Development SOP, allocating responsibilities between the Sponsor and the PV service provider for all AE related process;
An Unblinding for Expedited Purposes SOP: maintaining the blind to non authorized individuals while complying with Regulatory reporting expectations
A Signal Management SOP: which includes signal detection, risk management and escalation;
An Aggregate Report Preparation SOP for annual IND reports, DSURs and other ad-hoc safety reports.
An Escalation and Urgent Communication SOP: it will include a description of the Safety Governance Model in place for critical safety decision making.
Many activities can be included in these QDs rather than being separate, especially when the PV function is in the making; Literature Searches, MedDRA coding, PV Compliance are a few examples. Needless to say that many other non PV-owned SOPs must exist in the organization, and are not covered here. As many activities will be outsourced, establishing internal company standards prior to outsourcing is essential, rather than the other way around. As multiple vendors will be involved across programs, the availability of company standards will become essential for the management of complex business model with many vendors.
This is just the beginning.
Depending on how you cut and dice the different PV activities during the development phase, you may end up with between 10 and 20 SOPs and WINs, with some fortunately also applicable to future post-marketing activities. When activities grow, it is logic to move complex activities to a separate QD. The growing number of pages in an SOP will be a good indicator that it is time to split and reallocate some QD content to a separate one. Start simple, ensure you cover all regulatory mandates, be precise enough to reduce process deviations, define clearly activities’ ownership and you will be well equipped to develop further the system when your business will grow. Always prepare a roadmap for your PV QDs development, short term and long term.
Key takeaways and Principles.
Keep in mind a few important rules when creating or enhancing your PV Quality System:
You need a Master Plan: Quality Assurance is the Architect and the Conductor of the quality system being created for the company, including PV QDs. A Quality Master Plan should drive the development of all QDs across all departments, ensuring that all activities are captured, allocated to the right owner, and developed with the right priority.
Build in flexibility for execution, with clear rules for ownership and oversight: as your business model will likely involve outsourcing, make sure that opportunities to delegate and outsource are included, but ensure that there is no confusion on who is ultimately responsible for the process output and compliance. A lot of operational details can go into the study specific SMP rather than the company SOPs. A RACI matrix exercise will help defining who completes the task(s) and where the buck stops.
Do not lose the sense of urgency: writing SOPs feels often as lengthy and frustrating exercise, but until you are done you are still at risk. Your current gap for not having adequate QDs will never disappear and will always be a significant liability at the time of the pre-approval inspection, so focus on reducing quickly these gaps and get these SOPs completed and in effect to minimize future regulatory risks.
In the meantime, prepare for the question that you will always have during the pre-approval inspection: “how were you able to demonstrate adequate oversight and control during all this time without adequate SOPs?” No time to waste to get ready, indeed.
JP Clement, MD