5 Common Mistakes That Can Derail a Clinical Trial Inspection (Part 3)

In a business niche as highly critical, closely scrutinised and heavily regulated as pharmacovigilance it remains a puzzle why clinical development organisations struggle so often with the “end of process task” of distributing Safety Reports*. These are commonly known as Suspected Unexpected Serious Adverse Reaction or SUSARs. Timely safety report distribution is important because of its part in improving patient safety but also due to the compelling regulatory obligation to distribute this material promptly.

A Pharmacovigilance Process Summary

  1. Site reports Serious Adverse Reaction (SAR) within 48 hours.
  2. Sponsor determines if SAR is unexpected or not.
  3. Sponsor reports SUSAR to relevant regulators within days (for EMA within 7 days and typically 15 days for the FDA).
  4. In parallel to step 3 the sponsor has a responsibility to promptly inform other sites once the matter is identified as a safety issue. While there is some scope for interpretation here, “promptly” is normally interpreted as meaning a number of days and not some longer period of time. Typically sponsors will aim to distribute safety reports within 15 days.

For reference here is how the FDA explain things – p16 of FDA Guidance Safety Reporting Requirements for INDs and BA/BE Studies.

The reality is that this end of process task sounds simple to define but it is in fact pretty complex and time critical. In addition – organisations are often so blindly addicted to using email that alternative, more dynamic and reliable means of information distribution are strangely alien and fantastical. But why not use distribution means that allow for active information distribution, with real-time dynamic readership information? In an age where audience behaviour is closely tracked, isn’t it time you knew who has read your latest Safety Report, and more crucially who has not?

Mistake #3: Lack of Appropriate Document Controls

The path of a document from its origin to its distribution must be known and controlled. It is not a could. It is not a should. Document control is a must for those documents that may be described as regulatory, essential, supporting and ancillary. In reality, any document and all documents key to ensuring that the study is conducted accurately, consistently and according to the protocol, legislation and Good Clinical Practice (GCP) must be prepared, reviewed, approved and implemented in a controlled manner.

For the record, the choice of the word must in this context is entirely my own. Published guidance on this topic goes to great lengths to define the must and the should and an equally great length to distance from any must not necessitated by law. The word must appears just three times in the ICH E6 (R2), each instance buried in an italicized legal notice that precedes the table of contents.

Getting back to the point, every organization should have appropriate controls in place for all information that is distributed to clinical trial sites in the name of, and in support of, study conduct. Here is a simple outline that can provide a framework for that painstakingly detailed SOP that will inevitably follow:

1) Assign responsibility for the document.

The person leading the charge can be anywhere on the organizational spectrum from a medical writer to a clinical scientist to a regulatory affairs expert to a clinical trial leader or associate. Titles are for reference only.

2) Decide how much rigor to apply to the process.

An essential “must” document headed for the TMF (see Section 8 of the E6) merits a written procedure describing the naming convention for the document, who will contribute, how the contributors’ comments were reconciled, what it will look like both online and in printed format, how the QC will be accomplished, who will sign and with wet ink or not, how unauthorized changes to content will be avoided, how authorized changes to final documents will be handled …

3) Decide how much rigor to apply to the process.

That was not a copy and paste error, the redundancy is intended for emphasis. If a document is not a “Section 8 essential must” — if it is instead a supporting document such as a manual, a training slide deck, a protocol clarification letter, a communication that informs something administrative in nature is new or changing (like contact information for help desk support, kit re-supply, safety reporting, etc.), rigor is still in order. Skippable steps might be the strictness of naming conventions, the number of functional contributors, the formality of comment reconciliation…

4) Assign responsibility for the document.

That was (also) not a copy and paste error. Circling back to assigning responsibility to lead the preparation and finalization, the importance of a responsible party to see to it the document is properly distributed is equal. The clinical trial leader gets my vote for this one. S/he may delegate but must (my use again) oversee and verify to ensure the correct and most recent documents and communications are distributed to all clinical trial stakeholders.

5) Choose wisely the method of distribution.

Any document so painstakingly prepared and reviewed and approved, that is attached to an email composed without the same level of care and addressed without the surest level of intent, is not a good method of implementation. Choose a secure platform to deliver study documents and communications to sites. Eliminate email for all but the truly rare 1:1 or 1:few communications that are personal or confidential.

The investigators and their staff, the monitors and study team members must all receive the right version of the right document at the right time. And, at the end of the day, there must be evidence to prove this was the case.

This is the third installment of the myClin series on 5 Common Mistakes That Can Derail a Clinical Trial Inspection series. Check back again when we tackle Mistake #4 : Overlooking the Oversight Responsibilities Associated with Trial Communications.

By Eileen Daniel, SVP, Development Operations at Caelum Biosciences

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