How Will You Be Inspection Ready Next Time? (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?

Real world perspectives from a clinical site, a sponsor, and a technology vendor.

myClin and Clinical Works recently organized the Clinical Innovators Summit (CIS) West Coast 2019 to help clinical trial professionals simplify, unify, and advance Oversight and collaboration processes in clinical trials.

In part 3 of our “Inspection Readiness” discussion, our questions touched on eISF (Electronic Investigator Site Files).

James Denmark, CEO & Founder of myClin

“If ISF and TMF aren’t the same thing, they’re at least 90% overlapping”

“We could go on for a whole afternoon about the ISF part of the TMF (Trial Master File). Right now there’s a splinter group. The TMF working groups don’t agree with this and are forking out and creating competing initiatives, specifically around the ISF.”

“Speaking on behalf of the myClin platform, we are somewhat agnostic when it comes to that. We recognize that some material is going to come from the sponsor and it’s going to come via myClin. Other material is going to come as a shipment of clinical supplies. Many of those things are going to end up in the TMF, and ultimately much of that ends up in the ISF. So we’ll end up with this Venn diagram with all these overlapping folders and systems.”

“When it comes to myClin specifically, even if the sponsor distributed a TMF document, the sites action on that is going to be governed by their local SOP. If their local SOP permits them to leave it on the online system, then that filing record on myClin forms part of their ISF and your TMF. On the contrary, if their SOP requires that they move it into their own document control workflow within three days, then that’s what they’re going to be concentrating on. They won’t care much about the myClin side. So I think it depends. But at the end of the day, it’s clear that if the ISF and TMF aren’t the same thing, they’re at least 90% overlapping.”

Todd Tullis, Product Manager, Veeva

“Since I’m on the TMF Reference Model Steering Committee, I’m very familiar with Trial Master Files. This is actually a question that has come up a lot lately because there’s so many different terms that are used and it gets confusing. Sponsors called the ISF the sites regulatory binder, as well as the pharmacy binder, the subject binder, and in recent guidance calls, the EMA calls it ‘sponsor TMF’ and the ‘investigator TMF’. The whole thing collectively is called the TMF. There are some records where originals are intended to be held in the investigator TMF, and some records where originals are held in the sponsor TMF, and as James pointed out, a lot of records where copies go back and forth and are actually held by either party.”

“We are about to publish a position statement, along with a list of the reference model artifacts. We will also be addressing where we think the original belongs for each artifact within the reference model. This will go out to the reference model project members for public comment. This is something that we’re very much interested, as well as working more with sites. Thus far, the reference model has focused mostly on sponsor driven activity. We haven’t been directly involved with many sites and for communication purposes, it would be very valuable to understand the sites perspective on important clinical trial records as opposed to the sponsors perspective. We want to try and minimize some of the confusion that is caused by each group using different terms to describe the same thing.”

“Right now MAGI has initiatives in place to try and define this situation. I think that everybody is trying to do what they think is right for the industry. Ultimately, we all want to communicate better and be brought closer together as an industry.”

Why is it important to spend more time on oversight in the beginning? What is it going to buy us on the backend?

Erin Silverman, Ph.D. CCC-SLP, CRCC, Research Coordinator and Adjunct Assistant Professor, University of Florida

“As a study evolves from conception to implementation, more and more people are added to the equation. With each new person you add more freedom, more opportunities for cross signals, misinterpretation, and process breakdowns. I would rather address a process breakdown early on, when it involves as few people as possible, as opposed to later on in the study. I think sometimes with the rush to enroll, we ignore this, and then the sites are left cleaning up the mess. This leaves us wondering what version we on, and it leaves a bad taste in the mouths of the sites. Some sites have the luxury of being able to pick and choose which studies they want to take on, and we don’t want to accept studies that we know are going to be a mess from day one.”

John Silowsky – Clinical Operations Consultant & former Snr. Director Clinical Operations

“I think it’s all about taking the time to get things right at the beginning. It’s not something that’s going to take you years, it’s just about investing a few extra minutes to develop your plans and conduct a risk assessment. In my opinion this results in two important developments.”

“Firstly, communication is enhanced which means that engagement with investigators is enhanced. Higher investigator engagement is key because it means that the whole process will go much faster. When you have engaged investigators, enrollment goes quicker, and turnaround times for data and query responses and all of the other things that we wait patiently for is faster because you care about them and they care about you. Secondly, you will have a deep understanding of your study, methods, and processes, and virtually everyone will be on the same page and give the same response. So it won’t matter if the inspector shows up at Erin’s office or my office – they will get the same, consistent response, and that’s what they’re looking for.”

Lorne Cheeseman – Managing Director, Kestrel Biologic

“When it comes to processes, one of the things that we’ve alluded is the data mapping process. These can be be very long and painful meetings. There’s a lot of discussions that take place and there can be a tendency to just gloss over things and keep going. But, it’s important to pay attention to this process otherwise you’re going to run into problems. I mean, I’ve got to the end of studies where nobody really figured where the data was going to come from or how it was going to be conducted, and then suddenly it’s a big problem.”

“By having discussions early on, you will identify problems and risk factors in the beginning. This will allow you to put processes in place that can mitigate or avoid possible problems later on.”

“A protocol simulation visit is also key. I’m surprised that more studies don’t do it. Walking through the protocol step by step is very helpful. If you can go to a site and run through the protocol in the different departments and different places, and just get a feel for the whole thing, it can be very beneficial.”

“On every single study that I’ve worked on, when a protocol simulation visit has been done there has been huge learning points that have resulted in a protocol change. I can’t overstate the value of doing this early on versus a third of the way through the study when everything is a mess. When the study is already well in progress and you only notice that something isn’t working, you have to stop the study and make a protocol amendment, nobody involved is thrilled.”

“By doing things like a protocol simulation visit upfront, it may take a day or even a week or two of planning, but it’s much better than doing a protocol amendment in the middle of the study that stops the whole process a third of the way through. By this stage it could take you as long as three months to rewrite the protocol and get IRB approval, and all that kind of stuff. So this is just one example of how working slow and steady can actually speed things up in the long run.”

Erin Silverman, Ph.D. CCC-SLP, CRCC, Research Coordinator and Adjunct Assistant Professor, University of Florida

“I can really see sites responding positively towards this. I think that if the sponsor negotiates the protocol simulation visit in from the very beginning (during budget negotiation), the sites will be onboard with the plan. I think that it’s one of those things that once a site does it once with one sponsor, they will push other sponsors to do it too, and have them include it into their budget.”

Follow myClin and Clinical Works’ official pages and stay tuned for our next article on inspection readiness. Catch up on the Clinical Innovators Summit with this recap video and join our next event at

By Adam Wood, VP, Business Development at myClin

About myClin: Are you really ready for an inspection? Start using the myClin platform to take control of intricate and error-prone study documentation. Keep essential information at your fingertips to stay audit-ready at all times. Get started with more free resources and a demo at

About Clinical Works: Are you ready to move faster and smarter with a high impact, curated ClinOps team? We help new bio-pharm ventures and start-ups bridge the gap from investment to clinical development. Find out more at