Over the past 10 years, the Clinical Trial Master File, or TMF, has evolved into a powerful and digital “single record of truth” known as the eTMF. This evolution of the eTMF was driven by the industry’s practical need to digitize all the essential documents of a clinical trial.
An eTMF itself is not an automation solution for managing essential documents. Think of eTMF as a highly organized electronic file cabinet. Even if you assign users rights to upload, approve or reject document versions, essential document workflow is still missing. Most eTMFs cannot track a document’s history, its edits or any collaboration around each document. That leaves the entire essential document workflow in manual mode without an automation solution.
Why is eTMF Automation Important?
eTMF automation represents an opportunity to cut millions of dollars in expense while ensuring that clinical trial regulations are followed with technological precision. When we talk about eTMF automation, we are talking about automating all the manual processes that move essential documents back and forth from the first site startup of a trial until the study is closed. eTMF automation must support digital document exchanges between the trial sponsor and the trial investigators.
eTMF automation workflow begins with a premise that there shall never be more than one copy of a document, regardless of the status of a document, or the number of collaborators that are involved. In an automated workflow, documents are not downloaded or uploaded by users. Instead, users work together in an online portal designed for clinical trial collaboration.
Automation improves trial speed, CRA productivity, site satisfaction, and provides a perfect audit trail of documents on their way into the eTMF. Automation also enables sites and sponsors to fulfill regulatory requirements that require sites to maintain their own TMF that mirrors the sponsor’s eTMF but keeps patient data hidden from the sponsor.
A typical study can involve millions of documents, hundreds of sites, weeks of collaboration, multiple revisions, eSignatures, wet signatures, complicated regulatory requirements, and many associates to manage the tons of paper that all end up in your eTMF. None of these processes require paper documents in today’s world.
4 Strategies to Automate your eTMF
There are 4 possible strategies you can consider to automate the complex and essential document workflow of a clinical trial.
- Wait and see if your eTMF vendor develops an automation product in the future
- Build in-house software customized to meet your company’s specific needs
- Contract with a large consulting company to lead the project and develop a solution
- Organize a project team to evaluate commercial software solutions
The Wait and See Strategy: Waiting to see if new automation solutions are delivered by your eTMF vendor will protect you from making a wrong automation decision today, but it won’t help you solve challenging compliance hurdles that are trending toward more auditing of essential document compliance in eTMFs and ITMFs.
The Build In-house Strategy: Building in-house software has some advantages, including more control over the software requirements and eventual ownership of a finished system without depending on a software vendor. But a disadvantage to this approach is that it could end up costing more money than commercial software and not provide the same product maturity a commercial product can provide.
The Consultant Strategy: This approach is most effective when your goal is to transform your business processes and redeploy human capital to become more productive and therefore more competitive. Consultants offer their clients the opportunity to rethink organizing people and processes. They are capable of making recommendations that should put your company on par or ahead of the competition. On the other hand, over the last decade, the number of consulting companies that specialize in creating software solutions for their clients has declined. More often than not, the technical and business challenges of a large company are mature and need only a little fine-tuning, not reengineering. Licensing commercial software has become a standard approach as companies try to avoid “reinventing the wheel”.
The Commercial Software Strategy: Organizing a team to evaluate commercial software solutions is a great strategy for multiple reasons. By watching a demonstration of commercial software designed to support eTMF automation, you gain insight into the dozens of ideas that other clinical trial sponsors have added to that product over the years. Additionally, you can view commercial software as a viable alternative to any other strategy. Look for a product that can save your organization money, improve your service level to sites, and always allow documents to be audit ready.
What Exactly Gets Automated?
Specific regulatory requirements must be adhered to during a clinical trial and essential document requirements can get complicated. An eTMF automation product must at a minimum automate the following document processes:
- Assemble and distribute the correct study startup package to each site, regardless of country, language, or local requirements.
- Support each document’s essential workflow requirement without the need to download or print any required document.
- Create a clinical site TMF that mirrors the sponsor’s eTMF and protects private patient data from being reported to the sponsor.
- Distribute safety reports to every applicable trial site, collecting acknowledgement electronic signatures from those sites where it is required
- Replace the current trial Protocol with an amended protocol document, collecting acknowledgement statements from every site.
- Convert a site’s paper documents with wet signatures into digital documents without the need for a scanner.
Each essential document has specific requirements for sending, receiving, acknowledging, collaborating, signing and storing. Moving those documents back and forth using postal mail, fax machines, or email messages is not automation. No matter how efficient your manual processes might be, in a manual system of SOPs, it requires a lot of human effort to keep essential documents organized and moving forward during a trial. Time, money and frustrated clinical sites make manual processes undesirable in a modern clinical trial.
InnovoCommerce has worked with several of the top 10 pharmaceutical companies for the past 7 years to design and build a commercial software solution that fulfills all the requirements of eTMF automation. Our product, the Study Collaboration Portal, plugs into any commercial eTMF system, and gives it the power it needs to automate its essential document workflow. Regardless of which strategy you choose to automate your eTMF, a deep dive into our commercial software will give your team the clarity they need to make an eTMF automation decision.
Novo Nordisk and Boehringer Ingelheim have automated the distribution and collection of regulatory documents from study startup to study closeout. We asked both companies to make the business case for paperless essential document workflow. Their feedback inspired this article: “The Top 10 Reasons to Automate Your Essential Documents.”
(Both Novo Nordisk and
Boehringer Ingelheim use software from InnovoCommerce to automate
their regulatory document workflow)
#1 – Update study documents faster
It is always faster to
update a digital document than a paper document. Consider the time it
takes to print an update to a study protocol, insert
the update into the protocol while archiving the old version, and documenting
those changes in an audit trail. Sponsor study teams and site staff could spend
an hour on a task that would have taken 10 seconds in a
paperless trial. Keep in mind that in this example, over the course
of a Study, the Protocol gets amended multiple times. So, going paperless has
an absolute speed advantage over paper.
#2 – Retire old document versions automatically
When you hold two paper
versions of the same document in your hand, it can be difficult to
identify which document includes the latest changes. During a clinical
trial, paperless systems retire old documents as the new document versions are
published, so you never have to discern which document is the newest version.
Paperless binders at a trial site are always up to date. This simplifies
CRA monitoring visits since there is no need to review a traditional paper
binder during their routine site visit.
#3 – Harmonize the document distribution process
The success of paper
processes is highly dependent on people to stay organized.
The standard operating procedure for one site could be vastly different at
other sites. Additionally, the sense of urgency to keep paper
processes moving along varies from site to site. When automated
processes are put in place, they keep things moving along according to
a unified process configured in the software system itself.
#4 – Speed up Study Start-up at every site
fact is, study documents are complicated. Paper complicates distribution
because paper moves slowly. And preparing a paper package requires meticulous
attention to detail, reviews by individuals, and finally some form of shipping
and receiving. For the study site, paper is received with all the other paper
that is used to run a business and is processed as time permits when patients
are not waiting in the lobby. But electronic study documents move at light
speed and are always in a highly organized state, dictated by the workflow of
the software system that moves the documents along. This shortens the time for
starting up the study at the sites, and site staff have more time to
focus on patient recruitment and care.
#5 – Decouple document collection
from site monitoring
paper documents, electronic document distribution and
collection is decoupled from site monitoring. Using an electronic
study document exchange system, the status of each document is
always known. There is no reason to call or visit the site to check the status
of a document or to make sure the site has filed all the paper artifacts
correctly. This saves time not only for
monitors, but also for the busy study site staff.
#6 – Find every document in one
world of paper is a complex set of processes and places. Most of these
processes have to do with moving the paper and most of the places are ad hoc repositories
(for example an email in-box), until eventually every paper document ends
up in the correct place. Electronic systems move the study
documents using workflows and keep every document in the
same repository while moving the document through each stage using distribution
requirements. This gives sponsors a huge cost savings while ensuring there is
only one record of truth pertaining to all regulatory study
#7 – Improve site satisfaction in a
By any measure, the elimination of paper at sites increases site satisfaction. Sites that use electronic systems provided by the sponsor or CRO never need to wonder what actions are needed by the sponsor, CRO or the site staff. Tasks are presented at the correct time and when action is required (like acknowledge or sign). Site staff is never asked to move regulatory documents from one place to another. They never need to print a document to sign it, and they never need to file a document since all of this happens automatically in an essential document shared system.
#8 – Reduce time required for Quality
a paperless system, documents are distributed, edited, and collected within the
system, creating an indisputable audit trail. The dates, times, user
identity, and various metadata of a document are recorded and updated
automatically. This removes a significant QA burden by
eliminating some QA checkpoints, and enables the quality assurance
staff to review and approve hundreds more documents each day.
#9 – Achieve a contemporaneous
The reason ICH introduced the concept of contemporaneousness is that in the past, many paper artifacts were found to contain curious details. For example, a signed document that shows the signer’s receipt date is later than the signers signature date. Paper-based processes are often paused for any number of reasons that have nothing to do with the clinical trial, leaving staff to try and catch up on work by signing with dates that “should” have been met. This can result in a sloppy TMF and could give regulatory inspectors a reason to look further into a trial’s accuracy.
#10 – Solve the completeness
biggest challenge to maintaining a state of completeness during a
study can be managing paper documents. Paper by its very nature is an
offline product that exists outside of the clinical trial itself. As the sites
get added to the trial or removed from the trial, the complexity of tracking
documents increases substantially. TMF managers even create “place holders” in
their eTMF for paper documents they expect to receive, and then run reports
showing the place holders so they can contact sites to request the missing
documents. In a properly designed electronic system, the expected
count of the study documents based on currently active sites is always known
along with the actual completion status of the document at any point in time.
The completeness challenge is solved because documents are never lost, delayed,
or missing. As soon as a document is signed, it appears in the QC work area,
ready for inclusion in your eTMF.
The transformation from a paper-based system to a paperless model in clinical trials is a goal at many clinical sponsors and research organizations. Connecting your eTMF to a clinical trial automation product is key to this transformation. The software product that helped achieve this goal at Novo Nordisk and Boehringer Ingelheim is the Study Collaboration Portal and can be further researched at www.innovocommerce.com
How to save millions of dollars during clinical studies by automating SUSAR distribution
Boehringer Ingelheim (BI) is one of the largest pharmaceutical companies in the world, and has lead the way in study treatments and cures in the areas of cardiovascular, oncology, respiratory, central nervous system, immunology and metabolic diseases.
BI conducts clinical trials to determine the safety and efficacy of its drug candidates. Real-world data gathered during a clinical trial is studied to determine whether a candidate drug merits further study and, eventually, whether the drug should be submitted to regulatory agencies in a new drug application (NDA).
Like every other pharmaceutical company, BI has either developed in-house software solutions or adopted commercial software solutions to improve both the speed and accuracy of every clinical trial. Without question, software plays a mission critical role in the effort to improve the conduct of clinic trials and ultimately to improve human health around the world.
While there have been industry-wide improvements in electronic data capture (EDC) and electronic trial master file (eTMF) technology, little has been done to improve the flow of essential documents during the study itself. During a clinical trial, essential documents move back and forth between trial sponsors, clinical research organizations, investigational review boards, clinical sites, investigators, patients, ethics committees and regulatory agencies.
Depending on the type of document, it may require edits, collaboration, signatures, acknowledgments, timely distribution and even mandated distribution timelines. That amounts to a high number of documents, distributions, and people involved, so companies need to rely on efficient and reliable systems.
The essential documents of any clinical trial are specified by the ICH (International Council on Harmonization) as mandatory to good clinical practices. While ICH guidelines describe more than 50 essential document types, the majority of clinical trials involve more than 100 essential document types.
Over the course of a clinical trial, hundreds of thousands of interactions with essential documents take place. The numbers are so vast that sponsors of large trials spend hundreds of thousands of man hours sending, receiving documents, editing, signing, approving, reviewing and storing essential documents. The human effort spent managing essential documents during a trial adds millions of dollars in cost to each and every clinical trial.
One type of essential document is the Suspected Unexpected Serious Adverse Reaction, or SUSAR. Each SUSAR report identifies a single patient’s unexpected and serious reaction to a drug being studied.
Depending on the severity of the reaction, a SUSAR report must be sent to regulatory agencies 7 to 15 days. In addition to agency reporting requirements, some countries require SUSARs to be shared with investigators studying the same drug, regardless of whether that investigator is involved in the same clinical trial. The sooner this information can be distributed to each clinical site investigating the drug in question, the sooner a decision can be made whether to continue investigating a drug, whether a particular patient should receive the drug, or whether one patient type seems to be more susceptible to side effects than another patient type. It is worth noting that reporting these events to principle investigators at clinical sites can be a matter of life and death for patients.
The BI team was also interested in the possibility of electronically distributing all SUSARs involving a drug under study to all sites conducting a study of the same drug. In the previous paper-based process, such wide distribution would have been impractical and even confusing to some investigators. BI determined that by using technology to automate the distribution of SUSARs, it could improve its own efficiency in reporting SUSARs to sites.
Considering the complexity of global and local regulations, short reporting deadlines, as well as the legal requirement to add previously unlisted adverse events to revisions of the Investigator Brochure (IB), there were many challenges to overcome in SUSAR distribution.
BI created an internal team to implement a change management process that would allow it to migrate from a paper-based workflow to an automated workflow. This change would reduce the workload on local affiliates and clinical sites by using the advanced workflow and distribution capability available in the InvestigatorFIRST™ software product. In doing so, BI were aiming to achieve timely service levels, oversight, and efficiency, while supporting further automation in the future.
Keeping in mind the goals of the project, BI configured the InvestigatorFIRST™ Study Collaboration Portal™ to mirror the ideal SUSAR workflow identified in the change management process workshops held by BI. Special configurations based on geography were categorized into IND Countries, expedited SUSAR countries and countries where distribution is restricted if the event origin is in the same country.
The process was simplified to achieve full transparency with the guiding principle that each investigator should get the same set of safety information. This meant that some Investigators in some countries would receive more SUSARs than regulatory agencies require. Because the Study Collaboration Portal™ could self-organized all SUSARs, it was determined that investigators would not be burdened by a more complete SUSAR distribution.
Enabling centralized distribution of all SUSARs to all applicable investigators at all applicable sites dramatically improves an investigators ability to gain insight into the safety of a particular drug for a particular patient.
Quality checks were also added at various workflow steps to ensure that all received reports (from the pharmacovigilance team) are actually distributed, the assigned drug and the target audience matched, and cross reporting rules are consistently followed by the software.
The final distribution logic configured in the software workflow was implemented with an appropriate notification period to users. A dedicated audit role created in the Study Collaboration Portal™ allowed BI to conduct real-time compliance tracking to support oversight of distribution timelines.
The system was also configured to automatically distribute all other study safety documents including: Periodic Safety Reports, Dear Investigator Letters, Startup of Safety Report Distribution Letters, Expedited SUSARs, Expedited SUSAR Translations, SAEs, and SESARs (Suspected Expected Serious Adverse Report).
During the four year period since BI implemented the InvestigatorFIRST™ Study Collaboration Portal™, the automated SUSAR workflow has governed each of its clinical trials and based on each drug under investigation, every investigator has received the appropriate safety information during a clinical trial, achieving the goal of a harmonized process capable of handling exception scenarios. The process was also demonstrated in detail to the US FDA during a meeting with BI’s global pharmacovigilance team.
Not only have compliance timelines been consistently met since adding SUSAR distribution to BI’s Study Collaboration Portal™, but many productivity gains have been achieved, including all received reports being distributed without manual processes, assigned program and target audiences are always correct, cross reporting rules are automatically followed, and every trial is inspection ready at all times.
By any measure, BI’s Study Collaboration Platform™ developed by Innovo Commerce has been a runaway success for Boehringer Ingelheim.
Not only is regulatory compliance achieved in real-time, productivity gains can be measured in hundreds of thousands of man hours per year. The Study Collaboration Portal™ has been in place for four years and has been credited with saving BI tens of millions of dollars each year.
Today, all clinical trials are conducted in an advanced state of completeness employees and other associates of BI are more productive and no longer spend countless hours distributing tens of thousands of documents of all kinds throughout each clinical trial.