Great Expectations for the eTMF

 We all want more out of our electronic trial master files (eTMF). More functionality. More strategic capability. Better business process. That’s the word from Sharon Ames, Enterprise Program Director for NextDocs, a provider of eTMF and compliance solutions. Ames is referring to the fact that the eTMF industry is starting to mature, and has evolved beyond the early adoption phase from several years ago, when discussions focused mostly on the transition from the paper trial master file to an electronic version. 

 

According to Ames, “Making the move to electronic is a goal of many companies that are still using paper, but now, people expect more. The eTMF is not just an electronic document repository anymore.” 

 

Sharon Ames

Specifically, Ames says that stakeholders are now viewing the eTMF as a document management system that allows users to author documents at the beginning of the study and optimize business process for functional contributors along the way. Also, the mature eTMF customer expects to use the metadata associated with the documents to provide valuable business insights. “By looking at the metadata, companies can assess factors such as cycle times for document completion, and identify issues in document processing by person, study, country, or region,” Ames explains. 

 

From the sponsor’s perspective, the eTMF is seen as housing a wealth of data, and tapping into it is the next horizon. “This is exactly where the dialogue is,” says Ivan Walrath, Trial Master File Business Process Owner at Pfizer. “As we move past the eTMF as an electronic file cabinet, we are just starting to understand that we have a great opportunity to use all of the data in the eTMF, that it has incremental business value. We can do analyses on issues in clinical trial execution that we see are trending, such as, are there issues with the protocol? With CRO performance? With site performance? We’ve got all of this data to mine. How can we use it?” asks Walrath.

 

Walrath comments that Pfizer first implemented an eTMF in 2000, but updated to a more full-featured version built in 2011 by Wingspan, an eTMF provider. With its current eTMF, Pfizer is working to tap the extensive information it houses, which Walrath says offers two key benefits. “First is benefiting from the overall visibility, transparency of the completeness of the eTMF. Second is using the information and metadata to identify potential areas of concern that the company would want to investigate,” He explains further that anticipated improvements aren’t so much about cycle time issues, as they are about limiting or avoiding rework. For example, reducing the numbers of missing documents throughout the trial, and making sure all of the documents have the proper electronic signatures are hugely helpful instead of waiting until the study ends to discover these rework issues.

 

Walrath says the biggest challenge to implementation was not the technology, but changes to business process focused on continuous improvement. Given these changes, Pfizer has attempted to quantify improvements linked to the eTMF. Walrath says that in the 12 month period following implementation of the updated eTMF, the company saw a 50% improvement in eTMF quality, as measured by completeness and accuracy. He adds, “Definitely, going forward, Pfizer plans to keep more metrics.” 

 

The eTMF, the electronic version of the essential documents that enable the conduct of a clinical trial, mostly started as web-based and was maintained on in-house client servers. As technology has evolved, eTMF providers have cloud options, which offer increased visibility among stakeholders, an ability for documents to be always audit ready, and capability for functioning as a business planning tool, all without having to maintain the IT infrastructure in-house. Ames of NextDocs says, “Everybody wants to have the cloud conversation. People aren’t fearing the cloud the way they were a year or two ago.” 

 

Ivan Walrath

But there is a long way to go in eTMF acceptance. The 2013 NextDocs State of Trial Master File survey indicates that 28% of respondents are still using paper systems to handle clinical trial documents. Twenty-four percent report using a commercial eTMF; 22% use a shared file system; and 20% use a hybrid approach. But other data indicate that the eTMF is gaining traction. Results from the 2013 survey from the Drug Information Association (DIA) TMF Reference Model group show that 13% of respondents use a fully electronic system, as compared to 7% in 2010. The hybrid paper/electronic approach is proving popular, with 42% of respondents reported using it, versus 27% in 2010. 

 

Walrath observes, “We have seen a dramatic shift in the past four years. When we go to TMF summits, the dialogue four years ago was that everybody was using paper or people were scanning in documents. Now, many are in the middle of the transition to eTMF, and we are starting to see the dialogue around the incremental business value that it offers.”

eTMF

Hello eTMF

Study: Side Effects Emerge After Approval For Many U.S. Drugs

Almost one-third of new drugs approved by U.S. regulators over a decade ended up years later with warnings about unexpected, sometimes life-threatening side effects or complications, a new analysis found.

The results covered all 222 prescription drugs approved by the U.S. Food and Drug Administration from 2001 through 2010. The researchers looked at potential problems that cropped up during routine monitoring that’s done once a medicine is on the market. The 71 flagged drugs included top-sellers for treating depression, arthritis, infections and blood clots. Safety issues included risks for serious skin reactions, liver damage, cancer and even death.

“The large percentage of problems was a surprise,” and they included side effects not seen during the review process, said Dr. Joseph Ross, the study’s lead author and an associate professor of medicine and public health at Yale University.

While most safety concerns were not serious enough to prompt recalls, the findings raise questions about how thoroughly drugs are tested before approval, said drug safety expert Thomas Moore. But Ross said the results suggest that the FDA “is kind of doing a great job” at scrutinizing drugs after approval.

New drugs are generally tested first in hundreds or even thousands of people for safety and effectiveness.

“We know that safety concerns, new ones, are going to be identified once a drug is used in a wider population. That’s just how it is,” Ross said. “The fact that that’s such a high number means the FDA is working hard to evaluate drugs and once concerns are identified, they’re communicating them.”

The researchers analyzed online FDA data on new drugs and the agency’s later safety announcements. Problems surfaced on average about four years after approval. Results were published Tuesday in the Journal of the American Medical Association.

The FDA said in a statement that it performs post-market monitoring “to identify new safety information that may impact product labeling.” The agency said it would review the study findings but declined to comment further.

The study counted black-box warnings for dozens of drugs; these involved serious problems including deaths or life-threatening conditions linked with the drugs. There were also dozens of alerts for less serious potential harms and three drug withdrawals because of the potential for death or other serious harm.

Among the drugs with added warnings: Humira, used for arthritis and some other illnesses; Abilify, used for depression and other mental illness; and Pradaxa, a blood thinner. The withdrawn drugs and the reason: Bextra, an anti-inflammatory medicine, heart problems; Raptiva, a psoriasis drug, rare nervous system illness; and Zelnorm, a bowel illness drug, heart problems.

Safety issues were most common for psychiatric drugs and biologic drugs — made from living cells rather than chemicals — than for older drug types. Drugs brought to market through “accelerated” approval were slightly more likely to have later safety issues than those approved through conventional channels, a link seen in some previous research.

In recent years, there has been increasing pressure on the FDA from consumers and others to speed up its regulatory review process to get new drugs to the market sooner, Ross said.

Moore, a senior scientist for drug safety and policy at the Institute for Safe Medication Practices, said the new results raise concerns about whether new drugs are being extensively tested before approval. He noted that since 2011, drugs have increasingly been approved based on studies in small numbers of patients amid public criticism questioning whether the FDA is keeping potential cures away from patients.

“The answer is, you can’t know whether they’re valuable and lifesaving treatments unless you test them” adequately, Moore said.

PhRMA, a drug industry trade group, is reviewing the study, said spokeswoman Holly Campbell. In a statement, she said the industry is committed to post-market surveillance of new medicines, but added, “Even with rigorous clinical studies and regulatory review it may be impossible to detect certain safety signals until several years after approval, once the medicine is in broader use.”