RSSBy Paul Thomas, Senior Editor
Anyone who's ever run a clinical trial in the EU, Canada or in a number of other locations worldwide, knows the headache of dealing with use-by dates — aka "retest dates."
In short, product must be retested as it approaches expiry to make sure it is still safe and efficacious for trial use. Assuming it is, a new retest date is assigned. The new date, and the data to support it, must be submitted to regulatory authorities well in advance of the original retest date to allow for review of the data. Simple enough? If the manufacturer fails in this obligation, the trial can be suspended.
The retest date requirement isn't so much of a nuisance as it is a roadblock. The cost of dating and re-dating clinical trial products can run into the millions, not to mention take staff away from the work they really should (and would rather) be doing.
This hasn't been an issue with U.S. trials. FDA has long allowed manufacturers to provide an electronic or other means to indicate their confidence to sustain and control expiry dates. A typical solution would be a system that allows the manufacturer to enter a manufacturing date by lot for a product, at which time the system would automatically calculate a retest date based on pre-defined criteria. The system would then send an email alert when a batch is due to expire. The system might even process retest date extension requests and approvals.
Fortunately, a breakthrough with OUS regulators may be on the horizon. Progress has been made, thanks to a joint ISPE/FDA task force that has been advocating for change for the last year. ISPE task team members represent Pfizer, Eli Lilly, Evidence CPR, Fisher Clinical Services, Aptuit and AstraZeneca. PDA members are from Novartis, Lilly, Boehringer-Ingelheim and Wyeth.
From the beginning the group's goal was clear: Is it feasible to remove test dates from IMP (investigational medicinal product) labels, and can we convince regulatory bodies that we're able to do it effectively?
A survey given to company representatives at the 2007 ISPE show in Las Vegas found this to be a major issue for most of the 60-plus respondents. Five anonymous respondents said that their companies were already supplying materials in the EU without retest dates — that is, they felt confident that they already had the technology in place with which to be fully compliant.
For most trial operators, it's a cost and quality issue — a Quality by Design issue, if you will. "We want to get more effective and efficient," says Christine Milligan, Director of Client Services for Fisher Clinical Services, who led a discussion session on the topic at the recent ISPE annual meeting in Boca Raton, Florida. "For all our people in [clinical trial] operations, they would like a much more efficient process. Is the process we currently use really adding value?"
A look at EMEA's Annex 13, which defines the information that must be put on the labels, including period of use, shows that there is room for change: "The following information should be included on labels unless its absence can be justified."
There is also precedent. Two major manufacturers have direct and published experience of working with EU regulators to get relief from the labeling requirement. "Already we have the opportunity to look for a better system than physically putting retest dates on labels," says Milligan. Justification is typically done in the regulatory submission.
As the joint task force continued its work, it realized that the blame for the retest date headache was not only with regulators. As those two manufacturers demonstrated, regulators are willing to accept change. As the task force learned, sometimes their own Quality Assurance teams and Qualified Personnel are resistant to forego the retest requirement.
"We are our own worst enemy," says Milligan. "You've got to sit down with your QA and QP people and discuss this with them."
The task team has a few main objectives to create change: to understand the relevant technologies that can be used to advance current retest methods, and to create a proposal to take to "Competent Authorities" to justify the need for change.
So far, the group has already communicated their objectives with EMEA and other regulatory bodies. It has sent two letters, one from PDA and one from ISPE, to EMEA and the Clinical Trial Facilitation Group (CTFG). Both letters were well received.
Now, the group is identifying appropriate processes or technologies that will provide the appropriate level of control and ensure patient safety — which includes the accurate and immediate identification and location of supplies down to the patient level, Milligan states.
It is also benchmarking and collecting data related to the successes and failures for avoiding retest dates on IMPs. It continues to share these findings with the Competent Authorities, and these discussions are serving as the basis for a guidance document. (The most recent document can be accessed by ISPE members at http://cop.ispe.org/cop/IPCOP.)
Next steps include receiving written feedback from the authorities and then moving forward to publish the guidance formally, perhaps even by the end of 2008, Milligan says.
If approved, the guidance will need to be communicated clearly to investigational sites in Europe and elsewhere, Milligan notes. Some manufacturers have chosen to pass the information through their clinical research associates to their investigational sites, but there are likely other effective methods as well.