US FDA Eyes New Investigational Drug Label Requirements That Bring International Harmonization

To help reduce medication errors that can harm patients and compromise research results, FDA – pushed by clinical trial sites – looks to exert more control of the labels of investigational drug products.

The US Food and Drug Administration is considering new regulatory action to create more consistency in the labeling of investigational drugs to help reduce medication errors and protect patients as well as the integrity of the clinical trial results.

The agency is looking at recommending a harmonized global approach to the issue.

Recent studies that have pointed to missing or confusing information on investigational drug labels as a contributing factor for medication errors have recommended global harmonization of the labels, said Gerald Dal Pan, director of the Office of Surveillance and Epidemiology in FDA’s Center for Drug Evaluation and Research at an 18-19 May agency meeting held with the Reagan-Udall Foundation for the FDA on the topic.

“A creation of minimum best practices for investigational drug labels, aimed at reducing medication errors,” might be able to address the varied requirements for medication error reporting and investigational drug labeling among different regulators, added Lubna Merchant, Deputy Director of the Office of Medication Error Prevention and Risk Mitigation in CDER.

“This would certainly benefit our patients, but can also benefit the pharmaceutical industry by decreasing the regulatory burden on manufacturers that produce drugs for the global market.”

One avenue for new FDA recommendations could potentially come in upcoming guidance for sponsors and investigators on responsibilities for IND safety reporting, which is due out this year per FDA’s 2021 unified agenda, the agency indicated at the meeting. 

The potential changes and the FDA/Reagan-Udall meeting were partially motivated by concerns and pressure raised by clinical sites about problematic labeling and in some cases completely missing labeling or “naked containers.” The sites argue they bear the brunt of the work that comes from navigating inconsistent product labels.

The clinical sites said common problems include missing information, labels with too much extraneous information that make it difficult to find key information, illegible font sizes, and protocol and investigator brochures that don’t align with the naming information on the label.

Other issued raises by sites include the “license-plate naming,” of products with a combination of letters and numbers that change over the course of a study or are too similar to other study drugs. Drugs that change hands from one sponsor to another during development often experience labeling issues, the sites said. Another problem is that labels are often formatted with keys or legends that lack clear explanations for pharmacists.

Richard Needleman of Fox Chase Cancer Center presented slides with standardization recommendations from sites for oral and vial labels including information on font size and presentation, minimum required information and technology elements like barcode requirements.

While the agency has detailed requirements for approved product labels, there are much more minimal standards for investigational products. Those requirements are that labels of an investigational drug must include specific language indicating the product’s investigational status, the label must not contain any false or misleading statements and it must not contain any messaging indicating the drug is safe and effective for the use it is being investigated.

At the Reagan-Udall meeting, the agency acknowledged its division of medication error prevention and analysis (DMEPA) also does not currently review content of labels for investigational drugs.

Another gap in regulations is that medication errors that do not result in an adverse event may be reported to FDA in inconsistent ways.

While FDA does see some adverse event reports due to medication errors in trials, the agency knows from postmarket experience that these errors “often go unreported, said Jo Wyeth, postmarket safety program lead in CDER. “The reports that we receive are often just the tip of the iceberg," Wyeth said.

And for multicenter trials it is not clear that medication errors are shared with other sites to mitigate additional risks, she added.

Sites Push For Labels That Look More Like Marketed Products

The regulatory holes means that clinical sites are often left on their own to address inconsistent, unclear, and missing information on labels.

“Currently, site pharmacies are taking the primary responsibility in preventing untoward events by using various workarounds to prevent errors. Patient safety must not rely on workarounds. There needs to be uniform labeling regulation and guidances so that clinical sites aren't the gatekeeper,” said  Neddlman.

Smaller clinical sites might not have the staffing, expertise, or redundancies in place to catch the errors that might occur because of poor labeling, added Raymond Muller of Memorial Sloan Kettering Cancer Center.

“The bottom line is that we need to standardize our practice. We really want investigational drug labeling to be as close as possible to what the FDA approval package looks like,” Muller said.

CROs Want Non-Regulatory Path For Improvements

Contract research organizations and sponsors were open to some changes but with caveats suggesting that improved labeling and harmonization might better occur through more voluntary collaboration rather than regulation.

“Bringing in intense regulation in this area may not be the way to go forward,” said Neil McCullough, of IQVIA Holdings Inc. “I always assumed that one of the key things  that was really beneficial around FDA is that there was a relatively light approach from a regulatory perspective, which lends to innovation and flexibility. Unfortunately, the downside of that can result in either lowest standard approach as well. But I think to try and regulate it down to a finite detail would in some cases grind the process of the labor and the supply chain, and changes within it to a halt.”

“Industry is definitely wanting and willing to work to improve this," said James Duhig, director of patient integration at AbbVie Inc. Reducing medication errors is cost-effective as they introduce noise into the data and cause trials to take longer, he said.

But exactly what is standardized and harmonized matters, sponsors at the meeting said.

“Harmonization of things at the quality system level is going to be overly complex, given the complexity of global supply chains, the number of sites, the size of companies,” said Alexander Mills, director of combination product development at Merck & Co., Inc.

“Harmonization in terms of principles, identification of medication errors, better awareness of coding errors and getting them into the databases appropriately so they become searchable across all phases of development, I think is important and a goal,” along with harmonization of practices, Mills said.