Read the small print

Labels on investigational drug packaging represent one of the key elements of effective preparation for clinical trials. Without accurate and essential information, the labels can become a weak link in the chain that ideally leads to successful trials for new medication.

The consequences of poor labelling could be severe for the patient, who may suffer adverse effects from the wrong dose or application. If patients are participating remotely, it might be difficult to reach a health professional to ask their advice. These issues can be especially complicated in blinded trials, where patients are given minimal information about the drug they are taking.

Inaccurate labelling can also have a knock-on effect on clinical trial sponsors, for whom mistakes could cause the results of a trial to be inaccurate, meaning they lose the resources they have invested for very little gain. It always takes a significant financial commitment to set up a trial, and to see it through to a successful conclusion. If a trial fails because of flawed labels, which can be easily avoided, then it could prove to be a very expensive error.

Cynthia Tanguay, who was the lead author of a study by researchers from the Practical Pharmacy Research Unit at the Sainte-Justine Hospital Center in Montreal, (investigational drug labelling variability), says that labels vary greatly in the reliability of the information they contain. She believes that international standards are needed to ensure all countries comply, and that there is a consistent standard that’s met.

She also says: “With trials being conducted in multiple countries, study drugs often have labels that would work for many different countries, so they contain many pages (the label is often a multiple-page/multiple-language leaflet attached to a container), and the information can be hard to find.”

“Some sponsors differentiate their product with various strategies, but there is no standardisation across different companies,” added Tanguay, who is also pharmacy research coordinator at the Centre Hospitalier Universitaire (CHU) Sainte-Justine.

Better safe than sorry

The Montreal study found that the lack of international regulations covering drug labelling on investigational drugs used in clinical trials, meant that errors were made at different stages in their production and distribution. Mistakes in the labelling could be introduced, for example, at the point of dispensing, or when the medication is being stored prior to distribution.

The researchers found that errors on labels included no expiry date and storage instructions missing. There was also a variety of different presentations on labels, such as bold characters and empty space to make them easier to read, which were often not used.

Tanguay explains how new international guidelines could be introduced: “Canada has distinct regulatory requirements for clinical trial drugs labelling, and this is independent from the ICH (International Council on Harmonisation) GCP (Good Clinical Practices) requirement.

“The ICH GCP are adopted by most countries in order to standardise the way clinical trials are conducted. Labelling could be addressed there. I’m not an expert in other countries legislation, but I’m sure that they also have distinct regulations which explain why sponsors are using labels with so many pages and information in them,” she continues.

“Other organisations not specific to clinical trials such as ISMP (Institute for Safe Medical Practices) exist to reduce the risk of errors with drugs, and their standards could be useful for clinical trials. I’m thinking for example of ‘tall-man lettering’, which is seldom found on clinical trial labels.”

Matthew Grissinger, director of education at ISMP in the US, agrees that some guidelines are much needed.

“There are no regulations that dictate the labelling, and that is a pretty fundamental problem,” he says. A clinical trial may be testing a fantastic drug, but if there is an error caused by poor labelling then we may never know how good it is.

Grissinger points to a public meeting in May last year organised by the US Food and Drug Administration, which discussed error risks with investigational drug container labels, as a cause of optimism that the problems are being addressed.

Pharmacists and researchers, who contributed to the meeting, highlighted a list of labelling risk areas, including missing drug names, missing or hard-to-find information on the strength of IMPs, small font sizes, and unsafe abbreviations and dose expressions. A representative from the FDA told the meeting the purpose was to hear about the experience of professionals working in clinical trials.

“We have received medication error reports associated with investigational drugs, and we are aware of global regulatory differences for labelling investigational drugs and medication errors. And we understand that the situation can be improved,” he said.

A needle in a haystack

Draft guidance around the reporting of clinical trial safety issues in the US was published by the FDA in September 2021, but it did not cover labelling. A spokesperson for FDA told Clinical Trials Insight that there were no immediate plans to introduce guidance on labelling.

Only the World Health Organisation could produce global guidelines, says Grissinger, but he doubts that will happen as it has other priorities at present.

He highlights the common use of bottle containers for medication instead of boxes or packets for clinical trials, as a problem, as everything depends on the label to ensure the patient takes the correct dose. It is easier to ensure the right dose is taken if the tablets are in ‘unit-dose’ packets, which can help to identify how many should be taken each time. Sometimes drugs are supplied in multiple vials, he says, which is “asking for trouble”, as it could lead to an overdose.

“Atrociously small” font sizes on labels, and the over-use of numbers to identify details such as the patient’s name and the dose, are serious issues, adds Grissinger.

The ISMP itself has highlighted a list of concerns in its regular newsletters, which include the issues Grissinger describes, as well as others. Some investigational drugs come without an expiration date because it may change during a trial. They ask participants to call an interactive voice response system, which is time consuming, the ISMP says, and in some cases drugs are being used beyond the expiry date.

It is a “low priority” for some trial sponsors to ensure they are using safe labelling, the ISMP says, and this is also the case when outside companies run the trials for sponsor companies. Clinical sites are advised by the ISMP to return or destroy any drugs that arrive without labelling.

Another examination of investigational drug labelling published by the National Center for Biotechnology Information in the US, (The Near- Term Viability and Benefits of eLabels for Patients, Clinical Sites, and Sponsors), also found that there was often poor use of large font sizes for the print, which would make it easier to read, and the text was not spaced well on the label. Regulations in some countries prevented a reduction in the amount of information on a label, the researchers found.

They recommend a more ‘patient-centric’ approach to labelling so that clarity of information provided to patients is as clear as possible. They say the industry needs to start laying down these conditions now as a foundation for the future.

Perhaps, ensuring that the patient is always the prime consideration at every stage of a clinical trial, is a principle worth sticking to.

Recommendations from the ISMP for improvements include:

• Select and approve a standardised identifier for a new investigational drug that is unique and distinctive from other investigational drugs and the protocol number.
• Assign a generic drug name as early as possible, preferably before the investigational drug begins Phase II trials.
• Perform a risk assessment on the new investigational drug’s name, labelling, and packaging to identify any potential risks that might result in medication errors.
• Never refer to an investigational drug solely by its protocol number, IRB number, study acronym or title, investigator’s name, or other common name.
• Package oral investigational drugs in patient-ready unit-of-use packaging (for example, no large bulk bottles of 1,000 capsules that need to be repackaged for multiple patients, but rather patient-specific bottles of capsules containing exactly one-month’s supply).
• Package parenteral investigational medications in vials/containers in the size and volume that best corresponds to the dosing, so that dozens of vials/ containers or serial dilutions/aliquots are not required for single doses.
• For label text on product containers, use a font size of eight or larger, and make the drug name and strength most prominent. Use tall man letters to help distinguish look-alike names. Avoid extraneous information and known error-prone abbreviations and dose expressions.

Source: ISMP