Over two-thirds of clinical studies are carried out outside of the USA. It is not unusual for Phase III trials, in particular, to be carried out in over 30 countries across five continents. More study sites outside of North America and the UK and EU region are being introduced each year, including in countries like Georgia and Guatemala.

With the proliferation of clinical studies happening across borders, pharmaceutical companies need to anticipate the multilingual and multicultural aspects in all aspects of clinical study planning. This is especially so for the labelling of Investigational Medicinal Products (IMPs), owing to the complex regulatory issues associated with them.

An Investigational Medicinal Product (IMP) is the pharmaceutical form of an active substance or a placebo that is being tested in a clinical trial. An IMP can also be a medicine that has marketing authorisation and is already available commercially but is being trialled for a different indication other than its approved commercial use, or for an indication that is not included in the product’s Summary of Product Characteristics.

Not all medicines that are used in a clinical study are being tested. Featuring alongside IMP is the Auxiliary Medicinal Product (AMP), known in some countries as ‘Non-Investigational Medicinal Product’ (NIMP). An AMP is a medicine that is made available to study subjects as a support drug, a rescue/escape medication or for preventive, diagnostic or therapeutic treatment during the trial. These medicines are usually specified in the study protocol and they often already have marketing authorisation in the study country. However, in some cases, they have not yet received approval in specific study countries. Therefore, special approvals are usually requested to use these auxiliary medicines for the sole purpose of the trial. Some regions, such as EMA, have specific labelling requirements for AMPs.

In clinical studies, pharmaceutical companies use labels to provide important information to stakeholders. These labels must include instructions for use, mode and route of drug administration, product strength, storage requirements and expiry dates, amongst other information.

Each label is unique to the individual patient and must also be specific to the trial and country in question. If a patient experiences a severe reaction, the study sponsor needs to be able to trace what was given to that patient. For blind studies, labels for placebos must appear identical to the labelling of the active product, while still being identifiable to the trial sponsor. This traceability is achieved via a unique identifier that is contained in the label.

Regulatory authorities around the world require all IMP labels to be designed according to guidelines and affixed to all study drug packaging, such as study kit boxes and shipping boxes. In order to design label content to meet differing regulatory requirements of each study country, the labelling process must be planned at the earliest possible stage. In addition, some Competent Authorities, such as EMA, have one set of regulations for IMPs and another for AMPs.

According to clinical best practice, a study protocol outlining the specific requirements of the clinical trial is compiled when the product is ready for testing. As part of this protocol, the pharmaceutical company determines the countries where the drug will be tested, as well as the languages in which the labels will be presented. This means that the label contents of both IMPs and AMPs need to be checked against each country’s labelling requirements for clinical trials. Once the label content is approved, the regulatory reviews and translations can be completed.

At this point, the pharmaceutical company must submit the labels and gain approval from regulatory agencies in each study country.

The next article deals with some of the regulatory challenges that may arise with IMP / AMP labelling.

By Mark Gibson, Health Communication Specialist

21st September 2019, United Kingdom

References:

Auxiliary Medicinal Products in Clinical Trials, European Commission, 28th June 2017
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 13: Investigational Medicinal Products, February 2010
Guidelines: Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014, European Commission, 8th December 2017
EFPIA position paper: EU Clinical Trial Regulation Annex VI: Labelling of investigational medicinal products and auxiliary medicinal products – impact on patient safety and validity of study data, EFPIA, 4th August 2014
Gaffney A., New Data Show Clinical Trials Conducted Outside of US, EU Have Nearly Doubled since 2005, Regulatory Focus, 9th April 2013.
Kane A, Williams J, Yeo L, Clinical Trials in Europe: An overview of quality requirements, Regulatory Rapporteur, July-August 2008.
Weyermann A, Labelling Requirements for Investigational Medicinal Products in Multinational Clinical Trials: Bureaucratic Cost Driver or Added Value?, Rheinischen Friedrich-Wilhelms-Universitat Bonn, 2006 (Published Master’s Thesis)

Investigational Medicinal Product labelling: an overview