The complexity of the regulatory approval process for labels increases with each clinical phase, as patient numbers increase, from 10-20 patients in Phase 1, to 100-200 people in Phase II, to as many as 10 000 patients in a Phase III trial. As many Phase III trials are conducted across an increasing number of countries, the complexity of dealing with multiple regulatory agencies is magnified.

Because an IMP or AMP label must receive approval from a regulatory authority before a trial can begin in that country, there is little room for error.

A rejection due to an omission, oversight or translation error in the label text can cause a significant delay in starting the clinical trial in that country. This means that the translation and regulatory review process before submitting to a regulatory authority must be as robust and compliant as possible.

Competent Authorities may reject labels for a variety of reasons. The most obvious one is that the country’s labelling guidance and legislation have not been fully adhered to. To avoid such obstacles, it is often not enough merely to consult and follow the labelling section of a country’s legislation, which is usually in the public domain. For many countries, it is also necessary to be well acquainted with several other interconnecting laws. This is an area where submissions fall short and rejections on regulatory grounds occur.

Another example of a simple, yet common, error that may lead to labelling rejection is the improper presentation of the date of expiration. Some pharmaceutical companies prefer to keep the date uniform across countries, only to find that their labels have not been adequately localised and, therefore, rejected by several Competent Authorities. Special care must also be given not only to how the day-month-year format differs from one country to another, but also to how dates are punctuated. For example, using a hyphen is culturally unacceptable in some countries, while a forward slash is inappropriate in others.

Special care must also be taken to ensure that additional text required by individual countries is incorporated into the label design for that country. Germany, for example, requires additional information on top of the EMA requirements. Brexit will be a potential area for regulatory pitfalls for trials across Europe and the UK’s MHRA has already published what the likely labelling regulations will be in a no-deal scenario for study sites in the UK.

In summary, IMP and AMP label design and the underlying labelling process are critical components of clinical trial logistics. It is essential to understand the design process and to be aware of regional differences in order to create compliant practices and to prevent rejections by Competent Authorities.

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)
Guidance: Importing Investigational Medicinal Products (IMP) from EEA to UK, Medicines & Healthcare products Regulatory Agency, Gov.uk, 11th March 2019 [retrieved from: https://www.gov.uk/government/publications/guidance-on-importation-of-investigational-medicinal-products-from-approval-countries/importing-investigational-medicinal-products-imp-from-eea-to-uk ]

IMP labelling: Regulatory challenges