Comparison of EU and US variation requirements

 Key points in regulatory management of variations

• Lifecycle management of pharmaceutical products varies between the EU and US in terms of different submission requirements and assessment timelines. However, similarities do exist in regional approaches to a general categorization of post-approval changes (variations) and in many cases also the principles of implementation.

• Post-approval variations in the EU and US can be administrative in nature, simple changes requiring minor review, or major changes that are often complex.

• Administrative: EU regulators go as far as to define “administrative” as a category in their classification guideline, whereas in other regions they fall into the lowest variation category and have significant crossover with minor variations, e.g. new addresses. Many agencies accept that these changes can be implemented without the need for approval. Prior approval of administrative changes is time-consuming for agencies and costly for industry. Additionally, in certain cases such as a marketing authorization holder (MAH) moving address, the change would actually need to take place prior to submission.

• Minor: Minor variations are generally considered to have either no impact on the quality of the product or have a very low chance of impact; and hence lower risk. Consequently, the level of agency review, and hence the time required is reduced. As regulatory frameworks have developed, agencies have introduced means to allow the most minor of variations to be implemented before review. For example, in the EU, when a Type IA variation is submitted the MAH must state which of a pre-defined list of conditions applies to its change, thereby reducing the amount of review required. With minor variations, many agencies have documentation requirements that are well-established and must be met before variations are submitted. This ensures that MAHs know what is expected before a submission and can prepare sufficient supporting data. This leads to faster review times as assessors have less need to request further data from applicants.

• Major: Where notable alterations to product registration are required, these are expected to have an impact on a product’s quality and efficacy and as such are tightly controlled, requiring in-depth assessment and review. The MAH must demonstrate that the product will retain the same level of quality and efficacy. Comparative data is a significant requirement for such changes and must reliably show the proposed changes do not impair product quality. Assessment times for such variations are often much longer, as agencies carefully review submissions and frequently make requests for additional data and answers to questions and concerns.

Table 1: Summary of variations and anticipated implementation dates in Europe and US.
Europe				US
Variation	Type	Anticipated implementation time	Guideline approval timeline	Type	Anticipated implementation time	Guideline approval timeline
Admin	Type IAIN	14 days before submission	N/A	AR	Up to 1 year before submission	N/A
	Type IA	Up to 1 year before submission	N/A
Minor	Type IB	Up to 3 months after submission*	30 days	CBE-0	On receipt of submission by FDA	N/A
				CBE-30	30 days after receipt of submission	6 months
Major	Type II	Up to 6 months after submission*	30 days	PAS	Up to 6 months after submission*	4 months
*The noted anticipated dates are based on experience with submitting variations to the relevant agencies and incorporate the time taken for validation, application assessment, applicant’s response to questions (clock stop) and assessment of responses.