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.

European (EU) Variation Requirements

What is Variation:

Variation means any amendment to the terms of the decision granting the marketing authorization as well as any change to the summary of product characteristics and the documents forming the basis for an authorization to market a medicinal product.

European Commission has classified the variation type as type IA/IAIN, type IB and type II.

Type IA/IAIN (do and tell):

Changes that fall under this category are commonly referred to as “do and tell” variations because the applicant is required to implement the change and then notify the agency of the details.

This level of variation is reserved for administrative changes that are anticipated to have no impact on the quality, safety or efficacy of a product.

Variations that can be submitted as Type IA must be implemented and then the required submission made within 12 months of the implementation date.

 For changes that are categorized as Type IAIN the applicant must notify the agency within 14 days of implementation and for a single product multiples variation can be made at the same time, as long as all of them fall within the required submission deadline.

Type IB (tell, wait and do):

Minor variations that require assessment of supporting data and are anticipated to potentially have an impact on product quality, safety or efficacy are classified as Type IB and these are also referred to as “tell, wait and do” variations.

Type IB variations are minor variations, which are neither a type IA variation, a type II variation nor an extension.

The applicant must make the submission, including all required supporting data, and await agency approval before implementing the change.

The process follows a defined assessment period of 30 days, but with agency questions it can often take up to 03 months.

Post-Notice of Compliance (NOC) Changes

Introduction:

Following are the reasons for Post NOC changes:

·         To improve the quality of the drug.

·         To improve the efficiency of the manufacturing process.

·         To solve marketing issues.

·         Changes in the labeling of the drug for “warning” or managing the “risk factors” or limiting the “targeted population” or limiting the “dosage”.

These drugs may include pharmaceuticals, biologics, and radiopharmaceuticals for human use and pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary use.

Health Canada recognizes that:

·         any change to a drug may impact the safety, efficacy and quality of that drug and;

·         any change to the information associated with the drug (for example [e.g.], labeling) may impact the safe and effective use of that drug.

To manage the safety and risks of the public in using the drugs and foods, there are certain rules and regulations administered by “Health Canada”.

One important area of these regulations are administrative rules managing the “Post Notice of Compliance” (Post NOC) related to a drug.

Post NOC provides sponsors with recommendations on the data required to enable Health Canada to make an accurate determination of the impact of a change on the safety, efficacy and quality of the new drug.

Level of changes to a drug and subsequent obligations of the sponsor are as followings Levels:

ü  Supplements. (Data should be submitted to Health Canada for review prior to implementation.)

ü  Notifiable Changes. (Data should be submitted to Health Canada for review prior to implementation.)

ü  Annual Notifications. (Data should not be submitted but should be available to health Canada upon request)

ü  Record of Changes. (Data should be retained by sponsor)

Reporting Categories:

Level I – Supplements:

These changes to a new drug are “significantly different” as it relates to the matters specified in C.08.003 (2) of the Food and Drug Regulations and have the potential to impact the safety, efficacy, quality and/or effective use of the drug.

The changes included in this reporting category shall be filed, along with the recommended supporting data, to Health Canada as a Supplemental New Drug Submission (SNDS) or Supplemental Abbreviated New Drug Submission (SANDS).

The change may not be implemented by the sponsor until a NOC has been issued.