Regulatory Requirements in US and EU: A comparative view

As you may know, pharmaceutical products are highly regulated.

However, the different regulatory requirements in various regions impose obstacles when considering expansion into other markets.

These difficulties have sometimes prevented new drugs from reaching patients in a timely manner.

Inter-regional co-operations were begun to harmonize international coordination, leading to the International Council of Harmonization (ICH).

In the US and Europe, most ICH guidelines have been incorporated into regional regulations.

In particular, ICH guideline M4 regulates the Common Technical Document (CTD) format, which is provided electronically to the evaluating health authority.

These incorporations take the form of US Guidance for Industry and Europe Notice to Applicants.

The Food and Drug Administration (FDA) in the US is responsible for food, drugs (including medical devices) and cosmetics regulation. The European Medicines Agency (EMA) in Europe only regulates medicinal products that qualify for centralized procedures and all regulations in Europe need to be coordinated between the member states.

Relationship between industry and the regulatory agency in Europe and the US is also largely different. In Europe, the pharmaceutical industry approaches the health authorities with trust, while in the US, the FDA approaches the industry from a more demanding position, requiring raw data and GMP documents and examining them in detail.

It is therefore crucial to keep these distinctions in mind while comparing the CMC dossier requirements for these two locations in order to comprehend their various needs.

Overview of differences:

The main differences between the two health authorities are the mindset and focus of the respective health authority, as well as tradition and legislation already in place before harmonization processes began.

The FDA assessors expect an amplitude of data to evaluate and draw a complete picture, while the European assessors expect an application which guides the evaluator through the critical aspects of the product.

An application to the FDA is more data driven and a submission in Europe contains large portions of narrative, selects the data to be provided and abstracts information from GMP sources rather than presenting them directly.

1. Regulatory Framework

- FDA (U.S.): Governed by the Code of Federal Regulations (CFR) and guidelines issued by the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). The FDA follows its unique process for reviewing New Drug Applications (NDAs) or Biologics License Applications (BLAs).

- EMA (Europe): The EMA operates under the European Union Directives and Regulations, specifically following the EU Clinical Trials Regulation (CTR) and Directive 2001/83/EC. The Committee for Medicinal Products for Human Use (CHMP) evaluates marketing applications, and the EMA coordinates approvals through a centralized process applicable to all EU member states.

2. Submission Format

- FDA: The FDA mandates submissions in the eCTD (Electronic Common Technical Document) format, which includes modules 1 to 5. Module 1, which is regional-specific, contains the administrative and prescribing information. For the FDA, the data submitted in Module 1 needs to be very detailed, covering extensive product labeling, patent information, and specific U.S. regulatory information.

- EMA: The EMA also follows the eCTD format, but its Module 1 focuses on EU-specific requirements, such as product information for all EU languages and specific regional application forms. Module 1 for the EMA often includes national considerations, such as pricing or reimbursement strategies which are not required in the U.S.

3. Data Requirements

- FDA: For the FDA, the focus is on risk-benefit analysis with a strong emphasis on product safety and efficacy data. The FDA requires robust stability data and often requests more extensive biopharmaceutics data, including bioavailability and bioequivalence studies, especially for complex or generic products.

- EMA: The EMA also emphasizes safety and efficacy but places additional weight on risk management plans (RMPs) and environmental risk assessments (ERAs). European regulators often ask for more detailed comparative data for biosimilars and products derived from biologic sources.

4. Post-Approval Considerations

- FDA: Changes post-approval (like CMC modifications) often require a Supplemental New Drug Application (sNDA) or Prior Approval Supplement (PAS) depending on the extent of the change. The FDA categorizes changes by their potential to impact product quality.

- EMA: The EMA uses the Variation Regulation process for post-approval changes, categorizing them as Type IA, IB, or II variations, depending on the potential impact on product quality. The EMA may also require extensive post-authorization safety studies (PASS) for certain products.

5. Timelines and Review Process

- FDA: The FDA operates under the Prescription Drug User Fee Act (PDUFA), which sets strict timelines for the review of marketing applications, generally around 10 months for standard reviews or 6 months for priority reviews.

- EMA: The EMA review process is centralized and aims to complete the review within 210 days, followed by a decision-making period by the European Commission.

Summary of Key Differences:

- Regional Module 1 requirements differ between the FDA and EMA, with the FDA demanding more localized regulatory information, while the EMA's submission includes broader EU considerations.

- Data requirements differ in focus, with the FDA emphasizing biopharmaceutics and stability data, while the EMA often requires comparative studies and environmental impact analyses.

- Post-approval change management also follows distinct processes between the agencies, with the FDA using sNDAs and PAS, and the EMA using the Variation Regulation.

In essence, while both the FDA and EMA follow similar frameworks for quality, safety, and efficacy, regional regulatory requirements and submission details mark the key distinctions in preparing a CMC dossier for a Marketing Authorization Application.