Factors influencing non-approval in Europe

Negative clinical outcome results seem to contribute most significantly to current non-approval rates. Also relevant learning-phase studies are valuable in reducing the number of failed dossiers and speeding up pharmaceutical innovation

Caterina Lucchini

First of all, a Marketing authorization application (MAA) should be submitted in the EU-CTD (Common Technical Document) format.The MAA is composed by five main modules as detailed in Box.

MARKETING AUTHORIZATION APPLICATION (MAA)

Module 1: EU administrative and prescribing information. Details: Application form, summary of product characteristics, labelling text and mock-ups, information about the experts, environmental risk assessment, information relating to orphan- market exclusivity, description of the pharmacovigilance system, risk management plan.

Module 2: High-level summaries. Quality, non-clinical overview, non-clinical summary (pharmacology, pharmacokinetics, toxicology), clinical overview, clinical summary (biopharmaceutics, clinical pharmacology, efficacy, safety, study synopsis).

Module 3: Quality documentation. Body of data, references.

Module 4: Non-clinical documentation. Study reports, references.

Module 5: Clinical documentation. Tabular listing of studies, study reports, references.

The first step of the review process is for the EMA to assess the MAA to determine whether the reviewers require additional information, data or clarification in order to conduct the review. Once the MAA is deemed valid, the CHMP establishes the timetable for scientific evaluation. The rapporteur/co-rapporteur conducts the scientific evaluation. The EMA ensures the CHMP completes the full review within 210 days. Once the CHMP has the preliminary assessment reports or critique from the rapporteur and co-rapporteur, it prepares a list of any outstanding issues the sponsor must address. A consolidated list of questions identifying “other concerns” and/or “major objections” is prepared. These are sent to the sponsor with the CHMP recommendation and scientific discussion. The clock will then be stopped (day 120).

The CHMP can make one of two recommendations:

1. The product could be approved provided that satisfactory answers are given to “other concerns,” and that the indications, the elements of the summary of product characteristics, and other conditions for marketing are amended as outlined in the list of questions.

2. The product is not approvable since there are “major objections.”

The sponsor has three months from the date of receiving the questions to respond to the CHMP. Sponsors are permitted to request a three-month extension, if required.

On or before day 210, the CHMP will adopt its final opinion after the final recommendation of the rapporteur/co-rapporteur. The CHMP opinion, wherever possible, is reached by consensus. If a consensus cannot be reached, the majority opinion will hold (i.e., favourable votes by at least half the members plus one).

Favourable opinion: The sponsor can proceed to preparing the drug for marketing launch.

Unfavourable opinion: The sponsor is informed that the application does not satisfy the criteria for marketing authorization.

Table 1. Summary scorecard of EMA assessment of 68 MAA. Source: Putzeist et al, Nat Rev 2012

The development plan was classified as negative when at least 1 major objection on any of the 10 variables on day 120 of the procedure was expressed; otherwise it was classified as positive. Major objections on day 120 were studied because these were considered to provide the most comprehensive overview of development problems encountered during a procedure. The clinical outcome was scored negative if no convincing statistical significant effect on primary endpoints was reached and/or when serious safety concerns were raised during the 210 days of the procedure; otherwise it was classified positive. Clinical relevance was classified as negative when none of the 3 clinical relevance variables during the 210 days of the procedure were scored as large, important or compelling; otherwise it was classified as positive.