May 9, 2013 | By Márcio Barra
It’s the fourth day of regulatory week! This means a new regulatory affairs themed short article! Today, how do Marketing Authorization’s renewals work in Europe. If you like this article, please share it!
Renewal of Marketing Authorizations in EU
Marketing authorizations in Europe are valid for five years from the date of notification of the Commission Decision to the marketing authorization holder, and may be renewed on the basis of a re-evaluation of the risk-benefit evaluation balance according to Regulation (EC) 726/2004(1).The application for renewal of a MA must be sent to the appropriate competent authority at least 9 months before the expiration date(1).
The start of the evaluation process by the CHMP, more precisely by an elected Rapporteur and Co-rapporteur, shall be the earliest starting date possible, and it can take up to 120 days of active time. Once renewed, the MA is valid indefinitely, unless, due to pharmacovilgilance reasons or exposure of an insufficient number of patients to the medicinal product concerned, there is a need to conduct an additional five-year renewal(2-4).
If any changes are necessary to the SmPC or labeling of the drug product arising from a PSUR evaluation or any other document, the MAH may submit an updated SmPC as part of the renewal process. Major changes like a new indication however, cannot be introduced during the renewal process. The renewal application should come in the EU electronic Common Technical Document (eCTD) format(5).
After the start of the renewal evaluation process, the CHMP Rapporteur’s Assessment Report is sent to CHMP Co-Rapporteur and PRAC Rapporteur. The joint CHMP Rapporteur/ Co-Rapporteur assessment report is then prepared, alongside the PRAC Rapporteur advice, and sent to EMA, CHMP and the PRAC. Members of these committees comment on the joint assessment report, and the CHMP and PRAC hold meetings to discuss the renewal request. Some interaction occurs between the MAH and the committees, and a final opinion is given by the CHMP(2).
Renewals in the mutual recognition and decentralized procedures
The rules regarding renewal in medicines approved by the mutual recognition and decentralized procedure are the same as medicines approved by the centralized procedure, except that the evaluation is conducted by the national competent authorities of authorizing countries, instead of EMA.
The MAH must provide the competent authority with a file containing information on the quality, safety and efficacy of the product, including an evaluation of data contained in suspected adverse reaction reports, the Periodic Safety Update Report (PSUR) data and any other relevant new information that may affect the benefit/risk of the product since the MA was granted.
For the mutual recognition procedure a common renewal date should be agreed by the Member States and the applicant. Also, an optional procedure for earlier renewal is available for drugs approved by the MRP(3).
The assessment approach of the Member States will consist of a benefit/risk balance re-evaluation, on the basis of a consolidated version of the file and any relevant new information affecting the benefit/ risk for the product. First, the competent member states are informed of the start of the procedure, and the RMS then prepares a preliminary assessment. After receiving comments on the report by the Competent Member States (CMS), the RMS sends a request for supplementary information to the MAH, if needed. A finalized assessment report is readied, alongside a draft decision, and the CMSs give their opinion on the decision. If disagreements occur between the MSs, the CMDh is called upon to handle the disagreement(3).
The Pharmacovigilance Risk Assessment Committee (PRAC) may be involved in the assessment of the renewal and advice may be sought in the following situations(6):
- If the product contains a substance listed as subject to additional monitoring;
- If the application includes a new or updated Risk Management Plan that requires PRAC agreement;
- If the RMS has proposed a further 5-year renewal based on pharmacovigilance grounds.
A conditional marketing authorization is an authorization to a drug that may be granted in very specific conditions, and is reviewed annually by the Agency. In some cases, in order to meet unmet medical needs and the interests of patients, it is needed to grant a MA on the basis of less complete data than usual and usual marketing authorization. A conditional marketing authorization can only be granted for medicines for:
- Seriously debilitating or life-threatening diseases;
- Emergency threats (WHO, EU Commission);
- Orphan medicinal products.
The following requirements have to be met:
- The Benefit/Risk balance is positive;
- It is likely that lacking clinical data will be provided;
- Unmet medical needs will be fulfilled;
- Benefit to public health of immediate availability outweighs risks.
Given the conditional nature of the MA, the MAH is obligated to complete ongoing studies and conduct new studies in order to confirm the positive benefit/ risk balance. These authorizations are valid for one year instead of five(1).
In the renewal process, the MAH has to confirm the benefit/ risk balance and review the status of the specific obligations. Furthermore, the MAH has to submit an overview of all data acquired since the conditional MA was granted, PSUR data and an interim report on the status of the specific obligations. The CHMP renews the application in a 90 day period, in order to confirm the benefit-risk balance of the drug. Modifications to the SmPC may happen. If the MAH fulfills all specific obligations, the conditional MA may turn into a regular MA.
It’s worth mentioning that there’s also the «“MA Under Exceptional Circumstances”. Similar to the conditional MA, it is given to a drug when the sponsor cannot provide clinical data due to:
- Rarity of the disease;
- Present state of scientific knowledge;
- Ethical constraints.
However, here the MA is valid for five years instead of one. Like the conditional MA, the MAH is obliged to comply with very specific procedures/obligations. The MA is renewable, but an additional annual re-assessment of the benefit/ risk balance by the CHMP will be conducted. Last, unlike the conditional approval, an exceptional circumstances approval is not expected to result in a full approval later down the line (7-9).