Post-authorization studies of drug safety in Russia

After a pharmaceutical company gets a registration certificate for a medicine, clinical trials continue. In this article, we will talk about post-registration studies, specifically post-registration safety studies for a drug.

First, let’s define what are “Post-Authorisation Safety Studies”?

According to the Good Pharmacovigilance Practices of the EAEU, a post-registration safety study (PASS) is a study conducted to identify, characterize or quantify a safety hazard, confirm the safety profile of a medicinal product, or evaluate the effectiveness of risk management measures. A PRIS also analyzes potential risks to special patient populations. Post-registration safety studies can have both interventional and non-interventional designs.

What is the purpose of a PASS?

One of the most important purposes of a PASS is to evaluate the benefit-risk ratio of a drug product.

The RF holder independently performs the work of controlling the data from the study and assessing its impact on the benefit-risk ratio of the drug in question. If any information appears that can affect the assessment of the “benefit-risk” ratio of a medicinal product, it is immediately reported to the authorized bodies of the Member States, on the territory of which the PASS is conducted and the medicinal product under study is registered. The benefit-risk assessment may be affected by data obtained from the analysis of information on suspected adverse reactions or the results of the interim analysis of summarized safety data.

What are the challenges and particularities of conducting PASSs?

Post-authorization safety studies of a medicinal product are started, controlled, or funded by the holder of the registration certificate voluntarily, or at the request of the competent authority, if there is a suggestion that there are risks associated with a registered medicinal product that require further investigation by a trial. The investigator hired by the registrant to conduct the PASS must have the qualifications in education, training, and experience to conduct the PASS.

PASS tasks may include the assessment of:

• risks of the use of the drug (occurrence of NNDs, NSAIDs);
• risks of drug administration for approved indications in patient groups that have not been studied or have been insufficiently studied in Phase 1-3 clinical trials;
• risks associated with long-term use of the medicinal product;
• standard clinical practice for prescribing medications with additional information on the safety of medical products;
• the effectiveness of measures to minimize the risk of taking a medicinal product.

PASS must be conducted under the Protocol, which will be submitted to the authorized body of the country, on the territory of which the study is planned. If a PASS is planned on the territory of other countries, the authorized bodies of these countries will be provided with a brief description of the Protocol.

Also, before the approval of the Protocol to comply with the Rules of Good Pharmacovigilance, the holder of the RI shall appoint an Authorized Person for Pharmacovigilance (APP), and in case of a PASS in other countries, a contact person shall be appointed, who will also receive a copy of the Study Protocol.

They recorded any significant changes that are made to the Protocol after the study has begun in the Protocol, for tracking and verification purposes, including the dates of the changes. During the conduct started by the RU PASS holder, it is recommended to pass the Protocol of the study with updates or changes to the authorized body of the country where the study is conducted.

In addition, the authorized bodies of the country where the PASS is conducted may request an interim report on this study. The reason for the request can be the emergence of information regarding the effectiveness and (or) safety profile arising in the study’s course, or the need to obtain information on the progress of the study in regulatory procedures, as well as the emergence of information on the safety of the medicinal product. The timing of Interim Reports must be agreed with the Member State authorities and specified in the Study Protocol.

It should appropriately reflect the progress of the PASS in the Periodic Drug Safety Reports and Risk Management Plan (RMP) updates, if applicable. After reviewing the reports, the regulatory authority may also request additional information.

Any post-authorization safety studies must be included in the RMP along with the Protocol. All relevant sections and modules of the SMP shall be changed accordingly to reflect the conduct of the study, including the Safety Data Sheet, the Pharmacovigilance Plan, and the Risk Minimization Plan, as well as a review of risk minimization measures.

With a request from the authorized body to conduct a PASS, it carried the study out mandatorily.  To issue this requirement, a reasoned expert opinion on the lack of data characterizing the safety profile of a given medicinal product is required. To get such data, it required active safety study methods due to the impossibility of proper study or risk assessment by routine pharmacovigilance methods with the safety profile of a registered medicinal product. The Authorized Body must be:

• properly substantiated by safety and efficacy profile assessment data;
• be documented in writing;
• include the objectives and timeframes for submitting and conducting the study.

According to the Good Pharmacovigilance Rules of the EAEU, within 30 calendar days after receiving written notification from the authorized bodies about a mandatory post-registration safety study, the RU holder may request an opportunity to submit written observations on the safety of the medicinal product instead of conducting a PASS.

However, with non-interventional PASS, it is the responsibility of the holder of the SAR to ensure compliance with the criteria of the non-interventional study. The holder of a SAR must ensure that it met its pharmacovigilance obligations and that the post-registration safety study can be audited, reviewed, and verified.

The Local Ethics Committee can start the study only after written approval of the Protocol. After the start of the study, it shall submit any significant changes to the Protocol to the Authorized Body before its introduction. The authorized body within 30 calendar days after the submission of changes to the Study Protocol reviews the proposed changes and informs the RU holder about their approval or rejection.

The holder of RI shall submit the last report, which includes a summary of the study for publication after completion of the study to the authorized body no later than 365 calendar days after completion of data collection. The Contracting Authority may grant written permission to the holder of the RU to extend the period for the submission of the report. The Contracting Authority reviews the last report, and they subsequently submitted the results of the evaluation of the report to the RI holder. Based on the results of the review of this report and the assessment of the impact of the data got on the benefit-risk ratio of the medicinal product, the Authorised Body shall develop recommendations to change the registration status of the medicinal product, or identify the need for other appropriate measures to ensure the use of the medicinal product in conditions exceeding the benefits over the risks.