Medicinal Products

The GCP Inspection procedures

Clinical trial selection for regulatory GCP supervision

Agency selects clinical trials for supervision based on a risk assessment. This assessment considers a range of different risks, e.g. risks inherent to the trial design, risks of the investigational medicinal product itself, the level of subject recruitment, reporting of safety information, involvement of multiple vendors or study-specific, including previous results of Agency,s supervision, etc.

Supervision can be routine or triggered, for example, by reported serious deviations, serious breaches, received or missing safety reports or other reports and/or information obtained from others (e.g. other parties or whistleblowers).

All clinical trials are regulated by the same regulation, and the Agency does not differentiate between investigator-initiated clinical trials and academic or company-initiated clinical trials.

Notification of GCP supervision

The Agency usually gives 2 to 4 weeks’ notice of a planned supervision, but supervision can also occur unannounced or at very short notice depending on the reason or scope of the supervision. The notification of supervision is given in writing to the sponsor and the principal investigator (by email).

The notification letter details the time and place of the supervision, the planned visit to the facility where the supervision will be conducted, and contains a preliminary daily GCP supervision plan. The notification also contains a list of documentation and data that the Agency needs to obtain or access to computerized systems before the supervision.

Who do we supervise?

The Agency carries out supervise of individual clinical trials, and in some cases, systemic supervision covering several clinical trials in which the supervision would have a specific focus, e.g. monitoring, handling of adverse reaction reporting, or similar. Or multiple sites where the same protocol is implemented.

Supervision may include anyone performing activities in a clinical trial, e.g., the investigator, sponsor, vendor, hospital pharmacy, laboratory, or computer systems vendor.

Supervision may be conducted before, during, or after the conduct of a clinical trial, including as part of the review of a marketing authorization (MA) application or as part of the follow-up on a granted MA.

Events during regulatory supervision

A supervision usually lasts three to five days, but sometimes longer, e.g. in the case of supervision of large companies or clinical trials or system supervisions.

It is usual for one person to be in charge of one supervision (in special cases there may be two people, one of whom is the lead person). Sometimes a person undergoing training may be present. Also, individual experts from the Agency may be asked to assist during the supervision if necessary. They will be accompanied by the person who is officially charge of supervision and may also ask questions and access documents and data and provide input for the supervision reports (experts from the Instrumental laboratory, IT sector, National Vigilance Centre or Clinical Trials Department).

During the inspection, the person in charge will verify on-site that the clinical trial is being conducted in accordance with the granted authorization, the approved trial protocol, applicable local regulations and the Good Clinical Practice (GCP) Guideline.

The inspection usually begins with an introductory meeting where the purpose and legal basis of the inspection and the parties to the inspection are presented. During this meeting, the person in charge of the supervision will also describe the methods, procedures and references for the GCP supervision to be carried out.

The GCP supervision usually includes interviews, supervision of the rooms and facilities and a review of data and documentation either in paper or electronic format.

Common areas covered during GCP supervision are (non-exhaustive list):

  • Organization and personnel
  • Quality control
  • Agreements/contracts
  • Trial documentation
  • Facilities and equipment
  • Regulatory approvals
  • Investigational medicinal product and other medicinal products in the clinical trial
  • Randomization/unblinding
  • Monitoring
  • Handling of adverse events, reactions
  • Data recording and reporting
  • Recruitment and treatment of subjects
  • Data management
  • Archiving
  • TMF

The supervision ends with a final/closing meeting at which the Agency presents its observations. These observations are preliminary and serve as the basis for the report on the supervision carried out. Observations do not necessarily lead to deviations in the report, but may appear as comments in the report.

In exceptional circumstances, supervision may be carried out in whole or in part via video conference (remote supervision).

Procedures after GCP inspection

Follow-up of the GCP supervision

Upon receipt of the report, the party or parties that were inspected will be asked to submit a corrective and preventive action plan (CAPA) for any non-conformities that were classified as Major or Critical, including information on the probable cause of the non-conformity and the timelines for implementing the corrective and preventive action (Minor findings do not require a response unless otherwise stated in the report; Observations sections of the report do not require a response). This should not, of course, prevent the sponsor from providing explanations if they wish.

The CAPA report should be submitted within 60 calendar days, but may be requested earlier if there were more serious nonconformities. The deadline for submitting the CAPA report will be communicated with the supervision report.

The person who was in charge of the supervision for the Agency, reviews the CAPA plan and assesses whether it can be accepted. If the plan is accepted, the supervision is closed, and the follow-up can be checked in a future supervision. If the person in charge of supervision does not accept the CAPA plan, communication will continue until an acceptable plan is reached.

Suspension or prohibition of a clinical trial of a medicinal product

According to the current Law on Medicines (Article 90, 91), the Agency may propose to the competent ministry to suspend or prohibit the conduct of a clinical trial of a medicinal product, if the irregularities are not eliminated within the period referred to in paragraph 1 of this Article, if it is determined that the conduct of a clinical trial of a medicinal product is not carried out in accordance with this Law, the regulations adopted for the implementation of this Law, the clinical trial protocol, the Guidelines for Good Clinical Practice. The competent ministry suspends or prohibits the conduct of a clinical trial of a medicinal product referred to in paragraph 2 of this Article on the basis of the inspection supervision carried out in accordance with the law.

The competent ministry may suspend or prohibit the conduct of a clinical trial of a medicinal product for which it has issued a permit for the conduct of a clinical trial of a medicinal product in the Republic of Serbia, if this is in the interest of protecting the health of the subjects, or if this is in the interest of science and society as a whole, based on a proposal from the Agency or ex officio.

The competent ministry shall suspend or prohibit the conduct of a clinical trial of a medicinal product referred to in paragraph 1 of this Article on the basis of an inspection carried out in accordance with the law. If the Agency determines, based on the inspection carried out, that the initiated clinical trial of a medicinal product is not

necessary to urgently suspend in order to protect the health of the subjects, or in the interest of science and society as a whole, it shall be obliged to request additional information on the conduct of the clinical trial from the sponsor or the principal investigator.

The sponsor or principal investigator is obliged to submit all requested data to the Agency within 8 days from the date the data was requested, on the basis of which the Agency informs the sponsor, principal investigator and the Ethics Committee of the proposed measures, in accordance with this Law (link to the current Law, Serbian version https://www.alims.gov.rs/wp-content/uploads/2022/02/Zakon_o_lekovima_30-10-107_12-113_2017-1.pdf

Report after supervision (Inspection Report)

When the Agency completes a GCP supervision at the site, it prepares a report on the supervision conducted for the parties and entities that were inspected and who are responsible for the clinical trial (sponsor) or the sponsor’s representative.

GCP supervision reports will be prepared as one report per supervision for the parties that participated in the supervision (if two sites were audited for one protocol, then two separate reports are prepared, one for each site).

The content of the report depends on the site inspected and the reason and scope of the supervision. It will state the time and location of the supervision as well as the participants who attended the supervision. The report describes the observations and summarizes any deviations from applicable regulations, guidelines, study protocols, guidelines, or own procedures.

Assessment of supervisory findings

Non-conformities in reports are classified as “Critical”, “Major”, or “Minor” in accordance with the classification used in inspection work carried out by the European Agency.

Non-conformities will be classified based on the specific circumstances of the individual supervisory activity and will be assessed in relation to the risk that the non-conformities pose to the safety and integrity of the subjects and the quality of the data. This means that seemingly identical non-conformities may be classified differently from one supervisory activity to another. The immediate assessment of the severity of the non-conformity is reflected in the conclusion of the report and any subsequent correspondence provided in the additional explanations.

Critical (explanation broader than mention in reports)

  1. a) Where there is evidence that there has been a significant and unjustified departure from applicable regulatory requirements with evidence that:
  • the rights, safety or welbeing of subjects have either been or have a significant potential to be compromised, and/or
  • the clinical trial data are unreliable and/or
  • there is a series of major non-conformities (as defined in (d) and (e)) in areas of responsibility, indicating a failure of systematic quality assurance and/or
  1. b) Where inappropriate, insufficient or untimely corrective action has been taken in relation to previously reported major non-conformities (as defined in (d) and (e))

Major (explanation broader than mention in reports)

  1. d) a non-critical finding where there is evidence that there has been a significant and unjustified departure from applicable regulatory requirements that may not have developed into a critical issue but could have the potential to do so if not addressed, and/or
  2. e) where where there is evidence that multiple deviations from applicable regulatory requirements and/or established GCP guidelines have occurred within an area of ​​responsibility, indicating a failure of systematic quality assurance.

Other:

  1. f) If there is evidence that a deviation from applicable regulatory requirements and/or established GCP guidelines and/or procedural requirements and/or good clinical practice has occurred, but it is neither critical nor significant (Critical, Major).

Before being sent to the supervised parties, the supervision reports are subject to quality control (peer review).