Circulation of labeled medicinal products in clinical trials using digital tools

Background

Modern clinical research practice is undergoing significant changes under the influence of digitalization and the introduction of information technologies [1]. In the medical community of Russia, the EAEU member states, and other countries, the use of real-world clinical practice data to improve the quality and reliability of results is being discussed [2, 3].

Legal regulation is developing in parallel with technical transformations [4]. In this regard, digital tools in clinical trials are becoming an integral part of data collection, management, and statistical analysis, particularly in reflecting the movement, accounting, and control of investigational medicinal products. Traditional paper‑based data collection methods are being replaced by digital ones, which optimizes processes [5].

Digitalization is especially important in the accelerated registration of medicinal products and in amending registration dossiers to analyze the benefits and risks of these procedures, highlighting the need for enhanced subsequent monitoring and collection of real-world clinical practice results [6, 7]. Also, for registered medicinal products, post‑registration monitoring data, including information on the results of any use of the investigational product, are significant [8–10].

One such tool is the digital labeling of medicinal products, which ensures transparency and traceability of drug movement, minimizes risks of accounting errors, and increases the accuracy of investigational drug control [4].

Objective

The above determined the aim of this study — to identify the features of the circulation of labeled medicinal products in clinical trials using calcium hydroxynicotinoylglutamate as a case study.

Methodology

The research methodology included a systematic approach to studying the regulatory framework for clinical trials, analysis of scientific publications on the organization of drug supply for clinical trials, business processes of drug circulation in clinical trials, and electronic document management (EDM). Content analysis, mathematical and statistical methods, and paired sample comparison using the Wilcoxon t‑test were applied.

The study materials included regulatory legal acts in the field of public health of the Russian Federation and the EAEU, data from official websites of the State Register of Medicines (GRLS), the Unified Register of Registered Medicines of the EAEU, EDM data from the medical organization’s inventory and accounting systems, the contract with the sponsor, and the study protocol. The selection of the investigational drug, the category of volunteers, and the study site were determined by the sponsor and formalized in the contract [11].

Object of the study — the circulation of medicinal products during clinical trials in a medical organization (investigator site).

Subject of the study — the features of organizing business processes for the circulation of investigational medicinal products in clinical trials using digital tools.

Results

The legal framework for conducting clinical trials is established both in Russia and within the EAEU. It has been shown that clinical trials are conducted in accordance with the EAEU Rules of Good Clinical Practice [9]. According to Russian legislation, a post‑registration clinical trial of a medicinal product for medical use is defined as a clinical trial conducted by the manufacturer of the medicinal product, whose civil circulation is carried out after state registration or registration, for additional collection of data on its safety and efficacy, as well as to expand the indications for use of this medicinal product and to identify adverse reactions of patients to its action [4, 12].

Consequently, after registration of a medicinal product, Phase IV development begins to optimize its use. Such studies scientifically substantiate the study of additional drug interactions and are conducted for the following purposes:

1. to establish the safety of the medicinal product for healthy volunteers and/or its tolerability by healthy volunteers, except for such studies of medicinal products manufactured outside the Russian Federation;

2. to select optimal dosages of the medicinal product and treatment course for patients with a particular disease, optimal doses and vaccination schedules for immunobiological medicinal products in healthy volunteers;

3. to establish the safety and efficacy of the medicinal product for patients with a particular disease, and the preventive efficacy of immunobiological medicinal products for healthy volunteers;

4. to study the possibility of expanding indications for medical use and to identify previously unknown adverse effects of registered medicinal products [4].

Clinical trials, including post‑registration trials, are conducted in Yaroslavl Region in several large medical organizations and medical centers that have the necessary equipment and qualified personnel. The general scheme is shown in the Figure.

It should be noted that investigational drugs are studied in public or private medical organizations and may or may not be included in the Russian Federation’s digital labeling system [13].

The Rules of Good Clinical Practice prescribe organizational measures for conducting clinical trials for all participants [9, 14].

The clinical trial organizer provides the medical organization with the current version of the clinical trial protocol and the investigator’s brochure before signing the contract with the medical organization for conducting the clinical trial and sets a time for reviewing the provided information. It then transfers the investigational drugs, comparator products, and placebo that have appropriate quality indicators and are, if necessary, coded for blinding purposes. The primary and secondary packaging of medicinal products intended for clinical trials may also be marked with the inscription: “For clinical trials”.

In turn, the medical organization is responsible for accounting for the received investigational drugs, their use, and their return to the organizer. For this purpose, the medical organization appoints a responsible investigator, a pharmacy worker, a pharmacist, or another employee of the medical organization.

Fig. Medical organizations participating in clinical trials

The activities of the medical organization’s pharmacy within the framework of clinical trials should aim to maintain the investigational drug in proper conditions in accordance with the sponsor’s instructions. The pharmacy worker (pharmacist) records the supply of drugs to the research center, their actual quantity at the center, use by each subject, as well as the return to the sponsor or other disposal of unused investigational drugs. Accounting records must include dates, quantities, batch (series) numbers, expiry dates (where applicable), and unique codes of the investigational drugs and study subjects.

The representative of the medical organization conducting the clinical trial is obliged to maintain study documentation, as well as records confirming receipt of the investigational drugs in doses provided for by the protocol and contract.

In March 2025, an open‑label, two‑stage comparative study was conducted at the Clinical Hospital No. 2 of Yaroslavl Region. To study the pharmacokinetics, safety, and tolerability in healthy volunteers, and consequently the business processes of drug circulation in clinical trials, a solution of calcium hydroxynicotinoylglutamate 5 mg/ml was provided.

An analysis of official websites for the registration of medicinal products in the Russian Federation and the EAEU was performed; summary data on the investigational drug are presented in the Table.

It was established that the investigational drug with the INN calcium hydroxynicotinoylglutamate has to date passed state registration both in the Russian Federation and in the EAEU with one trade name and is not included in the list of Vital and Essential Drugs.

When receiving the investigational drug included in the Russian Federation’s digital labeling system, the head of the medical organization’s pharmacy performed all drug circulation processes. Delivery accuracy and confirmation of receipt with date, signature, and its full name in the documentation were duplicated on paper (a copy of the documents is stored in the Investigator’s File). Storage and dispensing of the investigational drug to the investigator were carried out in accordance with current regulatory documents and local acts of the medical organization.

Further, during the study, the pharmacokinetic characteristics of the investigational drug calcium hydroxynicotinoylglutamate were assessed following intramuscular and intravenous administration in healthy volunteers [15–31]. Non‑parametric comparison revealed statistically significant differences (p <0.05 using the Wilcoxon test for paired samples) for all pharmacokinetic parameters except AUC0‑t and AUC0‑∞. For these parameters, a parametric method (paired t‑test after logarithmic transformation of the data) was additionally applied, which did not reveal significant differences. Thus, the drug calcium hydroxynicotinoylglutamate demonstrates similar values of the area under the concentration‑time curve for both routes of administration.

The bioavailability of calcium hydroxynicotinoylglutamate following intramuscular administration, calculated on the basis of AUC, was not statistically different from its bioavailability following intravenous administration. The study confirmed the comparability of pharmacokinetic parameters after intramuscular and intravenous administration of the drug, indicating equivalence of these routes of administration.

As part of the Phase IV clinical trial, the pharmacokinetics of calcium hydroxynicotinoylglutamate after intramuscular and intravenous administration in healthy volunteers were evaluated. Non‑parametric analysis revealed significant differences in most parameters (p <0.05), except for AUC0‑t and AUC0‑∞, for which a t‑test after logarithmic transformation was used. The results showed stability of AUC for both administration routes, confirming equivalence of the methods. Analysis of blood serotonin levels showed a significant increase: from 125.31 to 138.88 ng/ml (+10.8%) after 24 hours. In 15% of participants with low serotonin levels, levels normalized, and in all subjects, serotonin levels reached the physiological norm (70–170 ng/ml). Intravenous administration of the drug demonstrated a beneficial effect on the serotonergic system, which is important in cases of serotonin metabolism disorders.

The investigator was responsible for reporting on the investigational product (IP), including the receipt and expenditure of the investigational drug, as well as maintaining accounting documentation in accordance with current legislation and approved standard operating procedures conducted in the structural unit of the medical organization.

The dispensing of the investigational drug to the medical post strictly of the structural unit was recorded in the study reporting forms:
• confirmation of delivery of the investigational drug to the research center (medical organization);
• accounting of each dose of the investigational drug used.

Unused investigational drug was not subject to disposal, was not used for purposes other than those of this study, and upon completion, all unused investigational drug was returned to the Sponsor using return documents.

Conclusion

The use of digital business processes in the inventory and accounting systems of a medical organization using EDM allows for a reduction in receipt and dispensing times, which is necessary to meet clinical trial rules and timelines.

Digital labeling allows the selection of investigational drug packages without additional markings, since the study’s EDM includes unique digital codes designated “For clinical trials” in the Federal State Information System of Drug Labeling. In turn, this makes it possible to assign a specific package of the investigational drug to a specific volunteer, which is convenient for investigating adverse reactions that may arise, taking a short amount of time.

Since the investigational drug with the INN calcium hydroxynicotinoylglutamate has successfully passed preclinical and clinical trials of Phases I, II, III, and IV (post‑registration), during which its efficacy and safety were demonstrated and proven for intravenous and intramuscular administration, this allows the drug to be in civil circulation.

However, despite the advantages of digital technologies, the issues of organizing the circulation of investigational drugs in medical organizations during clinical trials are poorly understood. There are difficulties in integrating digital solutions with traditional business processes, as well as regulatory and technical barriers that require systematic analysis and optimization.

Table. Summary data of the study drug