The comparative analysis of the iso 9001 : 2015 standard and Good Clinical Practice guidelines : the framework for improving management of clinical trials

The principal concept of the ICH Q8, Q9 and Q10 guidelines is to encourage implementation of scientific and systematic approaches for quality assurance of pharmaceutical products. Clinical trials, which are the crucially important part of the pharmaceutical research and development process, are outside of these guidelines, and it actualizes the issue on introducing quality management into clinical trials. Aim. To analyze the ISO 9001 quality management methodology and the Addendum to GCP requirements in order to elaborate the methodical background for its combined use that will provide the effective work of the quality management system while achieving GCP compliance. Materials and methods. The methods of the comparative analysis, synthesis, generalization, abstraction and content analysis were used to determine the possibility of ISO 9001:2015 and ICH GCP integration. Results. The Addendum to GCP demonstrates the conformity of its provisions with prominent trends of quality management confirmed by the ISO 9001:2015 standard. The Addendum to GCP declares that the quality management system should use a risk-based approach, which allows conducting clinical trials more efficiently. Conclusions. The ICH GCP framework can be easily and effectively integrated into the ISO 9001 quality management system of a particular clinical study, as well as in the entire system of quality assurance during the drug lifecycle. Further studies should be focused on development of the practical approaches and methods for implementation of the riskbased quality management in clinical trials.

Nevertheless, the quality of the clinical development is an important issue since it provides scientific evidences about the principal properties of the drug quality -safety and efficiency [3,6,8].Thus, the quality of the clinical stage of the drug development should be assured at the appropriate level in order to contribute to the entire quality system of pharmaceutical products [1,9,10].
The fundamental framework for providing quality by any organization is described in the ISO 9001 standard [11].After 2015 revision of the ISO standard the risk-based approach was included into the quality management system.These changes were encouraged by the modern conditions related to the lack of resources, as well as simultaneous arising of the quality demands, and reflect the need for the efficiency increase [1,4,11].
The basic industry standard for performing clinical trials is Good Clinical Practice Guideline (GCP), which contains the requirements to study quality and perform its processes [12].Following the riskbased innovative approaches and considering the existence of the pharmacy industry guideline for the Quality Risk Management ICH Q9 the GCP framework was also reviewed concerning the quality system, introduction of risk-based approaches and electronic data management [1,3,4,8].The first question arising while implementing quality management into clinical drug trials (CDT) is the possibility of the combined use of ISO 9001:2015 and GCP, as well as conformity of their requirements.
Thus, the aim of our study is a detail analysis and comparison of the ISO 9001:2015 quality management methodology and GCP requirements in order to elaborate the methodical background in the context of its consistent integration for enhancing of the clinical trials system.

Materials and methods
In order to examine the conformity of the ISO 9001:2015 and the Integrated Addendum to ICH E6 (R1) the comparative analysis of these documents was performed.Conclusions and recommendations concerning integration of the GCP framework into the ISO 9001:2015 quality management system were formulated using the methods of synthesis, generalization, abstraction and content-analysis.

Results and discussion
The Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2) contains critically important aspects and a fundamentally new approach relating to the quality management system within the clinical research [12].Thus, a new version of GCP obliges the sponsor to implement the quality management throughout all stages of the clinical trial, including design, conduct, recording, evaluation, reporting and archiving of clinical trials.One of the main ideas of the new approach is proportionality of the methods used to assure and control the quality of the trial to risks inherent in the trial and the importance of the information collected.
To enhance implementation of the quality management standards into routine practice of clinical trials the analysis of particular paragraphs of the international standard ISO 9001:2015 and GCP provisions regarding the sponsor's and investigator's activities for the CDT quality assurance was conducted (Tab.).This comparison allows us to design the strategy of ISO requirements into the investigator's activities, as well as the sponsor's ones, and choose the strategy how to remove the main existing gaps for implementing the ISO 9001:2015 oriented management into the CDT practice [2,4].
Such analysis helps to reveal specificity in performing the quality management functions by investigators and the sponsor.It also substantiates the importance of the quality management system building at a trial site since an independent structure is focused on specific goals that represent needs and expectations of stakeholders interacting   1 during clinical trials while assuring high coordination and efficacy of the interaction.
In this way, the quality management system at a trial site, which is an important element of the clinical stage of drug development, can be easily integrated into the entire system of quality assurance that embraces all stages of the drug lifecycle [1,3].
It should be underlined that 2015 version of the ISO standard contains an idea of risk-based thinking [11].Thus, the risk assessment became an important part of planning the quality management system [4].As a result, the preventive actions were replaced by actions to address risks and opportunities.In practical context this transforms the reactive quality management style to the pro-active one.
The implementation of this innovative approach by a new version of GCP elaborated in accordance with the ICH Q9 Guideline will allow applying the "improved and more efficient approaches to the clinical trial design, conduct, oversight, recording and reporting while continuing to ensure the human subject protection and data integrity".The ICH GCP declares that the quality management system, which uses a risk-based approach, should have the following structure: 1) critical process and data identification, 2) risk identification, 3) risk evaluation, 4) risk control, 5) risk communication, 6) risk review, and 7) risk reporting [12].
Focus on risks described in detail in the Addendum to GCP demonstrates the conformity of its provisions with prominent trends of quality management set by the ISO 9001:2015 standard.The relevance of these issues encourages scholars and practitioners in the field of clinical trials to study the aspects of the risk-based management and quality assurance in clinical research and develop the corresponding knowledge-based methodical approaches.
CONCLUSIONS The analysis has shown that the Integrated Addendum to ICH GCP E6 (R1) reflects all fundamental principles of quality management declared by ISO 9001:2015.That will provide the consistency between the revised version of GCP and ISO 9001:2015.After reviewing of GCP it can be easily and effectively integrated into the ISO 9001 quality management system due to the additional paragraph that describes the quality system development.
This initiates the new stage of clinical trial quality assurance built on modern concepts of quality management, and it is encompasses the risk-based approach.Thus, at the next stage the practical approaches and methods targeted on implementation of the risk-based quality management in clinical trials should be scientifically substantiated and elaborated.In our opinion, the special attention should be paid to description of the role of an investigator and a trial site within the whole quality management system of clinical trials and, particularly, at the stage of risk assessment and treatment.
Conflicts of Interests: authors have no conflict of interests to declare.

Table The comparative analysis of the ISO 9001:2015 and the Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6 (R2) concerning clinical trial quality management
Continuation of Table

Table 1
The sponsor may consider establishing an independent datamonitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical effica cy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.The IDMC should have written operating procedures and maintain written records of all its meetings.5.18Monitoring.5.18.1 Purpose.1099Thepurposes of the trial monitoring are to verify that: (a) The rights and wellbeing of human subjects are protected.(b)Thereported trial data are accurate, com plete, and verifiable from source documents.(c)Theconduct of the trial is in compli ance with the currently approved protocol/ amendment(s), with GCP, and with the appli cable regulatory requirement(s) 4.1.4Theinvestigator/institution should per mit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies)