Leaflet: Operative Steps for interventional studies

Maria Meringolo; Sergio Delle Monache; Martella Giuseppina; Antonella Peppe

doi:10.20944/preprints202309.1148.v1

Submitted:

17 September 2023

Posted:

18 September 2023

Read the latest preprint version here

Abstract

Clinical trials often involve new substances characterized or developed for a specific pathology or class of pathologies. At other times, a clinical trial is observational; in other words, a known substance has a range of effects on a given cohort of subjects. The types of trials are different and complex, and often, the young clinical novice and the inexperienced researcher cannot correctly evaluate how to follow. In this paper, we want to create a mini guide for beginners in clinical trials and provide elements to design a clinical trial. We intend to point out where to find the materials and how to adjust even in the absence of sponsors so that even the most inexperienced and without means researcher can get an idea of the complexity of the process and deal with it in the right way. We do not presume to be exhaustive, nor claim to value all the elements, but instead realize a checklist. With this spirit, starting to talk about the experimental phases of the drug and ending with the clinical trial, we want to help those who face this problematic "world."

Keywords:

clinical trials

;

study design

;

law procedures

;

statistical approach

;

health

;

Patients

;

Non-Commercial Clinical Trials

;

enrollment

;

regulatory agencies

;

packaging

Subject:

Public Health and Healthcare - Public Health and Health Services

Introduction

Developing a new drug involves multiple research stages to ensure the compound's safety, effectiveness, and practicality. This process starts with the pre-clinical research and ends in the four fundamental phases of clinical research. Namely, the latter starts with phase 1, marked by the necessity to prove the drug's safety on a reduced number of healthy volunteers. During this phase, the researchers investigate the side effects of the drug and suggest a modality of administration of the compound [1,2]. Then, phase 2 includes using a placebo compound to compare the drug's beneficial effects with a non-active compound and fine-tuned doses. A group of patients is involved in this phase so that researchers can evaluate safety and efficacy in unhealthy conditions [1,3]. Phase 3 requires more patients than Phase 2 and is necessary to confirm/retract the drug efficacy compared to the placebo [1,4]. Usually, at the end of phase 3, the drug is approved/rejected by the competent authority (see Table 1). After the drug has been approved for use in the general population starts a post-marketing surveillance named phase 4 that allows the evaluation of the long-term risks and benefits in a real scenario [1,5].

Different is the process for drug repositioning, meaning that an existing drug is used with a different therapeutical purpose. This approach reduces the cost of experimentation and makes the compound readily available because the researchers do not test the safety and functionality of the compound since all the information on the drug can be obtained from life science databases. The candidate drug can be tested on a new group of patients alone or in addition to existing therapies. Comparison with placebo may be facultative [6].

Figure 1. Drug development and clinical trial stages.

The time required for the whole process is estimated at 15-20 years. From 1-2 to 6 years are required in the preclinical stage; then from 3 to 10 years are necessary to develop the central clinical stages (1-3), Phase 4 becomes active after the drug has been approved and is active for 10-20 years [7].

Overall, each clinical study must be planned carefully since every stage plays a vital role in the quality, execution, and interpretation of biomedical research [8]. The choice of study design is a very relevant part of the study goal. It relies on many variables, including previous research, availability of study enrollees, funding, and time limitations. In general, it is possible to identify two main types of clinical research: i) observational studies and ii) interventional studies. Other types of clinical studies are summarized in Figure 2.

In epidemiological studies researchers merely collect data from participants without acting directly on them, identifying relationships between factors and results. The data may concern the participants' health, habits, or environments. In experimental studies, participants receive one or more interventions, in cases of pharmacological substances this happens during the experimental clinical phase [9]. These interventions can involve drugs, medical devices, procedures, or participant behavior changes (e.g., diet or exercise). Such interventions may be related to control (no medication), to placebo (no-active medication), or, in other cases, to comparisons of several available interventions between them. According to the temporality of data collection, observational studies can be designed as i) retrospective studies, where data are collected from the past through logs or by asking participants to recall exposures or outcomes [10]; or ii) prospective studies, where participants are followed over time collecting data during the trial. Nevertheless, interventional studies have many variants in how they are designed [11]. Concerning how the data were collected, studies can be classified as i) randomized control trials or as controlled selection (i.e., non-randomized controlled trials). In the latter, the studied drug is administered to one group and the outcomes are compared with an alternative treatment/placebo administered to another group. Finally, according to the role of the researcher, the study may be i) open, where the subject and researcher know the phase of the study; ii) blind, where only the researcher knows; or iii) double-blind, when neither subject nor researcher knows [11]. All these experimental studies are used to evaluate study questions relating either to therapeutic agents, such as treatments, surgical approaches, or diagnostic tests; or to prevention, which may include changes in protective equipment, engineering controls, management, policy, or any element that needs to be evaluated as a potential cause of illness or injury.

This short manuscript describes an interventional clinical trial and the procedures needed for authorization.

Detailed procedures

Since not all clinical studies are pharmacological ones, we will focus our attention on the realization of a clinical study that is non-drug dependent (e.g., a study with well-known drugs or with a device).

The first step in a clinical trial is to clearly define all the research steps and draw up a document in which objectives, duration, and the number of patients involved are clarified. Subsequently, a trial protocol needs to be developed, in which the researcher must outline the aims, design, methods, statistical concerns, and organizational details of the study, including the rationale for carrying out the trial and its ethical issues [12]. Trial protocols are required to fulfill the standards of good clinical practice and are necessary for approval from local ethics committees [12].

There are some rules in designing a clinical study that needs to be taken into account and that regard i) subjects’ selection, ii) subjects’ evaluation, iii) variables taken into account in the study, and 4) the statistics used for their analysis [12,13,14].

First of all, i) It is important to be clear about the subjects to be studied, selecting patients with certain characteristics similar to each other, excluding subjects who show clinical symptoms that may deviate from the correct answers [12,13,15]. Then, ii) subjects' evaluation is performed through a working method, a tool that allows researchers to test the hypothesis. It can be an objective method through a tool, or a drug [13,14]. iii) Measures taken into account during the study can be objective, such as the speed stide or the response latency of an electrophysiological stimulus; or subjective, such as the rate of an evaluation scale or answers to a subjective questionnaire [12,13]. Finally, (iv) the statistical analyses need to be accurately chosen, for them to be suitable to the characteristics of the variables that need to be characterized and considering the researchers' role in the study (i.e., if the study is open, blind or double-blind). Therefore, the actual statistical analysis makes use of personal knowledge enriched by specialists who deal with the evaluation of clinical variables [12,13,14]. (https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-8-general-considerations-clinical-trials-step-5_en.pdf). The number of patients should be estimated according to the restrictive parameters by power analysis. Inclusion and exclusion criteria should be considered for enlistment and any criteria for removing or replacing subjects. In addition, a number of participants at least 5/10% larger shall be estimated depending on possible adverse effects during the procedure. Note all the parameters of the actual court size can be obtained with many available software (e.g.,: https://clincalc.com/stats/samplesize.aspx). The estimated number of subjects recruited, recruitment criteria, and recruitment methods should be listed in any groups in which the subjects will be divided and how to administer the drug [16].

Then, it is important to indicate how the entire process will be monitored, who will be available to the subject, how they will be contacted, and what time latency the responses provide. In addition, the researchers should indicate the procedure for emergencies and difficulties which may be deferred, prioritizing the well-being of the subjects involved in the study [16]. A post-trial observation period should also be estimated for each subject. The subject must be covered with health insurance for the entire study duration and its follow-up (Registries for Evaluating Patient Outcomes: A User’s Guide [Internet]. 3rd edition.).

The document should also include the periodicity of the visits and the type of evaluations, instrumental and not, to be performed on the patient.

Finally, it is the responsibility of the researcher to register the authorized clinical trial in the clinical trial registration system operated by the government or another organization. For example, ClinicalTrials.gov is a database of records and results of privately and publicly funded clinical trials conducted worldwide and managed by the US National Library of Medicine. Each clinical trial registration system provides detailed instructions and explanations that are also useful for submitting the document to the ethics committee (https///classic.clinicaltrialials.gov/ct2/manage-recs/present).

The last step for the drafting of the document is to point out i) the maximum benefit from the study, ii) which procedures will be performed to minimize harm to the parties involved, iii) the expected adverse effects and rescue procedures, iv) future resources if the study should be successful, and v) minimum resources allowed in case of failure.

The end of the study is represented by the deep development of all design sections: subjects, methods, and statistical procedures. This document must be submitted to the approval of the ethical committee. (https://health.ec.europa.eu/system/files/2020-02/12_ec_guideline_20060216_en_0.pdf)

How do you choose the ethical committee to present the trial? Ethics Committees/Institutional Review Boards (IRBs) shall be chosen in relation to the trial's location. Suppose the hospital or clinical presiding where the trial and enlistment will be held does not have an ethics committee. In that case, reference will be made to the one reported by itself or to the one competent for local headquarters or competent administrative health area.

The documentation prepared for the ethical committee and the written request for its acceptance will be the starting point. Usually, the presentation to the ethical committee includes the health insurance for the study. Otherwise, the researchers would need to look for an insurance company experienced in clinical trials, which should provide compensation in the event of physical damage occurring during the trial. CROs usually offer this service, but, if researchers want to make it autonomously, it is sufficient to contact a big company that provides one with a local organization dedicated to this procedure.

Contacting a pharmaceutical company, a licensed pharmacy, or a company authorized to package the drug is also necessary. Researchers should provide drugs with the package leaflet of the medical product. Several multinationals and non-CROs can carry out the process of packaging and making related documentation: (i.e.,: https://www.catalent.com/; https//stmpharmapro.it/it/https:///stmpharmapro.it/it).

Documents should include the i) manufacturing site (bulk production, primary packaging, secondary packaging, quality control, batch certification), (ii) manufacturing authorization (MIA), and other (iii) specifications (control processes of drug procedures).

Also, is possible to have a sponsor for the clinical trial as suggested by the FDA guideline. (https://www.fda.gov/media/75398/download).

Once all the authorizations and documents are ready, if a sponsor is missing and the intention is that of repositioning a substance that has already passed the four experimental stages, researchers need to think only about how to administer the drug.

This step requires carefully evaluating the possible statistical permutations of events between drug and placebo, considering the different groups of patients, stratified by age, sex, economic conditions, pathological conditions, etc.

To realize a good strategy of substance administration and provide a compound that is simple to recognize and administrate, it is crucial to avoid possible errors. For this reason, researchers must implement a system of labeling and randomizing the drug vs. placebo in the various subgroups of enrolled subjects. Labels, barcodes progressively numbered, should identify the patient, the year and month of administration of the substance, and the type of administered substance. The process must be done without the researcher knowing the details, but under their direction to indicate the possible permutations.

To better understand all the procedures for repositioning a drug, which is beyond the scope of this short article, we point out the work of Zamami and collaborators 2021, and of Jourdan and collaborators 2020 [6,17].

Conclusion

The purpose of this document is to provide newly graduated students or inexperienced researchers with the first elements to understand how to conduct a clinical study, bearing in mind the type of study they want to address and the regulations in force.

On the web, there is a flood of news that can confuse the reader and often the researcher at the beginning of their career does not have an extensive portfolio to deal with their experimentation. For this reason, we have decided to draw up a list ready for orientation in designing a clinical study to better understand its focal points. This manuscript does not claim exhaustiveness and should only be considered a collection medium for valuable items.

Author Contributions

Conceptualization, G.M; A.P; and G.M; Resources G.M; Methnalisys, M.M; A.P. S.D; and G.M; Writing – Original Draft Preparation, M.M; A.P; P.I; and G.M; Writing – Review & Editing, S.D; M.M; PB; and G.M; Visualization, P.I; M.M; A.P; and G.M.; Supervision, A.P; G.M; Project Administration, M.M; S.D; A.P; and G.M.

Funding

This work was partially supported by the Italian Ministry of Health “Ricerca Finalizzata” grants: RF-2021-12374979 to A.P. The funding source was not involved in the design or writing of the report and in the decision to submit the article for publication.

Data Availability Statement

All the data shown in this paper are available in the PubMed Library. The authors created all representative draws appositely and are available on request.

Acknowledgments

All authors thank Massimo Tolu, and Massimiliano Di Virgilio for their excellent technical assistance.

Conflicts of Interest

The authors declare no conflict of interest. No sponsors participate in the choice of the items; the design of the paper; the collection of literature, the interpretation of analyzed papers; the writing of the manuscript; or in the decision to publish in the NueroSci journal.

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Figure 2. Types of Clinical studies. The flowchart summarizes the major categories of clinical trials. The right choice is essential before designing a study protocol to increase scientific quality and clinical value. The Regulatory Authorities can apply different protocols for each type of study to oversee and evaluate the clinical trial.

Table 1. major authorities for clinical trials.


Country	Regulatory Body	Actually under control of

Austria	Austrian Agency for Health and Food Safety	The European Medicines Agency (EMA) 2022
Austria	Austrian Agency for Health and Food Safety	https://www.ema.europa.eu/en
Belgium	Federal Agency for Medicines and Health Products (FAMHP)	The European Medicines Agency (EMA) 2022
Belgium	Federal Agency for Medicines and Health Products (FAMHP)	https://www.ema.europa.eu/en
Bulgaria	Bulgarian Drug Agency	The European Medicines Agency (EMA) 2022
Bulgaria	Bulgarian Drug Agency	https://www.ema.europa.eu/en
Croatia	Agency for medicinal products and medical devices of Croatia	The European Medicines Agency (EMA) 2022
Croatia		https://www.ema.europa.eu/en
Cyprus	Ministry of Health - Pharmaceutical Services	The European Medicines Agency (EMA) 2022
Cyprus	Ministry of Health - Pharmaceutical Services	https://www.ema.europa.eu/en
Czechia	State Institute for Drug Control	The European Medicines Agency (EMA) 2022
Czechia	State Institute for Drug Control	https://www.ema.europa.eu/en
Denmark	Danish Medicines Agency	The European Medicines Agency (EMA) 2022
Denmark	Danish Medicines Agency	https://www.ema.europa.eu/en
Estonia	State Agency of Medicines	The European Medicines Agency (EMA) 2022
Estonia	State Agency of Medicines	https://www.ema.europa.eu/en
Finland	Finnish Medicines Agency	The European Medicines Agency (EMA) 2022
Finland	Finnish Medicines Agency	https://www.ema.europa.eu/en
France	National Agency for the Safety of Medicine and Health Products	The European Medicines Agency (EMA) 2022
France		https://www.ema.europa.eu/en
Germany	Federal Institute for Drugs and Medical Devices	The European Medicines Agency (EMA) 2022
Germany	Federal Institute for Drugs and Medical Devices	https://www.ema.europa.eu/en
Greece	National Organization for Medicines	The European Medicines Agency (EMA) 2022
Greece	National Organization for Medicines	https://www.ema.europa.eu/en
Hungary	National Institute of Pharmacy and Nutrition	The European Medicines Agency (EMA) 2022
Hungary	National Institute of Pharmacy and Nutrition	https://www.ema.europa.eu/en
Iceland	Icelandic Medicines Agency	The European Medicines Agency (EMA) 2022
Iceland	Icelandic Medicines Agency	https://www.ema.europa.eu/en
Ireland	Health Products Regulatory Authority (HPRA)	The European Medicines Agency (EMA) 2022
Ireland	Health Products Regulatory Authority (HPRA)	https://www.ema.europa.eu/en
Italy	Italian Medicines Agency	The European Medicines Agency (EMA) 2022
Italy	Italian Medicines Agency	https://www.ema.europa.eu/en
Latvia	State Agency of Medicines	The European Medicines Agency (EMA) 2022
Latvia	State Agency of Medicines	https://www.ema.europa.eu/en
Liechtenstein	Office of Health / Department of Pharmaceuticals	The European Medicines Agency (EMA) 2022
Liechtenstein	Office of Health / Department of Pharmaceuticals	https://www.ema.europa.eu/en
Lithuania	State Medicines Control Agency	The European Medicines Agency (EMA) 2022
Lithuania	State Medicines Control Agency	https://www.ema.europa.eu/en
Luxembourg	Ministry of Health	The European Medicines Agency (EMA) 2022
Luxembourg	Ministry of Health	https://www.ema.europa.eu/en
Malta	Malta Medicines Authority (MMA)	The European Medicines Agency (EMA) 2022
Malta	Malta Medicines Authority (MMA)	https://www.ema.europa.eu/en
Netherlands	Medicines Evaluation Board	The European Medicines Agency (EMA) 2022
Netherlands	Medicines Evaluation Board	https://www.ema.europa.eu/en
Netherlands	Healthcare and Youth Care Inspectorate, Ministry of Health, Welfare and Sport	The European Medicines Agency (EMA) 2022
Netherlands		https://www.ema.europa.eu/en
Norway	Norwegian Medicines Agency	The European Medicines Agency (EMA) 2022
Norway	Norwegian Medicines Agency	https://www.ema.europa.eu/en
Poland	Office for Registration of Medicinal Products, Medical Devices and Biocidal Products	The European Medicines Agency (EMA) 2022
Poland		https://www.ema.europa.eu/en
Portugal	National Authority of Medicines and Health Products	The European Medicines Agency (EMA) 2022
Portugal	National Authority of Medicines and Health Products	https://www.ema.europa.eu/en
Romania	National Authority of Medicines and Medical Devices of Romania	The European Medicines Agency (EMA) 2022
Romania		https://www.ema.europa.eu/en
Slovakia	State Institute for Drug Control	The European Medicines Agency (EMA) 2022
Slovakia	State Institute for Drug Control	https://www.ema.europa.eu/en
Slovenia	Agency for Medicinal Products and Medical Devices of the Republic of Slovenia	The European Medicines Agency (EMA) 2022
Slovenia		https://www.ema.europa.eu/en
Spain	Spanish Agency for Medicines and Health Products	The European Medicines Agency (EMA) 2022
Spain	Spanish Agency for Medicines and Health Products	https://www.ema.europa.eu/en
Sweden	Swedish Medical Products Agency	The European Medicines Agency (EMA) 2022
Sweden	Swedish Medical Products Agency	https://www.ema.europa.eu/en
Albania;		The European Medicines Agency (EMA) 2022
Albania;		https://www.ema.europa.eu/en
Bosnia		The European Medicines Agency (EMA) 2022
Bosnia		https://www.ema.europa.eu/en
Kosovo		The European Medicines Agency (EMA) 2022
Kosovo		https://www.ema.europa.eu/en
Republic of Macedonia;		The European Medicines Agency (EMA) 2022
Republic of Macedonia;		https://www.ema.europa.eu/en
Montenegro;		The European Medicines Agency (EMA) 2022
Montenegro;		https://www.ema.europa.eu/en
Serbia;		The European Medicines Agency (EMA) 2022
Serbia;		https://www.ema.europa.eu/en
Turkey.		The European Medicines Agency (EMA) 2022
Turkey.		https://www.ema.europa.eu/en
Herzegovina;		The European Medicines Agency (EMA) 2022
Herzegovina;		https://www.ema.europa.eu/en
Yugoslav		The European Medicines Agency (EMA) 2022
Yugoslav		https://www.ema.europa.eu/en

Bangladesh	Directorate General of Drug Administration (DGDA)	https://dgdagov.info/
China	State Food and Drug Administration (SFDA), National Medical Products Administration (NMPA)	http://www.sfda.com/
China		http://english.nmpa.gov.cn/
Hong Kong	Drug Office - Department of Health	https://www.dh.gov.hk/english/main/main_ps/main_ps.html
India	Central Drug Standards Control Organization (CDSCO)	https://cdsco.gov.in/opencms/opencms/en/Home/
Japan	Ministry of Health, Labor and Welfare (MHLW), Japanese Pharmaceuticals and Medical Devices Agency (PMDA)	https://www.mhlw.go.jp/english/
Japan		https://cdx-japan.mblbio.com/
Malaysia	Ministry of Health (MOH)	https://www.moh.gov.my/
Philippines	Department of Health (DOH)	https://lawphil.net/administ/doh/doh.html
Singapore	Health Sciences Authority (HSA)	https://www.hsa.gov.sg/
South Korea	Ministry of Food and Drug Safety (MFDS)	https://www.mfds.go.kr/eng/index.do
Thailand	Food and Drug Administration of Thailand (FDATA)	https://en.fda.moph.go.th/
Taiwan	Taiwan Food and Drug Administration (TFDA)	https://www.fda.gov.tw/eng/
Vietnam	Drug Administration of Vietnam	https://dav.gov.vn/dich-vu-cong-ce5.html

Brazil	National Health Surveillance Agency (ANVISA)	The HHS Office for Human Research Protections (2021)
Brazil	National Health Surveillance Agency (ANVISA)	https://www.hhs.gov/ohrp/index.html
Colombia	Ministry of Health	The HHS Office for Human Research Protections (2021)
Colombia	Ministry of Health	https://www.hhs.gov/ohrp/index.html
Perù	Ministry of Health	The HHS Office for Human Research Protections (2021)
Perù	Ministry of Health	https://www.hhs.gov/ohrp/index.html
Cile	Ministry of Health	The HHS Office for Human Research Protections (2021)
Cile	Ministry of Health	https://www.hhs.gov/ohrp/index.html

Canada	CanadaFDA, Health Canada (HC) reviews	https://www.canada.ca/en/health-canada/services/drugs-health-products
USA	The United States Food and Drug Administration (FDA or US FDA)	https://www.fda.gov/
New Zealand	Medsafe is the Medicines and Medical Devices Regulatory Authorit	https://www.medsafe.govt.nz/
Australia	The Therapeutic Goods Administration (TGA)	https://www.tga.gov.au/therapeutic-goods-administration-tga

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