Aoife Hayes, Kevin O’Regan, and Julie Scanlon of Atlantia speak in this interview about such randomized clinical trials, the definition of such and the different types that exist. They also discuss what that means to organizations like Atlantia on an operational level and the different considerations that must be taken into account when designing randomized clinical trials, along with observing some important features of the future of this industry.
What are randomized clinical trials, and what are they used for?
AH: Randomized clinical trials have been around for a very long time. They have been evaluated in many different ways over the last hundred years, particularly in terms of the health benefits of foods. The first RCT, published by Dr. Austin Bradford Hill in 1948 when he described using streptomycin to treat tuberculosis, has become, I suppose, the goal standard in our industry in terms of providing clinical evidence for drugs and food studies.
Randomized control trials are the most rigorous way of determining whether a cause-effect relationship exists between treatment and outcome and assessing a treatment’s cost-effectiveness. There are many different types of designs that are important for randomized clinical trials. The most common type of randomized control trial that we see here is an interventional trial.
The goal is to analyze an intervention and determine if a cause-effect exists. In this way, the design of the randomized control is vital, allowing us to minimize variation due to different confounding factors that must be taken into account.
Randomized human clinical trials are one of the most important evidence bases that can be provided if the user wants to look at submitting a health claim to either the FDA or the European Food Safety Authority in Europe. The RCT is essential in terms of providing medical knowledge and indicating the effectiveness of an intervention for either disease prevention or for a health claim that you may be looking to submit in terms of marketing.
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Could you provide an overview of operations in the management of randomized control trials?
AH: There are many different factors that must be considered in the operations aspect of our business. The design of a trial is vital when the cause and effect of the intervention are being analyzed so that users can eliminate any variation that may exist due to confounding factors. This is decided at the very beginning. Furthermore, during our design, it is really important to consider the regulatory advice that is provided by the EFSA and FDA in terms of if a client would like to go towards a health claim or a marketing claim. This is particularly important at the initial stages.
The system then moves on to recruitment, which is really important for us to ensure that we recruit the appropriate population for the intervention in question and the right population to conduct analysis and reporting. This is something that is taken extremely seriously in terms of quality and data management. ICH-GCP standards are really important to ensure that our data collection follows good clinical practice, as is the employment of good scientific principles during our clinical trials.
We ensure that products are made in an environment with good manufacturing practices and a comprehensive past clinical trial review. We also look at other studies to ensure that our design is correct. An informed consent form ensures that the participant knows exactly what their responsibilities are in the trial, which is a particularly important step. We also have trial registration, which is listed by the EFSA and FDA and supports participants in terms of whether they would like to go forward and submit a health claim.
What is the importance of quality management in clinical trials, and why is quality control so important in this area?
KOR: In short, a well-established quality management system (or QMS) is integral to all aspects of clinical trials and, ultimately, the safety and wellbeing of trial participants.
A robust QMS ensures good manufacturing practice has been adhered to in the making of trial investigational product, as well as ensuring ICH-GCP and company procedures are adhered to during the conduction of a trial. Quality management ensures all the necessary steps have been taken to ensure the end product or data is clean, reliable, and accurate. ISO 9001:2015 is recognized as the international standard that specifies requirements for a quality management system. Organizations use the standard to demonstrate the ability to consistently provide products and services that meet customer and regulatory requirements.
ISO 9001:2015, the quality management criteria, is based on seven principles. These include customer focus, evidence-based decision-making and risk-based thinking, leadership and engagement of people, and relationship management. As both are interdependent, completing things like due diligence and developing a strong working relationship enhances the ability to increase value and overall quality. Relationship management can also pertain to a company’s relationship with trial participants.
A quality-controlled recruitment and enrollment process should ensure all trial participants are fully informed, understand the requirements and are freely willing to take part in a clinical trial, thus creating a good relationship in line with the principles of GCP.
The process approach looks at utilizing the organization’s activities and resources to manage them as a robust, efficient process while also ensuring quality checks are put in place throughout. Improvement is a permanent objective for all organizations, including CROs and pharmaceutical companies.
What is the importance of documentation and document control in clinical trials?
KOR: Document control is another important area in clinical trials. A controlled document can be described as any digital or hard copy entity to be managed within a tightly controlled process that maintains the integrity of the document’s content through revisions. In clinical trials, document control and handling are critical to ensure the clinical team is working from the latest information available.
If, for example, a study protocol has been amended, the clinical team must undergo relevant training, and the new amended version and the superseded protocol must be marked as so and taken out of use. Controlled documents should be identifiable via a unique code or number. They should be prepared consistently, be comprehensive, understandable, and approved by the appropriate authority. ISO 9001 states: “An organization shall maintain documented information to support the operation of its processes.” This will include things like company SOPs, work instructions, policies, information sheets, or trial-specific control documents like the study protocol, the subject informed consent form, validated questionnaires, and so on.
In addition to maintaining these documents, ISO also states an organization shall retain documented information to demonstrate that the processes are being conducted as planned. This can be captured via internal quality checks such as internal audits or documented training procedures and records. All controlled documents should be stored securely. All trial-related paper documentation, including source documents and the study trial master file, should be kept in a locked cabinet in a locked storage area in accordance with ICH-GCP.
Documented information to display staff training, on-the-job training and experience are essential to prove an investigator has the skills necessary to carry out any trial-related activity. No trial can be conducted by any person who has not been ICH-GCP trained and who has not revised the relevant SOPs, policies, and company procedures.
GCP states that: “Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective tasks.”
A current signed and dated CV demonstrates education and prior experience. Staff CVS are reviewed regularly and updated as appropriate. Only the most current and relevant CV will be made available for use in things like the investigator site file upon request. If any further trial-specific related training is required for staff members, this is organized and then documented by the quality team.
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How do these training records add an additional form of internal quality management?
KOR: These training records are available to monitors and auditors alike. Once a clinical team has been assigned to a trial, they are fully trained on the study protocol and all trial-specific procedures. The principal investigator, or PI, can delegate trial activities to the team once the appropriate training and quality procedures have been completed. A monitor is normally appointed by the trial sponsor. This can be considered an additional layer of quality control. This monitor will revise all study processes, training and source documentation and ensure research staff are conforming with GCP guidelines and protocol specifications. The trial and the participants are randomized safely. A monitoring plan is devised and shared with the sponsor, along with monitoring reports throughout the study.
The monitor’s ultimate responsibility is to ensure the rights and well-being of the participants are being protected and the study is being conducted to the highest quality standards. The monitoring process includes a site initiation monitoring visit, interim monitoring visits, and a closeout monitoring visit. Continuous improvement, as noted, is a permanent objective for every company. This can be achieved in such a context by conducting regular internal quality checks or audits and generating reports to feedback information to the clinical team. Where non-conformances are found, a root-cause analysis should be performed, and corrective and preventative action or CAPA put in place.
All the necessary steps such as retraining staff and a procedure revision should be performed to ensure the non-conformance does not happen again. Continuous improvement and improved quality can be achieved by implementing practices such as subject and client feedback surveys, consistent staff, training team and management meetings, where feedback can be given and problems discussed, and attending the latest seminars and research events to improve overall team knowledge and technical abilities, conducting risk assessments and planning in advance.
Overall, a quality management system is required to ensure the desired product is achieved that meets customers’ expectations while protecting trial participants. A robust QMS also ensures all trial data and material is protected and backed up and that disaster recovery plans are put in place if needed. Ensuring a clinical trial is quality-controlled ensures traceability, repeatability, and reliability. Typically, the quality team will work closely with the data management team, as the two are closely interrelated.
What are the most important aspects of data management in a food environment?
JS: The role of data management is increasing as clinical trial management moves more towards risk-based approaches. The most important aims of GCP are to ensure that subjects who take part in clinical trials are protected and safely randomized and that the data collected from them is reliable. The new GDPR, the EU regulation that came in on May 25th, has also set additional constraints for randomized clinical trials.
As computerized systems are used more and more in clinical trials, both the European Medicines Agency and the FDA have issued strong and clear guidelines on electronic source data, and organizations like the PICS have produced great, more in-depth guidance on the use of computerized systems within MGXP environments. The two main objectives of data manager roles within clinical trials are to ensure data quality and data integrity.
Why is structure so important for SOPs in data management?
JS: SOPs need to be well structured. As we move more and more towards electronic data capture and direct data entry, it is important to ensure that you are keeping a clear track and log of the universe of software and the platforms to validate that you are using the most appropriate and up-to-date captured electronic signatures. Every data point that we capture must have ALCOA standards.
One of the easiest ways that we have found to make an ECRF more user-friendly is to carry out a risk assessment on each data point. Once that comes back, I take on the task of designing in-depth validation for each of these points to make sure that we minimize the risk as much as possible for data capture. When it comes to meeting GCP, we retain study data and documentation – including paper documentation and all of our electronic databases, which are both primary and ancillary for at least two years after the last approval of a marketing application.
In terms of working with statisticians and working with our project manager and operations managers for data management, setting out a data management plan prior to the launch of a study helps us to find a well-selected monitoring method so we can anticipate any problems and enable better management of sponsor expectations, which is one of the most important aspects.
What are the differences between food and pharma clinical trials?
AH: These differences include the objective of the trial, and thus the design, and the populations we are looking at.
One of the reasons that we run food clinical trials is to evaluate a health benefit. Very often as well, the design is exploratory. It aims to look at incorporating interventional products, such as food or a food-related product, into a normal dietary background, and it is often in a true-to-life environment. In a free-living environment and generally healthy populations as well, we do not have to show pharmacokinetic or pharmacodynamic details as you would in a pharma trial.
If we look at the populations that we normally look at in food trials, they are normally smaller in size and they are also typically persons from a generally healthy population and are not a specific disease population. They generally take a shorter amount of time, therefore lowering cost. Most of the evidence also goes towards providing evidence based on a health claim or a marketing claim.
What can be predicted in the future of the industry?
AH: It is important to think about how fast this industry is moving and what that will look like reflected in the agencies, institutions, and the guidance we have here. This always creates room for discussion. An area for us to keep an eye on is the use of probiotics in antimicrobial resistance trials and how we are now looking at foods in a way that will have more of a medical or a clinical effect rather than health claims. This brings food clinical trials into a new and unique space.
About Atlantia Clinical Trials
Atlantia Clinical Trials Ltd is a CRO that specializes in conducting studies on foods, beverages, and supplements for companies worldwide that want to scientifically validate their functional ingredients to support an: EFSA (European Food Safety Authority) Health Claim; FDA (Food & Drug Administration) Structure Function Claim; or General Product Marketing Claim.
Atlantia works with world-leading scientists (among the top cited 1% internationally, in the areas of digestive health and functional foods) at the: APC Microbiome Institute in University College Cork, Ireland; Teagasc, Moorepark, Ireland, and recognized centers of excellence globally.
Atlantia runs and operates its own clinic sites and conducts all studies to ICH-GCP standard (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice). Its team includes physician experts in digestive health, mental health (psychological stress and cognition), cardiovascular health, sports performance, metabolic disease, bone health, immune health, and healthy ageing. The clinical team also includes project managers, research nurses, nutritionists, certified sports trainers and lab researchers.
Atlantia manages all elements from protocol design, placebo manufacture, recruitment, and study execution, to sample and data analysis, statistics, and report/dossier preparation to provide a service that is technically, scientifically, and clinically superior.
The clinical studies cover a broad spectrum of functional food and beverage categories, such as dairy, cereal, probiotics, different protein forms, infant-specific foods, vitamins/minerals, plant or marine extracts, and medical foods.