A call for harmony on clinical trials
pharmafile | July 1, 2013 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | Frédéric Sgard, OECD, clinical trials
Clinical trials are an essential part of the development of medical treatments. They involve testing new medicines or new therapies, as well as optimising existing medicinal products and procedures, by carrying out carefully controlled investigations on patients.
Although the majority of these trials are still conducted by the pharmaceutical industry, an increasing number are initiated and driven by academic investigators for non-commercial purposes. Many of these trials are driven by pressing public health needs and scientific opportunities that do not offer a strong business case to private companies.
This can be due to the small number of patients affected (e.g. orphan diseases), to insufficient profitability of the treatments (e.g. paediatric therapies, pathologies in developing countries), or because the objective is simply to improve existing procedures and prescriptions (e.g. finding the optimal drug combination or timing).
To find the required diversity of trial participants as well as to enhance the likelihood that the research findings are broadly applicable worldwide, these clinical trials increasingly involve international studies and collaboration.
Strict national regulations have been introduced over time to ensure patient safety and methodological quality. Depending on the country and on the nature of the trial, supervision is either based on specific legislation, on rules originating from the competent authorities, or merely on ethical guidelines. As a result, applicable regulatory mechanisms differ widely across countries.
National regulations ensure patient safety and the methodological quality of clinical trials. The current administrative complexity is such that it leads many well-conceived clinical trials aimed at addressing important public health problems to either not be conducted, or to be so delayed that their impact is dramatically reduced (in the European Union alone, the total number of applications for clinical trials fell by 25% between 2007 and 2011).
This is particularly true for the conduct of international clinical trials that involve multiple centres, and for trials initiated by academic structures that may not have well-developed administrative support, and may not have the financial resources available to private companies to seek the support of contract research organisations which can help sponsors to perform their studies.
Unsuitable administration
In addition to the challenges presented by the existing national regulatory complexity, many clinical trial investigators have to abide by administrative requirements that are poorly adapted to the nature of their study.
Existing regulations have mostly been developed to guide the conduct of traditional trials for new medicines, which present an unknown risk for patients. They are often less suited to address the many academic trials that use drugs that are already marketed and often present lower risks.
To promote medical research and to help regulators overcome this problem, the Organisation for Economic Co-operation and Development (OECD) has therefore issued a Recommendation to its members to harmonise their clinical trial approval processes. The objective is to encourage international collaboration in clinical research and streamline procedures for conducting clinical trials.
The initiative results from an in-depth analysis of the problems encountered in medical research. In 2010, the OECD Global Science Forum initiated a project to investigate existing difficulties and to propose measures to facilitate international co-operation in clinical trials that are set up for non-commercial purposes.
This was carried out by a Working Group composed of experts appointed by member state governments through health ministries and /or research ministries, and representatives of major international organisations.
The Group’s findings and policy recommendations were published in late 2011. As part of the project, the Working Group conducted a global survey among the various stakeholder communities to identify the most critical areas of concern for the conduct of international clinical trials.
From the survey findings, it clearly appeared that the lack of harmonisation and problems with interpreting highly heterogeneous regulatory procedures created hurdles that were difficult to overcome by many academic sponsors wishing to collaborate with groups in other countries. There was a growing demand for better ways of aligning the regulations between countries, which should also take into account the risks associated with the study in their requirements.
Risk defining
Such a new regulatory system would, however, require a consensus on a number of key issues, such as how to define the risk, which institution should be in charge of defining and validating potential risk categories, and which existing regulatory and monitoring processes would be affected.
Although there was broad consensus on the desirability of adopting a risk-based approach to clinical trials regulation, there was not yet a mechanism to help align regulatory requirements for clinical trials worldwide, or to develop and validate the risk assessment tools and risk-adapted monitoring procedures needed for the use of such risk-based approaches in international clinical trials.
The set of principles adopted by the Council of the OECD in December 2012 were devised through a consensus effort by scientists, physicians and regulators. It introduces a risk-based oversight and management methodology for clinical trials.
This framework combines a stratified approach that is based on the marketing authorisation status of the medical product and can be applied in a common manner across countries’ regulatory frameworks, with a trial-specific approach that considers other issues such as the type of populations involved in a trial, and the informed consent of the patients.
Stratified categories
The proposed stratified approach distinguishes three categories, which can be related to the clinical development of medicinal products:
Usual care (Category A): Clinical trials testing authorised medicinal products in accordance with the marketing authorisation; Modified use (Category B): Clinical trials testing authorised medicinal products according to treatment regimens outside the marketing authorisation, either supported (a), or not supported (b) by published evidence and/or guidance and/or established medical practice (note that categories Ba and Bb are not necessarily related to clinical trial Phases II and III respectively); New product (Category C): Clinical trials testing non-authorised medicinal products.
This three-category system allows for a good alignment of the requirements for international clinical trials: category A roughly corresponds to the non-commercial (non-IND, non-chiken) trials outside Europe, where no oversight by the regulatory authority is usually required. This will facilitate the independent assessment by academic institutions of medicinal products and treatment strategies, which is a critical activity for the optimisation of healthcare and for cost containment.
In turn, clinical trials on non-authorised medicinal products, or medicinal products used outside the licensed indication require approval by the appropriate regulatory bodies. Making an additional distinction between category B and category C takes into account the fact that, for category B, information is already available on the efficacy and safety of the medicinal product (although for a different disease indication or population), and the fact that the product is already manufactured, labelled, marketed and distributed.
Compared with category C, category B is therefore associated with a lower risk, allowing for adapted requirements. This may facilitate the management of category B trials, conducted mostly by independent researchers to explore new indications, particularly in cancer and rare diseases.
Within the B category, a distinction is proposed between trials where the medicinal product is used according to treatment regimens outside the marketing authorisation, either supported (Ba) or not supported (Bb) by published evidence and/or guidance and/or established medical practice.
As Ba trials explore conditions that represent the standard of care, this distinction makes sense with regards to insurance/indemnity, and to the recommendation that the cost of the treatment given as part of the clinical trial be borne, for investigator-driven trials, by the usual public or private health insurance schemes.
Although this proposed stratification differs slightly from that proposed in the new regulation submitted by the European Commission, it does follow a similar spirit and extensive discussion between the OECD expert group and EC experts have ensured that both texts are broadly compatible.
Something new
The trial-specific approach however, is something new which provides a framework for taking into account, for each individual trial, not just the risk associated with the medicinal product, but the whole spectrum of risk determinants for defining trial management and operations: risk to the patient rights, to the patient safety and integrity, to the results and to the consequences for public health, preferably supported by a decision tree or a guidance document.
Risk assessment also considers the experience and training at the investigation site, as well as the robustness of procedures, as determinants for data credibility. The concept of quality-by-design broadens this approach, stating that the trial should be designed to maximise the robustness of data collection and analysis.
In particular, it aims at ensuring that the protocol identifies the critical data and procedures, and that the monitoring plan focuses on these critical points. Therefore, although the implementation of the OECD Recommendation would result in streamlined procedures for low-risk trials, it would at the same time strengthen the protection of the patients and increase the quality of the data and the credibility of the results.
This recommendation has been primarily driven by the need to facilitate co-operation among academic groups for clinical trials undertaken for non-profit purposes, but countries may wish to extend its implementation to the oversight and management of all clinical trials, thus adopting principles similar to those enumerated below regardless of the objective of the trial.
The policy guidance is optimised to reducing the burden of trial oversight as far as possible. It should help countries that are engaged in revising their existing regulatory mechanisms. It is expected that this will enhance international co-operation in the field of clinical research, to the benefit of the many patients who require better treatments.
The 2011 and 2012 OECD reports can be found at: www.oecd.org
Frédéric Sgard is a science policy analyst at the OECD Global Science Forum secretariat.
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