Each subsection below includes two parts. The subsection opens with an explanation of the subject and guidance on how to address it. This is followed by a list of tools that have been identified in relation to this subsection. The tools listed may not be unique to clinical trials in rare diseases, this is specified in the table to better understand the use of the tool. You can visit the different section by clicking on the buttons above or return to the full toolkit here.
DEFINE A QUESTION
The definition of the research question is key to research design. All research must have a primary question, clearly stated in advance, and founded on a systematic review of what is already known. Researchers who plan studies without reviewing what has been done, risk performing research for which the answer is already known or exposing participants to ineffective or inferior treatment.
Evidence suggests that research protocols often lack important information on study design. The study protocol should provide an adequate explanation for why the proposed study methodology is appropriate for the question posed, why the study design is likely to answer the research question, and why it is the best approach.
The planning of a clinical trial depends on the primary question, and researchers should clearly and simply explain in the study protocol what the trial is aiming to show, why it is worth asking and, through consultation with public and patient groups, why this is worthwhile to patients. The primary question should be consistently stated throughout the study protocol.
The question should generally include specific information on participants, intervention(s), comparator(s) and outcomes (PICO format):
- Population: what are the characteristics of the patient or population-e.g. condition?
- Intervention: what is the intervention under consideration for this patient or population-e.g. a drug or surgical intervention?
- Comparison: what is the alternative to the intervention-e.g. a different drug or a placebo?
- Outcomes: what are the key outcomes the study would measure and how do they answer the primary question? e.g. mortality, disease progression, surrogate parameter?
|Tool Name||Relevance||Year||RD/ Paediatric specific||Type|
|Cochrane PICO search||PICO searchBETA allows you to use PICO terms to find the Cochrane Reviews most relevant to your healthcare question. In particular, it allows you to find reviews in which a term is used specifically as a population, an intervention, a comparison, or an outcome||2020||No||Search tool|
DEVELOP A PROTOCOL
The ICH GCP (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice) guideline defines the protocol as “A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial”
The research protocol explains how the proposed study methodology is appropriate for the question posed, demonstrates that the design is likely to answer the research question and why it is the best approach. The protocol should explain:
- The rational, background information and literature review
- how the relevant successes and failures of previous studies have been taken into account in the design of the planned trial
- how the proposed research method is appropriate for the question posed
- the reasoning behind the choice of any treatment difference sought, as well as the other parameters used in the determination of the sample size
- the choice of comparators and end points
- the randomisation and blinding methods
- the suitability of the statistical tests
- how the sample to be studied is representative of the wider group of patients
The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement 2013 is a guideline for the minimum content of a clinical trial protocol. It includes a 33-items checklist that applies to protocols for all clinical trials and focuses on the content of a clinical trial protocol.
Clinical investigators in rare diseases research also regularly face challenges specific to the study of common disorders. Perhaps the most frequent problem is recruitment. These recruitment challenges and the reduced study sample sizes directly lead to the need for the adoption of specialized study designs and biostatistical techniques developed to maximize data from small numbers of subjects.
|Tool Name||Relevance||Year||RD/ Paediatric specific?||Type|
|ICH General considerations for clinical studies E8||Describes internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medical products||1997||No||Guideline|
|ICH General principles for planning and design of multi-regional clinical trials||Describes general principals for the planning and design of randomised multinational clinical trials with the aim of increasing its acceptability in global regulatory submissions||2017||
|ICH Clinical investigation of medicinal products in the paediatric population E11 (R1)||Provides an outline of critical issues in pediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the pediatric population. The purpose of this addendum is to complement, provide clarification and current regulatory perspective on topics in pediatric drug development.||2017||Yes||Guideline|
|European Medicines Agency Guidance for Applicants seeking scientific advice and protocol assistance||This guidance document addresses a number of questions that users of the scientific advice or protocol assistance procedures may have.
It provides an overview of the procedure to obtain scientific advice or protocol assistance and gives guidance to Applicants in preparing their request. This guidance document also explains the scope and nature of scientific advice and protocol assistance. It will enable Applicants to submit requests which are in line with Scientific Advice Working Party (SAWP) requirements and which can be validated and evaluated quickly and efficiently.
|IRDiRC E104 Building Block_ National Member State Scientific Advice||Procedures set up by many (but not all) National Member State to offer scientific advice
to developers of new medicines. The procedures can be similar but often less formal than
for CHMP scientific advice/protocol assistance at the EMA; they may include written
advice and/or face-to-face meetings. The procedures are not limited only to orphan product development and may vary between Member States.
|IRDiRC Building block_ Alternative designs for small population clinical trials||General recommendations to select the most efficient study design for each medical condition or trial and on potential adaptations of conventional designs to the low sample size scenario||2020||Yes||Guideline|
|EMA Guideline on clinical trials in small populations||This Guideline considers problems associated with clinical trials when there are limited numbers of patients available to study. It has been prepared by the CHMP (Committee for Medicinal Products for Human Use) Efficacy Working Party in joint collaboration with members of the Scientific Advice Working Party (SAWP), the Committee on Orphan Medicinal Products (COMP) and the Paediatric Expert Group (PEG).||2007||Yes||Guideline|
|Design and analysis of clinical trials for small rare disease populations (Hilgers et al., 2016)||This paper refers to the current state of design and analysis methods, as well as practical conditions to be considered when conducting a clinical trial for rare diseases.||2016||Yes||Article|
|Recommendations for the design of small population clinical trials (Day et al., 2018)||Recommendations of the IRDiRC expert group on clinical trials for RD around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients’ engagement in study design||2018||Yes||Article/Guideline|
|Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative (Bogaerts et al., 2015)||The IRCI (International Rare Cancers Initiative) trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.||2015||Yes||Article|
|Opinions and letters of support on the qualification of novel methodologies for medicine development||The European Medicines Agency (EMA) publishes opinions on the qualification of innovative development methods and letters of support for novel methodologies that have been shown to be promising in the context of research and development into pharmaceuticals.||Regular updates||No||Recommendation|
|COMET: Core outcome measures in effectiveness trials||The COMET Initiative brings together people interested in the development and application of agreed standardised sets of outcomes, known as ‘core outcome sets’ (COS). These sets represent the minimum that should be measured and reported in all clinical trials of a specific condition, but COS are also suitable for use in routine care, clinical audit and research other than randomised trials||Regular updates||No||Checklist|
|Cochrane Central Register of controlled trials||The Cochrane Central Register of Controlled Trials (CENTRAL) is a highly concentrated source of reports of randomized and quasi-randomized controlled trials. In addition to bibliographic details (author, source, year, etc.) CENTRAL records will often include an abstract (a summary of the article). They do not contain the full text of the article.||Regular updates||No||Registry|
|SPIRIT Statement (Standard Protocol items)||Reporting guideline defining standard protocol items for clinical trials. The evidence-based SPIRIT recommendations were developed using systematic, transparent methodology and broad consultation with 115 experts representing diverse stakeholders involved in the design, funding, conduct, review, and publication of trial protocols.||2013||No||Checklist|
|SPIRIT Statement (Standard Protocol items) for n-of-1 trials||Extension to the SPIRIT (standard protocol items: recommendations for interventional trials) guideline, SPENT (SPIRIT extension for n-of-1 trials), to improve the completeness and transparency of n-of-1 trial protocols.||2019||Yes||Checklist|
|SPIRIT PRO Extension for inclusion of patient-reported outcomes in clinical trials protocols||Extension of the SPIRIT (Standard protocol items: recommendations for interventional trials) guideline, SPIRIT PRO provides guidelines for inclusion of patient-reported outcomes in clinical trial protocols.||2018||No||Checklist|
|Measuring health-related quality of life in patients with rare disease (Lenderking et al., 2021)||This article explores some of the challenges in HRQoL assessment in rare disease, propose solutions, and consider regulatory issues||2021||Yes||Article|
|Patient reported outcome measures in rare diseases: a narrative review (Slade et al., 2018)||This review explores some of the current issues around the utilisation of PROMs in rare diseases, including small patient populations and dearth of valid PROMs. Difficulties in validating new or current PROMs for use in clinical trials and research are discussed||2018||Yes||Article|
|PROMs Repository||The ERICA Patient Reported Outcome Measures (PROMs) Repository is the first attempt to identify and centralize Clinical Assessment Outcomes questionnaires of relevance for rare diseases and constitutes a milestone in the Europe-wide standardization of Patient-Centered Outcome Measures (PCOMs) and PROMs for rare diseases.||Regular updates||Yes||Repository|
|COSMIN: Database of systematic reviews of outcome measurement instruments||Database of systematic reviews of outcome measurement instruments||Regular updates||No||Database|
|PARADIGM patient engagement toolbox||This project deliverable centralises all PARADIGM’s co-created recommendations, tools and relevant background information to make patient engagement in medicines development easier for all. The toolbox could help develop clinical trials with a further enhanced patient-focus and improve the experience of patients participating in the trials. Developed by PARADIGM project.||2020||No||Toolbox|
|EUPATIConnect||EUPATIConnect matches patient experts with researchers to create mutually beneficial opportunities and to enhance the future of patient engagement.||2022||No||Advisory board|
|EURORDIS Community Advisory Board (CAB) Programme||Patient Community Advisory Boards (CABs) are groups established and operated by patient advocates. They offer their expertise to sponsors of clinical research. For example, by being involved before a clinical study starts, patients help ensure that clinical studies are designed to take into account their real needs, resulting in higher quality research.||NA||Yes||Advisory Board|
|EDCTP Protocol development tool||An initiative of the Global Health Network, this Protocol Development Toolkit has been developed to support researchers in this process, to provide the tools and guidance to produce a high-quality health research Protocol.||Regular updates||No||Toolbox|
|Assessment of short-term outcome of neonatal trials: Points to consider||PedCRIN tool: This tool lists examples of data items for the assessment of short term efficacy and safety outcomes of neonatal trials||2021||Yes||Guideline|
|Assessment of long-term outcome of neonatal trials: Points to consider||PedCRIN tool: This tool lists examples of data items for the assessment of long-term efficacy and safety outcomes of neonatal trials||2021||Yes||Guideline|
|Protocol development for neonatal trials: Points to consider for pharmacovigilance||PedCRIN tool: This tool gives points to consider concerning pharmacovigilance and risk management at the time neonatal protocol development||2021||Yes||Guideline|
|Exclusion criteria in neonatal trial protocols: Points to consider||PedCRIN tool: This tool gives points to consider concerning pharmacovigilance and risk management at the time neonatal protocol development||2021||Yes||Guideline|
IDENTIFY A SPONSOR
The WHO and ICH for Good Clinical Practice guidelines, issued in 1995 and 1996 respectively, define a sponsor as “an individual, a company, an institution or an organization which takes responsibility for the initiation, management and/or the financing of a clinical trial”.
This definition reflects the situation at the time of these guidelines´ publication, when clinical trials were mainly conducted by commercial organizations (usually a pharmaceutical company) assuming both roles, sponsor and funder.
The latest EU Regulation (2014), defines the sponsor as “An individual, company, institution or organization which takes responsibility for the initiation, the management and for setting up the financing of the clinical trial”
This latest definition clarifies that the sponsor is equally scientifically, legally and financially responsible but with new wording acknowledges that the budget can either come from the sponsor itself or from sources external to the research group. This shift in the European legislation is in line with the growing attention paid to non-commercial research.
The sponsor is ultimately responsible for the scientific, ethical, regulatory and legal aspects of the trial, and also for financial aspects (i.e., if an external funder withdraws, the sponsor will be responsible to look for funds to complete the trial).
The latest European regulation for clinical trials on medicinal products for human use introduces the possibility of co-sponsorship in Europe, while for Sponsors located out of the EU a legal representative of the Sponsor is needed.
In commercial research, the same organization (usually a pharmaceutical company), funds, designs and carries out a trial, acting both as sponsor and funder.
Investigator-initiated trial (IITs)/Academic-sponsored trials
Commercially sponsored clinical trials are responsible for bringing most of the new drugs to the market. However these clinical trials only assess the safety and efficacy of drugs that are chosen by a commercial entity that funds the entire process. Non-commercial or academic trials have therefore their own additional specific significance, often focusing on refining indications of available treatments and to optimize therapeutic strategies that do not have as much financial gain to the pharmaceutical industry.
A good amount of IITs are driven by questions that generally arise beyond the completion of Phase III studies and which have not been studied during Phases I–III of drug development.
For IITs, academic institutions usually act as the sponsor (academic-sponsored trials), but not necessarily as the funder. Only in a few cases will academic sponsors be able to conduct trials without external funding, usually coming from different sources. This often leads to complex arrangements with multiple partners joining in international consortia. The setup of a complex multi-national partnership may sometimes be at odds with the concept of “single sponsorship” which was developed for ensuring the protection of participants in the context of commercial trials. Single sponsorship is rooted in the need to clearly identify the legal responsibility and does not hinge upon the funding aspect. Noteworthy, most funding agencies are unwilling to take on the role of sponsor and often they may not be suitable for it.
Sponsor-Investigator is an individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
Collaboration with industry - For some IITs, pharmaceutical companies might act as funders. The pharmaceutical company can support IITs with drug supply, funding, material and/or information, as allowed under local laws and regulations, provided that they align with the company defined areas of strategic interest. Some big pharma companies publish guidelines describing the conditions to establish collaborations with academic-sponsors for IITs.
|Tool Name||Relevance||Year||RD/Paediatric specific||Type|
FIND A FUNDER
Industry-initiated clinical trials are financially supported by the industry. The primary investigator (PI) salary and the costs associated with running the trial are all covered by the pharmaceutical or medical device company that conceived the clinical trial. In investigator-initiated trials, however, it is usually the PI who applies for funding through research programs and government grants to fund their conceived research project.
Industry funded trials
Industry- funded and industry-sponsored clinical research is paid by an industry organization that has contracted with a faculty member to conduct a clinical trial that involves an intervention with, or observation of, a disease or biomedical condition, or a registry/repository related to a disease or biomedical condition. For most industry-funded clinical trials, the industry organization designs the study and owns the protocol, data and results.
Academic-sponsored trials funded by industry
Collaboration between industry and academics is common in the development of vaccines, drugs, and devices, as it can be mutually beneficial. The academics provide access to trial participants and clinical and methodological expertise, and industry provides funding and expertise. The degree of independence and the roles of academics and industry vary across trials. Trials may be run by academic trial units independently but with unrestricted industry funding, or the only contribution from industry could be free provision of study drugs.
Publicly funded trials
Many national research funding agencies open regular calls for funding clinical research, supporting academia/investigators to set up clinical trials. This funding is nevertheless usually restricted to the national level. Indeed, despite the advantages of multinational clinical trials, just 3% of academic trials (vs. 30% of industry trials) involve more than one country. In Europe, the relative scarcity of multinational academic trials can be explained, in part, by restrictions with current cross-border funding options.
Funding by a central European Budget
Horizon 2020 (H2020) has been the biggest EU Research and Innovation programme ever, with nearly €80 billion of funding available over seven years (2014 to 2020). Most multinational clinical trials have been funded under the H2020 “Health, demographic change and wellbeing” programme. Starting in 2021, the Program Horizon Europe is the new Framework Program which will run from 2021 to 2027. Subsidy calls will include funding for clinical studies and clinical trials for rare diseases.
European and industry funding combined
The Innovative Medicines Initiative (IMI) is another source of European funding dedicated to public-private partnership projects. Non-industry partners in consortia receive public funding, while companies contribute to the projects through in-kind contributions.
In general, national funding agencies do not accept funding crossing borders, inhibiting international collaboration. Notable exceptions include Innovation Fund Denmark, which funds clinical trials with a significant share for international partners.
Other countries have limited cross-border funding. For instance, the German Research Foundation (DFG) considers provision of a maximum of 20% of a clinical trial budget to sites in Austria, Luxembourg and Switzerland.
An alternative strategy is creating a common pot for funding trials and has been adopted by the Nordic Trial Alliance (NTA), running from 2013 to 2015 and covering Denmark, Finland, Iceland, Norway, Sweden, the Faroe Islands, Aland Islands and Greenland. Funding supports the multinational expansion of clinical studies whose funding is secured in the coordinating country. Supported trials must be run in a minimum of three member countries.
ERA-Net funding mechanism
Since cross-border funding is not possible for most funding agencies, countries have begun to join forces by coordinating national sources to fund multinational projects using a European Research Area Network (ERA-Net), an instrument created by the European Commission.
In an ERA-Net, national agencies fund projects and the Commission supports coordination and evaluation and contributes to funding. An ERA-Net can cover a large number of diverse countries and combine national sources, with each country supporting the aspects of the trial that occur nationally.
Previous ERA-Nets for rare diseases (e.g., E-Rare), cancer (e.g., TRANSCAN) and neurosciences (e.g., NEURON) had focused on basic, translational and clinical research.
|Tool Name||Relevance||Year||RD/Paediatric specific||Type|
|Exploring new uses for existing drugs: innovative mechanisms to fund independent clinical research (Verbaanderd et al., 2021)||This paper describes and discusses funding opportunities for independent clinical repurposing research||2021||No||Article|
|An open, curated and structured research funding database||Regular updates||No||Database|