1. Overview
This guideline is aimed at sponsors who are planning to conduct a randomised, controlled clinical trial primarily using real-world data (RWD) sources to support a regulatory decision relating to a medicinal product.
This is one of a planned series of guidelines on the use of RWD for supporting regulatory decisions. For a general introduction see ‘MHRA Guidance on the use of Real-World Data in Clinical Studies to Support Regulatory Decisions’.
While the general principles outlined in the guideline are applicable to trials in any area, given the ongoing revisions to devices regulations, at this time the sections on trial approval are specific to medicines. Once the new framework for medical devices is developed this will be incorporated in future versions of the guideline.
Sponsors interested in the use of RWD in their development programmes are encouraged to engage with the MHRA for further advice on specific proposals).
2. Scope
This guideline provides points to consider when planning a prospective randomised trial using RWD sources with the intention of using the trial to support a regulatory decision. This guideline covers clinical trial authorisation (if applying for approval to run such a trial wholly or in part in the UK), and clinical trial design including choice of endpoints and safety data requirements. For requirements relating to the trial database quality and inspection please see ‘MHRA Guidance on the use of Real-World Data in Clinical Studies to Support Regulatory Decisions’.
The guideline does not cover other types of studies that could be run using RWD such as observational studies, or clinical trials using RWD as a control arm. It also does not discuss wider issues regarding randomised clinical trials that are not specifically related to the use of RWD, either general points on randomised trials or disease and product specific requirements.
In principle, evidence generated from randomised controlled trials (RCTs) using a RWD source is not generally considered of more or less value for regulatory decision making than evidence from traditional RCTs provided the data quality is robust and the trial is well-designed.
Many of the advantages of running a trial using RWD are related to reductions in patient and healthcare professional burden. Therefore, in terms of regulatory decision making, randomised trials using a RWD source may be most commonly used for label changes for already approved products, including drug repurposing, where reduced monitoring may be possible to justify. However, the use of RWD in support of a wider range of trial objectives, including the investigation of new products, may also be possible.
3. UK Clinical Trial Authorisation Definitions and Considerations for Trials of Medicinal Products
The trials covered in this document all involve randomisation of patients to one or more investigational medicinal products and therefore will be considered to be Clinical Trials of Investigational Medicinal Products (CTIMPs) as defined in the Medicines for Human Use (Clinical Trials) Regulations 2004. Such trials require a clinical trial authorisation (CTA) from the MHRA if the trial is to take place in the UK. As such, there is other guidance that is relevant when planning a trial which is applicable to all CTIMPs and can be found on the clinical trials pages of the MHRA website. Sponsors are advised to seek assistance where required using the associated contact details. The submission and approval process for all CTA applications is also detailed on the MHRA website.
As defined by The Medicines for Human Use (Clinical Trial) Regulations 2004 (SI 2004.1031): A “clinical trial” means any investigation in human subjects, other than a non-interventional study (see algorithm to determine this here), intended:
- to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products,
- to identify any adverse reactions to one or more such products, or
- to study absorption, distribution, metabolism and excretion of one or more such products, with the object of ascertaining the safety or efficacy of those products.
A “Type A” clinical trial is one where the potential risk associated with the investigational medicinal product (IMP) is considered no higher than that of standard medical care. Examples are trials involving medicinal products licensed in the UK or any EU/EEA Member State if they relate to the licensed range of indications, dosage and form or, they involve off-label use (such as in paediatrics and in oncology etc.) if this off-label use is established practice and supported by sufficient published evidence and/or guidelines. See Appendix 1 for a description of the different types of clinical trial as defined in “Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products”.
The regulatory situation will impact the Adverse Event (AE) reporting requirements. The starting point would always be full recording and reporting as per the Medicines for Human Use (Clinical Trials) Regulations 2004, and that reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) is key.
However, some flexibility is possible around the requirements for safety reporting, with more or less flexibility depending on the proposed population and expected AE profile compared to what is already known about the safety profile, and this would be considered on a case-by-case basis. For example, for type A trials, risk-adapted approaches can be taken in line with the guidance contained in the MRC/DH/MHRA joint project document “Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products”.
4. Types of RWD Trials and Points to Consider
For the purposes of this guideline, RWD is defined as data relating to patient health status or delivery of health care collected outside of a clinical study. Sources of RWD include electronic healthcare records (EHR) defined as structured, digital collections of patient level medical data, primary and secondary care records, disease registries, and administrative data on births and deaths. Other sources of RWD include patient reported outcomes (PRO) data and data which are collected outside of a clinical trial setting such as through wearable devices, specialised/secure websites, or tablets.
A hybrid trial where some of the data are RWD, and some are collected specifically for the trial outside of the RWD source is in the scope of this guidance.
In its simplest form a randomised, controlled trial using a RWD source involves patients in the real-world database being randomised to one of a choice of interventions which could include standard clinical care alone. They are then followed via routine practice. The interventions to be compared could be the intervention of interest added to standard of care, compared to standard of care alone. It could also be an active controlled comparison of an intervention of interest to another intervention indicated for the same disease or symptom.
The protocol for the study should be of the same standard that would be expected for a traditional RCT including pre-specification of the objectives, data to be collected, primary and secondary endpoints and analysis methods.
In a trial that is purely in the real-world setting, no additional data is collected on patients aside from that which is collected in the RWD source, and patients are not blinded to the treatment allocation. The triallists are given access to the specific data from the database required to complete the investigation described in the protocol. Aside from the acts of consent and randomisation, the patient experience would not be altered by being in the trial. Patient consent is required before enrolment.
Data from such a trial would provide evidence that from an MHRA perspective is equally acceptable (provided the data is robust and the trial is well-designed) for demonstrating the safety and efficacy of an intervention as data from a traditional RCT that was open-label and investigated the same population using equivalent endpoints and comparators.
Running a trial that would be acceptable for regulatory purposes in this way would be possible if the key endpoints necessary to make the regulatory decision are routinely collected in the database and are sufficiently objective such that they would not be subject to meaningful bias from the knowledge of treatment allocation in an open-label setting.
It may be necessary to introduce blinding of treatment allocation into the trial design. This could be blinding of patients or investigators/those collecting the endpoints, or both. The need for blinding should be carefully considered in the context of the particular trial being planned. In general, blinding is considered useful to reduce bias and trials should be blinded wherever possible. In particular, if the primary endpoint(s) is not sufficiently objective the trial would need to be blinded for these endpoints, unless otherwise justified. Unblinded studies may also result in different management practices depending on the drug the patient receives. Blinding of patients could represent an additional burden above routine care, as specific trial medication would need to be received rather than an open prescription, but it can be done while avoiding the need for any other deviations from routine.
If additional endpoints are needed that cannot be obtained from the RWD sources being used, a hybrid trial can be run, where the RWD can be supplemented by additional trial specific data such as additional clinical assessments or interventions. This could be done remotely but may require specific study visits.
Non-inferiority trials
If a non-inferiority design is being considered, it is important to understand the expected performance of the control arm in the trial. The non-inferiority margin is chosen based upon the expected efficacy of the reference product in such a way that ruling out inferiority of the test to the reference greater than the non-inferiority margin leads to a conclusion that the test product is acceptably efficacious. The efficacy of the reference product is usually estimated from past trials of the reference product compared to placebo, but such estimates may not be valid if all the previous evidence is from traditional trials.
Furthermore, non-inferiority trials should be run in a setting that is sensitive enough to detect treatment effect differences if these exist. In a real-world setting, clinicians are not all treating according to the same protocol; differences in background care or other factors that are usually controlled in a traditional clinical trial could introduce noise, and it will be important to ensure that the study has assay sensitivity.
Safety Monitoring
Participants in a clinical trial should be monitored appropriately, with regular safety monitoring and mitigation steps based on the identified safety profile and risk-benefit review. This includes when licensed products are used in a trial and when all or some of the monitoring is through RWD collection activities. There is a legal requirement in all clinical trials to report serious adverse events (SAEs), and this will apply to RWD trials. In particular, there is a requirement that all suspected unexpected serious adverse reactions (SUSARs) are reported as per the required timelines.
A risk-proportionate approach can be taken to Type A trials (see Section 3) and is possible for other types of trial, but must be prospectively agreed with MHRA if the trial is being run in the UK. The UK has published guidance on Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products (Appendix 1). For example, the nature and extent of patient safety monitoring should be based on the assessment of the risks of the trial intervention(s) relative to standard care and the extent of knowledge about the IMPs being tested. Any proposals should be clearly outlined in the trial protocol but can be discussed in advance with MHRA. Pre-submission discussion is particularly encouraged when frequency of collection of RWD in any arm of the trial may impact reporting of safety data to MHRA.
If products are being used outside of their licensed indications, then more frequent contact with patients is likely to be required to collect information, such as for adverse event reporting outside of routine care. The extent of safety monitoring needed would be considered on a case-by-case basis.
Detailed adverse event reporting necessitates more frequent contact with patients and the collection of information outside of routine care. The more involvement outside of routine care that is required, the smaller the advantages of running a RWD based trial become. Therefore, noting the points outlined in the last two paragraphs of section 3, randomised trials using a RWD source seem most suitable for label changes for products already approved for some other purpose, for example:
- use in a new population (different age group, different disease severity, etc. to what is already licensed) where appropriate
- change in dose, or route of administration
- adding a new indication (repurposing of existing medications)
This is not a comprehensive list of possible situations, and nothing is completely ruled out in principle, including the investigation of new drugs.
Regulatory Acceptability of RWD based trials
From a regulatory perspective whether the study data is all from the real-world setting or the result of a hybrid or traditional RCT is not critical. The important thing is that the trial is designed in a way which allows it to provide the evidence required to answer the regulatory question and a well-designed and conducted prospective randomised controlled trial provides a high level of evidence irrespective of the categorisation of the data source. The considerations regarding which endpoints are required, whether blinding is necessary, and any of the many other decisions made when designing, conducting and analysing a clinical trial depend upon the questions the trial seeks to answer and not upon the source of data. Existing regulatory guidance remains relevant to these requirements.
5. Examples of scenarios, endpoints and designs
Noting the points above, an example of a suitable scenario for a RWD based trial and an appropriate design would be:
- A trial embedded in routine practice with a well-established EHR database, defined as an EHR database that has a demonstrable record of use in research, is well characterised with an accompanying data specification, metadata and for which data quality assessments on completeness, accuracy etc. can be provided.
- An objective endpoint routinely and consistently collected in the EHR database(s) for the patient population considered of interest. For example, all-cause mortality and inpatient hospitalisations are known to be well recorded in the UK general population. Disease specific outcomes may require assessment within the proposed study population (e.g., HbA1c is known to be well recorded in primary care for the diabetic population, but less so for the general population)
- The intervention is an existing licensed product with a well-established safety profile, to be added to standard of care, and compared to standard of care with the objective of showing superiority.
- The intervention is already licensed for patients with a severe version of the condition and this trial aims to explore the benefit in patients with a milder form of the same condition.
For this example, the safety data collection requirements may be minimal as the product has a known safety profile and it would not be expected that additional knowledge which would influence a regulatory decision would be gained on safety from the new trial. Also, as the safety profile is known to be well-established, patients would not be considered to be at additional risk in this trial such that close monitoring is needed. Given that the product is already known to be efficacious in the same indication for another population, it would not be considered necessary to have a lot of supportive secondary endpoints and no additional data outside of that collected in routine care would be needed. As the endpoints are objective an open-label trial is acceptable.
If the new population is substantially different from the existing licensed population such that there is minimal confidence the existing knowledge of the safety profile could be carried across, additional safety monitoring and reporting outside of routine practice could be required.
The simplest endpoint to consider is all-cause mortality. Mortality is particularly suitable as an outcome for a RWD based trial with no blinding as it is objective and also does not require a patient to take any action to have the endpoint recorded. It is also not based on any time schedule and has a consistent method of being recorded and interpreted. If the event occurs it will be recorded in the EHR database, and if it does not occur, no action needs to be taken. All the data needed to capture the incidence of events after a particular duration, or the hazard ratio for comparing the time-to-event can be obtained with no additional patient burden. Whilst mortality will not be an appropriate outcome for all RWD based trials, its features provide a benchmark when considering other endpoints.
The completeness and validity of the recording of potential endpoints in EHR should not be assumed. For example, acute myocardial infarction, which may be perceived to be well recorded within UK primary care, was shown to be recorded with poor completeness in primary care, secondary care admissions data, and a disease specific registry, with each data source missing 25-50% of events. It is recommended that a feasibility study is conducted by the sponsor to assess the capture of study variables prior to undertaking a RWD trial, and data linkage or supplementary data collection considered as required. A feasibility study could be used to demonstrate suitable capture of exposures, key confounders and important variables.
Other measures which are used as endpoints, such as blood pressure recordings, while still objective and forming part of the EHR database, depend upon conscious actions to be recorded. Depending on the estimand of interest in the specific trial, it may be necessary to collect extra data. For example, if in a specific trial the primary estimand of interest is the effect of treatment on blood pressure at 6 months, and not earlier or later, and regardless of whether the patient stopped treatment before, then it is necessary that a blood pressure measurement is taken at that time for all patients. In this scenario, just using the value for the patient that is closest to 6 months or another imputation technique would not be an adequate replacement if a value is not generally recorded at 6 months, as it would not address the estimand of interest. Therefore, in this case, unless all patients are scheduled to have blood pressure measured at regular intervals as part of their routine care in such a way that an assessment 6 months after randomisation is expected, and it can be seen that this is reliably achieved, it would be necessary to at least perform a hybrid trial by scheduling blood pressure measurements outside of the patient’s routine care at the particular time-points of interest. Digital health technologies have the potential to be a source of data for such endpoints.
If the clinical situation necessitates that many additional requirements outside of routine practice need to be incorporated into the trial then there may be few advantages over a traditional RCT, or a traditional RCT may become necessary. However, there is a large middle-ground before this becomes the case. The MHRA is keen to meet with sponsors to discuss their trial designs for any specific situation.
An area of great interest is the repurposing of existing licensed drugs for new indications. This can often not be viable if a traditional RCT is required but could be viable in a RWD setting and sponsors are encouraged to approach the MHRA to discuss their plans.
6. Advice
This guideline lays out general principles and points to consider for sponsors considering running a randomised trial using RWD sources but cannot be comprehensive. If advice beyond what is contained in this guideline would be of interest, please request a scientific advice meeting. A scientific advice meeting to discuss your plans can include representatives with expertise in licensing, clinical trial approval, post-licensing studies, paediatric studies, medical devices, inspection and Electronic Healthcare Records as applicable.
7. Appendix 1: Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Product
The full paper is available here.
The current regulatory framework in the UK/EU allows for a range of risk-adapted approaches that may simplify the processes for initiating and conducting some clinical trials. These adaptations are largely related to how much is known about the investigational medicinal product (IMP). A simple risk categorisation is proposed, based on the marketing status of the IMP and standard medical care.
The potential risks should be balanced against the level of risk that a trial participant would be exposed to outside of the trial. We propose a three-level categorisation, based on the classification put forward by Brosteanu and colleagues in the ADAMON Project.
- Type A = No higher than the risk of standard medical care
- Type B = Somewhat higher than the risk of standard medical care
- Type C = Markedly higher than the risk of standard medical care
A pragmatic approach to achieving this would be to use the marketing authorisation status of the medicines being investigated, as proposed below.
7.1 Trial category based upon potential risk associated with the IMP
Type A: no higher than that of standard medical care
Examples of types of clinical trial
Trials involving medicinal products licensed in any EU member state if:
- they relate to the licensed range of indications, dosage and form or
- they involve off-label use (such as in paediatrics and in oncology, etc) if this off-label use is established practice and supported by sufficient published evidence and/or guidelines
Type B: somewhat higher than that of standard medical care.
Examples of types of clinical trial
Trials involving medicinal products licensed in any EU member state if:
- such products are used for a new indications (different patient population/disease group) or
- substantial dosage modifications are made for the licensed indication or
- if they are used in combinations for which interactions are suspected
Trials involving medicinal products not licensed in any EU Member State if:
- the active substance is part of a medicinal product licensed in the EU
(A grading of TYPE A may be justified if there is extensive clinical experience with the product and no reason to suspect a different safety profile in the trial population.)
Type C: markedly higher than that of standard medical care
Examples of types of clinical trial
Trials involving a medicinal product not licensed in any EU member state.
(A grading other than TYPE C may be justified if there is extensive class data or pre=clinical and clinical evidence.)