Introduction to R-RCT

What are registry-based randomised clinical trials (R-RCT)?

Registry-based randomised clinical trials (R-RCTs) are defined as prospective randomised trials (RCT) that to some extent use registries for their implementation. The most common type of registries used for R-RCT are quality registries. A quality registry is a structured collection of personal data established specifically for the purpose of systematically and continuously developing and ensuring the quality of healthcare, and not primarily for research purposes.

An R-RCT can use a registry in different ways. What is appropriate in each case depends, for example, on the design of the registry and whether there is any possibility of adapting the registry with a technical solution/study application for the needs of the study as well as how the registry is used by the staff in everyday clinical practice. For example, in an R-RCT, the registry can be used to find suitable study participants for inclusion, background and outcome measures, or for collection of existing patient reported measures (PROMs). If study-specific PROMs are to be collected, this is best done via a complementary Electronic Data Capture (EDC) system such as an eCRF.

Tasks/elements that can be performed with quality registries

This overview is mainly intended to support the planning and implementation of R-RCTs where the study is conducted by collecting data from an existing quality registry.

• Through a developed technical solution/study application, selected inclusion criteria for the study can be monitored and the clinic staff can be alerted in the quality registry if a patient would be suitable for the study.
• Screening/inclusion and possible randomisation of study patients in connection with registration in the quality registry through technical solution/study application.
• Study-specific variables for screening/inclusion and possible randomisation are collected in specific study database.
• Using existing registry variables as study variables. The variables of the registries can be found on the registry's websites and on the Swedish Research Council's metadata service RUT External link..
• Manage participating clinics, display the inclusion in the R-RCT on the registry website, display detailed information on screened patients in logged-in mode for each clinic.
• Export screening and inclusion information for each clinic through technical solution/study application.
• Data extraction for reports/monitoring/interim analysis. Extraction takes place according to the particular registry centre’s data extraction processes for quality registries.
  
  

When is R-RCT suitable?

R-RCT is best suited for questions about treatment strategies or method comparisons. Questions involving the comparison of already approved medicinal products or CE-marked medical devices are also possible but require permission from the Swedish Medical Products Agency (please read more under the section Consequences of trials that belong under GCP).

A well-defined primary objective with few secondary objectives based on existing registry variables is recommended. The more secondary objectives(outcome measures) and/or the desire to collect variables that are not in the registry, the more work and the higher the cost.

The simplest form of R-RCT compares established treatments for an outcome measure (endpoint) that can be taken from information already collected in the registry (or by cross-checking with another registry). Mortality, hospitalisation and/or readmission are common outcome measures (endpoints) that can be monitored without affecting the regular healthcare process.

Issues to consider for a successful R-RCT:

• The study is planned together with representatives of the registry.
• Do study-relevant variables have good coverage in the registry?
• Is it mandatory to fill in the critical variables of the study in the registry?
• The continuous development of the quality registry, which may involve changes in variables during the study period.
  
• What is the coverage of the study's target population in the registry?
• Is it a direct registration in the register or is the routine to register later? This must be considered during planning.
• How fast do clinics record data in the registry? What is the time delay between an event (e.g. a bleeding/myocardial infarction/other complication) and its actual registration in the registry?
• Are the data in the registry of sufficient quality, in terms of external and internal validity, to form the basis of research on?
• How is the ongoing monitoring of the registry conducted?
  
  

System support

Much of what makes an R-RCT cost-effective is that it can be integrated into the healthcare system and is a registry that is already used in the healthcare system. However, it is not evident that all qualityregistries are designed, implemented and used in a way that makes them suitable as a basis for an R-RCT. Regardless of the registry's design,, specific technical solutions/study applications must be adapted and quality assured for each individual study. The fact that the registry contains data on patients is only of value if it is the same data that the study needs and if it is maintained with sufficient quality.

Make careful analysis with the technical management

Once there is an idea for an R-RCT, a careful analysis of how the registry will be used in the study is needed. It should be analysed with the technical management of the registry whether it is possible to adapt the registry with the technical solution/study application required and at what cost. Other options for data collection that do not involve adaptation of the registry should be explored. A combination of registry data and eCRF is common in an R-RCT.

If the study is to be conducted under Good Clinical Practice (GCP)

If the study is to be conducted under Good Clinical Practice (GCP), it is a requirement that electronic systems used in the study must have been formally validated. In such a case, integrating randomisation into the quality registry is not recommended, as validation involves a high workload for the registry management team and a higher cost for the study. For these studies, an alternative technical solution should be used to use a study application independent of the registry where additional patient information is entered and the randomisation is done. Subsequently, manual or automatic data extractions are made from the registry. It could be beneficial to add a link to the study application in the quality registry to simplify the process for clinical staff.

Time and resources

Building a technical solution/study application for an R-RCT requires careful planning. All the requirements needed to develop the technical solution/study application must be carefully planned in collaboration between researchers, registry controllers and the “supplier” of the technical solution/study application. The planning should also include management of the study within the registry and a plan for data export and removal of the study within the registry. During the study, no variables used in the study should be updated (either registry variables or study-specific variables in the technical solution/study application) without discussing the implications of these changes. The study should be aware of the registry's long-term development plan and how it may affect the study. A plan for communication between the study and the registry should be established.

Time savings with R-RCT

The start-up period for an R-RCT is significantly longer and more time-consuming than for a traditional RCT. There is often a waiting period to start an R-RCT in a registry depending on the registry's regular priorities and other ongoing R-RCTs. The cost of preparing an R-RCT should be compared to the potential time gain estimated in the overall conduct of the study.
The time savings are made in the clinics where research support staff get more time to include patients. The entry time in the eCRF is reduced as the information is partly entered directly into the registry. Patients can be randomised and included faster because the registry can automatically give an alert when a patient is suitable for the study, if the technical support for it is available. However, this requires clinic staff to be logged into the register and enter data directly when the patient is present. Usually this means that the registry detects whether the inclusion criteria for the R-RCT are met and then provides a notification that the patient meets the requirements for the relevant R-RCT. Considering the practices of the clinics can therefore be crucial for a successful R-RCT.

Cost of an R-RCT

The cost of an R-RCT depends on many factors and needs to be calculated for each individual study. An R-RCT involves some new costs compared to a traditional RCT. Depending on the extent and complexity of the technical solutions and validation required for the study, there will be an increased management cost in terms of technical support such as:

• Operation
• Bug fixes
• Adjustment of solution
• Support
• Data extraction

This should be compared to the time and cost for clinicians to enter study data into a traditional eCRF. It is therefore important to take this into account at the planning stage of an R-RCT.

Quality

The possibilities to ensure data quality differ between quality registries and eCRFs. This is because in an eCRF there is the possibility to add logic controls to the specific study. Data in registries are collected for a different purpose and under different legislation and it is therefore possible that there is a different practice on how and what to document. Another factor that may make a difference is that there may be a larger group of staff entering data into a register. If specific instructions or directions are required for data entry in the study, an eCRF should be used.

Ongoing quality control

Ongoing quality control is most easily done by extracting data from the registry or by continuously saving the study data in an EDC or study database if a technical solution/study application for this is available. The agreement for data extraction for quality control should be established between the study and CPUA authorities before the start of the study and mentioned in the application to the ethical review board. If the study falls under GCP then please read more in the section Consequences of studies falling under GCP.

Advantages and disadvantages of R-RCTs and RCTs

As a rule of thumb, an R-RCT can be regarded as most effective when:

• The study is integrated in only one registry.
• All safety and primary outcomes are available in registries.
• Minimal changes must be made to the clinic's normal workflow.
• No completion/follow-up needs to be done in an EDC system.
• The study has a short recruitment and follow-up period.
• The patient population is large.
• Patients are randomised to compare established and approved treatments.
• Training requirements to comply with the protocol are low.
• The registry where the inclusion will be made is used at the time of meeting the patient.
  

When choosing between designing the study as an R-RCT or as a traditional RCT, the advantages and disadvantages of the concepts should be considered.

Advantages and disadvantages of an R-RCT