Introduction
The aim of the Health Technology Assessment (HTA) Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.
Research question
What are the benefits and harms of continuing biologic disease-modifying anti-rheumatic drugs (bDMARDs) compared with withdrawing bDMARDs in pregnant women with rheumatoid arthritis?
- Intervention: Continuation of bDMARDs throughout pregnancy (with/without standard [s]DMARDs). Applicants to specify and justify the bDMARDs of interest to be studied in this trial.
- Patient/target group: Pregnant women with rheumatoid arthritis controlled on a bDMARD (with/without sDMARDs). Applicants may wish to justify expanding the target population to include other conditions.
Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field. - Setting:Rheumatology and/or maternal services.
- Comparator: Discontinuation of bDMARDs.
- Study design: A pragmatic randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial.
- Important outcomes: Disease activity during pregnancy and up to 12 months post-partum.
- Other outcomes:Pregnancy outcomes (incl. e.g. preterm birth; pre-eclampsia); neonatal and infant/child outcomes (including neurodevelopment, congenital anomalies); child outcomes relating to vaccine administration and response to vaccines; infection (mother and/or child); health related quality of life; further escalation of therapy; side-effects; healthcare utilisation; cost-effectiveness; patient and clinician experience and acceptability. Subgroup analyses should be considered as appropriate. Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise.
- Minimum duration of follow-up: Two years post-partum for both mother and child.
- Longer-term follow up: If appropriate, researchers should consider obtaining consent from participants to allow potential future follow up through efficient means (such as routine data) as part of a separately funded study.
Rationale
Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting approximately one percent of the adult population. The condition is more common in women than it is in men. Although most common in older age groups, people can develop RA at any age. The predominant feature is a potentially deforming polyarthritis of synovial joints (especially the small joints of the hands and feet), although RA can involve other body systems such as the lungs, heart and eyes.
Historically, pregnancy has been considered to have an ameliorative effect on RA disease activity. Modern studies have shown that up to 60% of RA pregnancies improve, thus exposing 40% of RA pregnancies to increased disease activity causing joint pain, stiffness and swelling. In addition, many women experience disease flare up to six months post-partum. Given that active disease is associated with adverse pregnancy outcomes (e.g. gestational diabetes, pre-eclampsia, preterm premature rupture of membranes and caesarean section), maintenance of disease suppressive therapy is required in all RA pregnancies.
The mainstay of treatment in RA involves early initiation of standard disease-modifying rheumatic drugs (sDMARDs) such as methotrexate or sulfasalazine to alleviate pain and stiffness, control inflammation, and prevent progression, with the ultimate goal of achieving remission. Failure to respond to or intolerance of sDMARDs is an essential eligibility criterion for newer, more powerful and more expensive biologic (b)DMARDs to be used frequently in combination with sDMARDs. Use of bDMARDs have enabled substantial improvements in disease control, resulting in more women with severe disease considering pregnancy.
Prescription of many standard and biologic DMARDs in pregnancy are complicated by safety concerns. Some sDMARDs may be continued in pregnancy but other drugs must be stopped. Although, one bDMARD (certolizumab pegol) is licensed in pregnancy, as it does not cross the placenta not all women of reproductive age are prescribed this drug. Current RA guidelines recommend avoidance or withdrawal of many bDMARDs in pregnancy, unless there is concern that stopping these drugs will lead to loss of disease control. Consideration may then be given to their continuation in pregnancy. Real-world data however, comparing outcomes of pregnancies in women with RA who continue or stop bDMARDs in pregnancy are lacking.
Therefore, current clinical practice is to continue 'safe' sDMARDs and stop most bDMARDs in pregnancy. It is unknown what effect withdrawal of bDMARDs has upon disease activity, adverse pregnancy outcomes, number of hospital visits, patient experience in pregnancy and long-term response to the drug when re-started post-partum.
Continuation of bDMARDs in RA pregnancy could offer benefits in terms of maintaining disease control during and after pregnancy and reduction of adverse pregnancy outcomes, but could possibly increase patient anxiety about continuation of these drugs. However, bDMARDs are already safely used for other conditions throughout pregnancy, e.g. in inflammatory bowel disease, and increasingly in specialist centres for women with rheumatoid arthritis.
To our knowledge, the research question has not been explored in randomised controlled trials, and the management of RA controlled on a bDMARD during pregnancy remains an area of clinical uncertainty. The HTA Programme wishes to fund a study as outlined above that will generate evidence to guide future clinical practice and to inform patient choice. Applications should demonstrate buy-in from both rheumatologists and obstetricians, including maternal medicine experts, neonatologists and other relevant groups to provide a strong interdisciplinary team, including PPI. The HTA Programme expects applicants to address the issues of equipoise.
The programme acknowledges that in addition to rheumatoid arthritis, it is also unclear whether pregnant women with other inflammatory conditions should continue or withdraw biologic drugs during pregnancy. Applicants who wish to include additional patient groups in the proposed study should justify their decision and explain how multiple groups would be managed within the trial.
Applications should be co-produced, demonstrating an equal partnership with service commissioners, providers and service users (or their advocates) in order to provide evidence and actionable findings of immediate utility to decision-makers and service users. Applicants may wish to consult the NIHR Learning for Involvement guidance on co-producing research.
Additional commissioning brief background information
A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email htaresearchers@nihr.ac.uk.
Making an application
If you wish to submit a Stage 1 application for this call, the online application form can be found on the Funding opportunities page. To select this call, use the filters on the right of the screen or search using the call name and/or number.
Your application must be submitted online no later than 1pm on the 27 July 2022. Applications will be considered by the HTA Funding Committee at its meeting in September 2022.
Guidance notes and supporting information for HTA Programme applications are available.
Important: Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in January 2023.
Applications received electronically after 13:00 hours on the due date will not be considered.
For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application e.g. a lead from a named charity or a unique national expert in a condition.
For such exceptions (i) each application needs to state the case as to why the same person is included (ii) the shared co-applicant should not divulge application details between teams and (iii) both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared.
Should you have any queries please contact us by email: htacommissioning@nihr.ac.uk