Quantitative faecal immunochemical testing to guide colorectal cancer pathway referral in primary care

Most of the evidence was from populations that did not exactly match the population defined in the assessment scope. Some populations only included people with high- or low-risk symptoms (see section 2.3), and some populations were unclear. The external assessment group (EAG) explained that sensitivity analyses indicated that these differences in study populations did not have a detectable effect on the estimates of diagnostic accuracy. But there was a large amount of variability between studies. Because some tests did not have evidence in the scope population, the EAG chose to include studies from a broader population. The committee concluded that the estimates of diagnostic accuracy based on this broad population were likely representative of the accuracy in the scope population.

The quantity and quality of the evidence base varied between tests. The committee noted recent evidence that different devices produce different results from the same samples, and clinical experts stated that there is no universal reference standard for FIT. So, equivalence between devices could not be assumed. However, the committee noted that the available data was not clear enough for it to make evidence-based recommendations with different thresholds for different FIT devices. The committee concluded that methods for technical validation of FIT devices need to be improved to allow generation of comparative data without the need for large clinical trials.

The committee noted that most studies used either HM‑JACKarc (16 studies) or OC‑Sensor (17 studies). For FOB Gold, 3 studies were initially identified, but these had a low number of participants. The combined estimates of accuracy from these studies were uncertain. The committee acknowledged that FOB Gold was previously recommended in NICE's diagnostics guidance 30 on quantitative FIT to guide referral for colorectal cancer in primary care, during the development of which the committee concluded that although there was less data for FOB Gold than for HM‑JACKarc or OC‑Sensor, it was likely to perform similarly in practice. However, in this assessment the committee observed that the evidence base for HM‑JACKarc and OC‑Sensor was now larger and the estimates of diagnostic accuracy were more certain than during the development of the previous diagnostics guidance. But the FOB Gold evidence base remained limited. During consultation, the manufacturer of FOB Gold submitted additional evidence, which reduced the uncertainty in the estimates of specificity. However, the committee felt that the uncertainty in the estimates of sensitivity was still too large, so the risk of missing cancers was too high. It concluded that more evidence was needed to reduce the uncertainty around the diagnostic accuracy of FOB Gold. Only 1 study was identified for each of IDK Hemoglobin ELISA, IDK Hemoglobin/Haptoglobin Complex ELISA, NS‑Prime and QuikRead go iFOBT. No studies were found for IDK TurbiFIT. So, the committee recommended that HM‑JACKarc and OC‑Sensor could be used for FIT. It recommended further research on the clinical effectiveness (including diagnostic accuracy) of FOB Gold, IDK TurbiFIT, IDK Hemoglobin ELISA, IDK Hemoglobin/Haptoglobin Complex ELISA, NS‑Prime and QuikRead go iFOBT.

There was not enough evidence to make any alternative recommendations on how FIT should be used when there are factors that could affect test performance. During scoping, clinical experts suggested that factors such as age, sex, ethnicity, iron-deficiency anaemia, or medications or conditions that increase the risk of gastrointestinal bleeding could influence the threshold that should be used to guide referral, or affect the diagnostic accuracy of the test. Some people may also have difficulty providing samples because of cognitive or physical disability. The EAG found limited evidence in these subgroups and no conclusive evidence to determine whether FIT should be used differently in these groups. The EAG and committee members also noted that ethnicity and disability are generally poorly recorded in studies of FIT. Comments received during consultation suggested further research could be recommended for some subgroups. But the committee noted that evidence is already developing in this area, with algorithms such as COLOFIT that incorporate multiple factors alongside a FIT result. This should address some of these uncertainties and allow these factors to be considered alongside a FIT result. The committee recommended further research on the clinical utility of FIT in people aged under 40 and in people who have conditions or medicines that increase the risk of gastrointestinal bleeding because it felt that these were not already covered by ongoing studies.

The committee reviewed evidence showing differences in the rate of return of FIT between sociodemographic groups based on age, sex, ethnicity and socioeconomic status. The EAG highlighted publications that proposed strategies to help encourage test return in these groups, such as following up after a sample is not returned, providing information in multiple languages, or providing counselling and education services. But it was not clear which methods would be the most effective, and different methods may be more appropriate for different groups. The committee also noted comments received during consultation that highlighted that people with physical disabilities such as visual impairment or reduced dexterity may have difficulties completing a FIT kit. A patient expert highlighted that people who are neurodivergent or who have sensory issues may also have difficulty. Therefore, the committee recommended social research to determine the best way to improve access to and return of FIT, especially from groups in which engagement is less likely.

A patient expert suggested that healthcare professional involvement is important to drive engagement with testing. GP experts noted that the ability of primary care healthcare professionals to provide support is limited by workload and IT systems. They noted that support would be hardest to implement in the most underserved areas where engagement with testing is likely to be lower. Guidance or educational resources to help improve test uptake would be helpful to minimise geographical differences in care. Patient experts emphasised that information should be available in different formats and languages to maximise accessibility. The committee noted that NICE and associated stakeholders can support implementation of this guidance (see section 5).

Dual FIT was considered as a testing strategy. The committee noted that the term 'dual FIT' is not well understood and can be interpreted in different ways. The committee clarified how it was referring to different testing strategies:

• Dual FIT uses 2 separate faecal samples collected from different bowel movements within a short time period. A positive result from either sample would indicate a referral to secondary care.

• Repeat FIT refers to using FIT in safety netting, when a second test is offered to people who have had a negative FIT result (see section 3.19).

The committee considered evidence from the EAG's clinical-effectiveness review that found that dual FIT generally improved sensitivity but decreased specificity compared with single FIT at the same threshold. Clinical experts noted that FIT results can vary between bowel movements because bleeding can be intermittent. So, using dual FIT could reduce the risk of missing people with cancer. The evidence on test uptake with dual FIT in primary care was less clear. The committee noted that the evidence base for dual FIT was from secondary care and may not be generalisable to the primary care setting of this assessment because people may place more importance on a request from secondary care. The interval between the 2 samples also varied between studies, with some issuing the kits at the same time and others sending them separately. Therefore, the effect of asking for 2 samples on uptake in primary care was unclear. Patient experts said that confidence in FIT results may be higher with dual FIT. However, the committee recalled that certain groups may have difficulty with FIT kits or may be less likely to return a sample. It was concerned that asking for 2 samples could particularly affect these groups (see section 3.7) and may be difficult to implement, adding unnecessary complication or delay to the process. This could increase inequality in access to healthcare. The committee noted that the safety netting process is likely to include a repeat FIT for people with negative results (see section 3.19), so people may still do 2 tests when there is ongoing clinical concern. The committee recommended further research to evaluate the impact of using dual FIT on test uptake, decision making and clinical outcomes.

Several conditions other than colorectal cancer can cause gastrointestinal symptoms and blood in faeces, including inflammatory bowel disease (IBD; Crohn's disease or ulcerative colitis). IBD is also usually diagnosed in secondary care through investigations such as colonoscopy. The EAG's clinical review found that the estimates of the diagnostic accuracy of FIT for IBD were more uncertain than those for colorectal cancer, and the sensitivity was generally lower. However, clinical experts did not think that introducing FIT would have a substantial effect on people who have IBD because GPs are likely to order a calprotectin test at the same time as FIT, which is a more accurate test for IBD (see NICE's diagnostics guidance on faecal calprotectin diagnostic tests for inflammatory diseases of the bowel). The committee reiterated that the focus of this assessment was using FIT to guide referral pathways for colorectal cancer, and that FIT is not intended to replace investigations for other conditions. It highlighted existing guidance that can be followed to ensure people with IBD and other non-cancer conditions do not experience delays to diagnosis, such as the British Society of Gastroenterology (BSG) guidelines on the investigation of chronic diarrhoea or management of inflammatory bowel disease.

The committee agreed that using FIT for people with signs or symptoms suggestive of colorectal cancer was likely to be cost effective compared with using FIT as outlined in previous NICE guidance (see section 2.3). People with a rectal mass, an unexplained anal mass or unexplained anal ulceration do not need a FIT test before referral, as outlined in the recommendations on lower gastrointestinal tract cancers in NICE's guideline on suspected cancer. The economic model estimated that all testing strategies using HM‑JACKarc or OC‑Sensor were cost effective. This was because costs were saved by reducing the overall number of colonoscopies, but there was also a very small loss of health resulting from people who had false negatives from their FIT test. The EAG stated that the quality-adjusted life year (QALY) loss was equivalent to less than 1 day of full health for all people in the cohort. The committee noted that the model predicted that reducing the number of colonoscopy referrals would likely reduce secondary care waiting times for most people. However, the average time to diagnosis was increased overall because some people with false-negative FIT results would have very long waiting times.

The committee agreed that the overall conclusions of the economic model were reasonable. However, there was uncertainty in specific cost-effectiveness estimates because many inputs were based on clinical expert opinion when evidence was not available. Some committee members thought that the times to diagnosis used in the base case were pessimistic. But a scenario analysis that used shorter times to diagnosis resulted in a more favourable cost-effectiveness estimate for FIT than in the base case. Primary care experts thought that the number of additional GP appointments for people in primary care was too low, but not so low that the overall conclusion of cost effectiveness would be changed. The proportion of people who would be referred to secondary care despite a negative FIT result was based on clinical experts' experience with existing guidance (see section 2.5) and NICE's diagnostics guidance 30, which recommended a threshold of 10 micrograms of haemoglobin per gram of faeces. Clinical experts thought that using a higher threshold would reduce physician confidence in the test. As a result, the proportion of people being referred without a positive FIT result would be higher than modelled. Therefore, the cost-effectiveness results at higher thresholds were more uncertain.

The committee decided that testing a single faecal sample and using a single threshold to inform referral decisions was the best strategy. It noted that the economic model predicted that using dual FIT would be slightly less cost effective than single FIT but would also reduce the QALY loss from false negatives. However, it recalled that dual FIT could disadvantage groups that are less likely to return samples and introduce additional implementation issues (see section 3.7 and section 3.11). The committee concluded that the potential drawbacks of dual FIT were likely to outweigh the benefits of increased sensitivity.

The committee noted that using 2 thresholds to define low-, intermediate- and high-risk groups appeared slightly less cost effective than using 1 threshold. Clinical experts also advised that using 2 thresholds would complicate referral decisions and make it harder to understand what the results mean in practice, which may reduce cost effectiveness more than predicted by the model.

The committee concluded that a threshold of 10 micrograms of haemoglobin per gram of faeces should be used to guide referral decisions. It acknowledged that the economic model suggested a threshold of 100 micrograms of haemoglobin per gram of faeces would be most cost effective. However, the committee recalled that the cost-effectiveness estimates at higher thresholds were more uncertain (see section 3.14). Thresholds below 10 micrograms of haemoglobin per gram of faeces were not considered. This was because they were less cost effective and approached the limits of quantitation for many of the tests, which may reduce the reliability of results (see section 2.8).

Economic experts highlighted that cost-effectiveness estimates improved the most between lower thresholds. They suggested that moving to a threshold of 20 micrograms of haemoglobin per gram of faeces could produce a gain in cost effectiveness without losing physician confidence. Clinical experts disagreed that physicians would accept a higher threshold because of the risk of false-negative results but conceded that there was no evidence on how the choice of threshold affects decision making. So, the committee recommended further research on the clinical impact of using different thresholds to guide referral to understand if referrals would decrease by a similar proportion as predicted by the model.

The committee discussed safety netting for people who do not return a test or people with negative FIT results who have ongoing unexplained symptoms. It commented that no evidence was presented on the relative effectiveness of different safety netting approaches, but possible options had been explored in the economic model. The committee stated that clear guidance will be needed to ensure that safety netting is implemented consistently and effectively. It noted that advice is available in:

• the section on safety netting in NICE's guideline on suspected cancer

• the Association of Coloproctology of Great Britain & Ireland (ACPGBI) and BSG guidance on FIT in patients with signs or symptoms of suspected colorectal cancer

• the 2022 NHS England letter endorsing FIT.
  
  Clinical experts highlighted that the exact approach of available safety netting is likely to differ across the UK. The implementation of safety netting used in the model for people with negative FIT results or who did not return a test was based on clinical advice. Options included:

• referral to secondary care because of ongoing clinical concern, either through suspected cancer or non-urgent pathways

• management in primary care ('watch and wait')

• offering another FIT test (see the section on dual FIT).

Clinical experts emphasised that having a positive FIT result should not be an absolute requirement for referral to secondary care. This is because it is possible to have a false-negative result and some people may not be able to complete a test, either because of physical or cognitive disability or because of barriers to test uptake. So, the option to refer should always be available if GPs think it is needed, and secondary care centres should be able to accept referrals without a positive FIT result. Clinical experts highlighted that a non-specific symptoms pathway may be more appropriate than a colorectal cancer pathway for some people.