Introducing FIT to the clinical

laboratory: technical, logistical and

political challenges

Sally C Benton
Consultant Biochemist, BSPS
Director, Bowel Cancer Screening Hub (South of England)

Date: 6th June 2018

 Colorectal (Bowel) Cancer

• 4th most common form of cancer in UK (c. 41,500 diagnoses)

• 2nd biggest cancer killer (c. 16,000 deaths)

• Symptoms vague and non-specific

• Changes in bowel habit, abdominal pain, bloating, weight
loss

• Symptoms often not present until late in the disease

Development of Bowel Cancer

Polyp

Stage 1 Stage 2 Stage 3 Stage 4

>50 y.o. 1 in 4 have polyps 1 in 10 change to invasive cancer

Survival 5 years after treatment 95% 80% 60% 5%

10 years
Diagnosis of Colorectal Cancer

• Colonoscopy
• Gold standard method
• Enables visualisation of the whole bowel

• BUT
• Invasive
• Highly skilled endoscopists required
• Risks to patient
• Expensive
Surrogate marker for bowel cancers

Polyps and
cancers can bleed
Blood gets excreted in
the stool
Faecal Haemoglobin in Health
and Disease

Fraser CG, et al. Gut 2008;57:1256-60

Detection of blood in stool

V poor analytical
sensitivity and
specificity
Faecal Immunochemical Test (FIT)

Haemoglobin - Globin

 Antibody recognition of the

tertiary structure produced by the
folding of the amino acid chain in
the globin protein.
 Quantitative FIT systems

FOB SentiFIT NS Prime

gold

HM-JACKarc OC Sensor PLEDIA

Advantages of FIT vs gFOB

• Analytically superior
• not subjective
• semi-automated analysis

• Antibodies specific to human haemoglobin so minimizes

interference from diet

• Requires 1 stool sample not 3

Symptomatic cut-off
• Ability to quantitate concentration of Hb present in faeces
• Analytical range <10 – 400+ ug Hb/ g faeces
Laboratory challenges

• Lack of familiarity with the test and sampling process

• Logistical challenges – kit to patient and kit back to lab

• Analytical challenges
• No standardisation of assays
• Huge pre-analytical variation
• Challenging for external quality assurance schemes
• No independent internal quality control materials

• Funding – needs to be approved/ available to enable successful lab

business cases for FIT
Logistical Challenges

• FIT “kits”
• Include sample collection device and instructions for us

• How to get kit to patient and back to lab

• GP surgery hold stock
Or Lab send to patient

• Patient returns sample direct to lab via pre-paid

envelope
Or Patient drops sample back in GP practice
Pre-analytical Variability

• Stool
• isn’t homogenous
• has variable consistency

• “Pickers” from all manufacturers are different

• Instructions from manufacturers are different

• Inconsistent sampling techniques by patients

• Haemoglobin stability
• Storage and transit temperatures
• Buffer composition
FIT laboratory challenges

• No assay standardisation
• Different buffers Different methods
• Different antibodies give different
results
– Impact of eg Hb variants
• Different calibration
Is a single cut-
• No primary reference material or method off appropriate?

• External Quality Assurance scheme challenges Unable to confirm if

results are correct

• No established independent Internal Quality Control

• How to validate FIT analysers for UKAS

• Symptomatic FIT threshold close to detection limit
FIT EQA Scheme Challenges

• Matrix – how to make a faecal like matrix?

• Hb is unstable – how to stabilise Hb in the matrix?

• Do we need to measure Hb in a faecal like matrix?

EQA for FIT

• What is the best matrix for EQA material to be provided in?

}
UK NEQAS:
Faecal like matrix
CEQAL (Canada):

SKML (Netherlands): Lyophilised samples

WEQAS (Wales): Pre-loaded devices

Examples of Faecal–like EQA samples

UK NEQAS CEQAL
UK NEQAS report

Spiked with 80 µg Hb/g ‘stool’

HM
JACKarc
FIT EQA Challenges

• EQA report results – high between lab variability

• ?pre-analytical variability Or analytical variability

• Labs need to be able to assess analytical variability

• Labs receive FIT tubes NOT faecal samples from patients

• Therefore, should we be receiving pre-loaded FIT tubes from
EQA schemes….?
IFCC FIT Working Group
(International Federation of Clinical Chemistry & laboratory
medicine)

Chair
Sally C. Benton UK
First meeting held
Group Members
Marieke Fasa NL
Corporate members in Athens in June
Maurizio Gramegna Italy Sentinel
Barcey Levy USA
Michael Zacherl Italy Sentinel 2017
Han Mo Chiu Taiwan
Hideyuki Hayashi Japan Eiken
Josep-Maria Auge Spain
Takuo Ichiyanagi Japan Eiken
Erin Symonds Australia
Tsuyoshi Fukuda Japan Kyowa
Petr Kocna Czech Republic
Natasha Djedovic UK
Yasunobu Masuda Japan Kyowa 2nd meeting held
Mr Yosuke Doi Japan Alfresa
Judith Strachan UK
Dr Tetsuya Kosaka Japan Alfresa
in Barcelona in
Ingrid Zegers
Shizuka Takehara
Belgium
Japan
Motohito Fujimura Japan Wako October 2017
Samantha Jones UK

Terms of Reference
• To attempt to standardize analysis of haemoglobin in faecal samples by immunochemistry
(FIT)
• To identify all sources of pre-analytical variation and standardise if possible
• To establish external quality assurance and third party internal quality control programmes
• To determine impact of assay interference of Hb variants and other factors
 Update on recent analytical FIT progress

• IFCC group working with reference lab in Belgium to identify a suitable

FIT reference material

• Global EQA scheme review carried out by IFCC group

• Two pre-analytical papers recently accepted for publication in Annals

• Does the mass of sample loaded affect faecal haemoglobin concentration using the faecal
immunochemical test? Piggott C, John C, Bruce H, Benton S. Accepted May 2018

• An assessment of the effect of haemoglobin variants on detection by faecal immunochemical

tests. Carroll M, John C, Mantio D, Djedovic N, Benton S. Accepted May 2018

• C Fraser & SC Benton – paper submitted to CCLM

• Detection capability of quantitative faecal immunochemical test for haemoglobin (FIT)
and reporting of low faecal haemoglobin concentrations
FIT in Screening Programmes
Symptomatic FIT testing……

…………….where has it come from?

NICE guideline NG12 (June 2015)
Suspected Cancer: recognition and referral

1.3 Lower gastrointestinal tract cancers

Colorectal cancer
1.3.1 Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer if:
•they are aged 40 and over with unexplained weight loss and abdominal pain or
•they are aged 50 and over with unexplained rectal bleeding or
•they are aged 60 and over with:
•iron-deficiency anaemia or
•changes in their bowel habit, or
•tests show occult blood in their faeces (see recommendation 1.3.4 for who should be offered a test for occult blood in
faeces). [new 2015]

1.3.2 Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults with a
rectal or abdominal mass. [new 2015]

1.3.3 Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults aged
under 50 with rectal bleeding and any of the following unexplained symptoms or findings:
•abdominal pain
•change in bowel habit
•weight loss
•iron-deficiency anaemia. [new 2015]

1.3.4 Offer testing for occult blood in faeces to assess for colorectal cancer in adults without rectal bleeding who:
•are aged 50 and over with unexplained:
•abdominal pain or
•weight loss, or
•are aged under 60 with:
•changes in their bowel habit or
•iron-deficiency anaemia, or
•are aged 60 and over and have anaemia even in the absence of iron deficiency. [new 2015]
NICE guideline NG12 (June 2015)
Suspected Cancer: recognition and referral
1.3 Lower gastrointestinal tract cancers
Colorectal cancer
1.3.1 Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer if:
•they are aged 40 and over with unexplained weight loss and abdominal pain or
•they are aged 50 and over with unexplained rectal bleeding or
•they are aged 60 and over with:
•iron-deficiency anaemia or
•changes in their bowel habit, or

• tests show occult blood in their faeces (see recommendation 1.3.4 for who
should be offered a test for occult blood in faeces). [new 2015]
• Guaiac FOB – very poor analytical
1.3.2 Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults with a rectal or abdominal mass. [new 2015]

sensitivity
1.3.3 Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults
symptoms or findings:
aged under 50 withand specificity
rectal bleeding and any of the following unexplained

•abdominal pain
•change in bowel habit
• Most labs in the UK had stopped
•weight loss
•iron-deficiency anaemia. [new 2015]
offering the FOB test

1.3.4 Offer testing for occult blood in faeces to assess for colorectal cancer in
adults without rectal bleeding who:
•are aged 50 and over with unexplained:
•abdominal pain or
•weight loss, or
•are aged under 60 with:
•changes in their bowel habit or
•iron-deficiency anaemia, or
•are aged 60 and over and have anaemia even in the absence of iron deficiency. [new 2015]
 July 2015

Ref: Steele et al BMJ 2015. 350h3044

 July 2017

Recommends use of FIT in

primary care referral pathway.
 July 2017

Recommends use of FIT in

primary care referral pathway.

Specific about which

analysers should be used

Cut-off to be used;
10ug Hb/ g faeces

Service evaluation to add

to evidence
 Quantitative FIT systems

FOB SentiFIT
gold
3 FIT systems recommended by NICE

HM-JACKarc OC Sensor PLEDIA

NICE guidance: Evidence Base

•10 studies
•(25 publications and 2 unpublished manuscripts)
•Total number of patients = 4,575 (4091 OC-Sensor; 484 HM-JACK)

• Concerns about applicability of the population of all studies to English population

10ug/g cut off – as recommended in NICE guideline

Patients Number of Cancers

Author Year Country in study cut off (ug/g) NPV PPV Sensitivity Specificity cancers missed
Mowat et al 2015 Scotland 755 10 99.5 14.2 89.3 79.1 28.0 3.0

Rodriguez-Alonso et al 2015 Spain 1003 10 99.9 12.8 96.7 79.8 30 1

Godber et al 2015 Scotland 484 10 100 100 11 0

Droste et al 2011 Netherlands 2145 10 92.4 86.4 79 6

McDonald et al 2012 Scotland 280 10 100 7.6 100 93.9 6 0

Cubiella et al 2014 Spain 787 20 97.8 35.3 87.6 77.4 97

 NICE guidance: Evidence Base Good rule out test

Does miss cancers

10ug/g cut off for CRC – as recommended in NICE guideline

Patients Number of Cancers

Author Year Country in study NPV PPV Sensitivity Specificity cancers missed

Mowat et al * 2015 Scotland 755 99.5 14.2 89.3 79.1 28.0 3.0

Rodriguez-Alonso et
al * 2015 Spain 1003 99.9 12.8 96.7 79.8 30 1

Godber et al ** 2015 Scotland 484 100 100 11 0

Droste et al * 2011 Netherlands 2145 92.4 86.4 79 6

McDonald et al * 2012 Scotland 280 100 7.6 100 93.9 6 0

*OC-Sensor
** HM-JACK
NICE guidance: Evidence Base

10ug/g cut off – as recommended in NICE guideline

Patients Number of Cancers

Author Year Country in study cut off (ug/g) NPV PPV Sensitivity Specificity cancers missed
Mowat et al 2015 Scotland 755 10 99.5 14.2 89.3 79.1 28.0 3.0

Rodriguez-Alonso et al 2015 Spain 1003 10 99.9 12.8 96.7 79.8 30 1

Godber et al 2015 Scotland 484 10 100 100 11 0

Droste et al 2011 Netherlands 2145 10 92.4 86.4 79 6

McDonald et al 2012 Scotland 280 10 100 7.6 100 93.9 6 0

Cubiella et al 2014 Spain 787 20 97.8 35.3 87.6 77.4 97

Cut off – “undetectable” Hb

Patients NPV for Specificit Number of
Author Year Country in study cut off (ug/g) CRC PPV Sensitivity y cancers Cancers missed
Mowat et al 2015 Scotland 755 Undetectable (7ug/g) 100 6.4 100 43.4 28 0

Rodriguez-Alonso et al 2015 Spain 1003 Undetectable (0) 100 5.2 100 43.3 30 0

Widlak et al 2016 England 430 Undetectable (7ug/g) 99 44 84 93 24 3

On-going studies in England

• York
• James Turvill (Gastroenterologist) and Daniel Thurnock (biochemist)
• Clinical study of FIT (HM-JACK) and calprotectin in patients referred for
colonoscopy

• North West London Vangard

• GP referring patients for colonoscopy also asking them to do a FIT test
• OC-Sensor (analysis carried out at Barts Health Trust)
• Aim to recruit 2,000 patients

• NICE FIT study (NIHR supported)

• South West London hospitals (and extending outside London)
• All patients referred for colonscopy by GP being contacted by research team and
being sent a FIT kit
• HM-JACKarc (analysis being carried out at Southern Hub, Guildford)
• Aim to recruit 10,000 patients
• Analytical sub-studies also approved
Question……?

• Would you support symptomatic FIT implementation

based on the evidence provided?

• Considerations;
• Clinical utility of test
• Clinical safety of test
• Patient experience
• Pathology business - income generation
Why so much interest in
FIT….?
Colonoscopy capacity
challenges

Endoscopy services are struggling to

deliver capacity to keep up with
demand from combination of screening,
symptomatic and surveillance patients

Demand expected to increase significantly

over next few years

Does FIT provide a solution?

 Benefits of FIT

• Decreased referral to endoscopy

• No published evidence yet to support although anecdotal
evidence from Scotland suggests significant decreased referral

• Simple, less invasive first-line test for patients

• Potential cost saving if FIT testing leads to decreased colonoscopy’s

• Frees up colonoscopy resource for eg screening programme,

surveillance, high risk patients

• Need to ensure “safety netting” in place to detect missed cancers

Implementing FIT

• Evidence base

• Commissioning

• Laboratory procurement of FIT

• ?tender required – workload, managed service
contracts

• Clinical pathways
FIT Clinical Challenges

• Safety netting of patients with a negative FIT

• FIT does miss cancers

• FIT to be implemented in screening programme in 2018

• VERY different cut-offs
• 10 ug/g (symptomatic) vs 120-150 ug/g (screening)
• Risk of confusion high for healthcare professionals and patients

• Does FIT decrease referral to colonoscopy?

• No published evidence yet to support this
Commissioning symptomatic FIT

• CCG’s need to find the money to fund the test

• Business cases required
• Challenge: No published data on impact of FIT on colonoscopy

• Laboratories need to acquire FIT

• Local business cases and possibly tender

• Cancer Alliances keen for FIT testing to be implemented

• Challenge: Lack of understanding of how pathology tests are
commissioned
• Causing confusion in some parts of England
 Cancer Alliances

“Cancer Alliances are a way to bring together local senior clinical and managerial leaders
representing the whole cancer patient pathway across a specific geography.
Together with the National Cancer Vanguard, they will lead the local delivery of the Independent
Cancer Taskforce’s ambitions for improving services, care and outcomes for everyone with
cancer.” https://www.england.nhs.uk/cancer/strategy/alliance-guidance/

• Work regionally

• Appears to be lack of awareness of pathology involvement and commissioning

process
• Experience of centralised screening programme testing so some confusion

• Very motivated to implement new pathways

• potential opportunity for implementation support
Eg South West England Cancer Alliance successfully bid for transformation
funds to support set up of FIT
 Discussion points

• What threshold = “negative” FIT test

• Comparative evidence required to support cut-offs being the same on every analyser

• Potential for confusion between screening and symptomatic FIT

• 10 ug/g (symptomatic) vs 120 ug/g (screening)

• Does FIT decrease referral to colonoscopy?

• No published evidence yet to support this

• Safety netting of patients with a negative FIT ie risk of false negative

• Practicalities and impact of operationalizing FIT in the colorectal diagnostic pathway

• Commissioning the test
• Laboratory procurement of equipment/ referral lab identified
• Different referral pathways
• Logistics of getting samples to labs
Challenges

• Funding
• Laboratories procuring FIT
• CCG’s acquiring funding for FIT testing
• Stakeholders understanding procurement pathway for symptomatic FIT

• Evidence base to support

• Implementation
• business cases

• Analytical and pre-analytical issues

• Symptomatic vs screening confusion

• Cut-off
• FIT kits looking the same
Opportunities

• GP’s enthusiastic
• Improved patient experience
• Appropriate patients referred for colonoscopy
• Timely colonoscopy

• Laboratories willing

• Cancer Alliances enthusiasm

• Multi-centred trials and service-evaluation work being carried out

across England to increase evidence base
• Analytical studies being incorporated into these
What next?

• Decisions will be made locally as to whether to implement FIT or not

• Confidence in evidence-base
• Funding
• Analyser procurement
• Logistics
• Where in pathway FIT is requested

• Address analytical challenges of FIT

• Await outcomes from on-going studies

• Collate service evaluation data from labs across England offering FIT
• Pathways and where FIT is requested
• Results summary
• Impact on colonoscopy referrals
 Essentialism vs Consequentialism
(Prof Patrick Bossuyt)

“the theory that the value “the theory that the

of a marker or a medical value of a marker or a
test should be judged by medical test should be
the ‘trueness’ of its judged by the value of its
results” consequences”

FIT
Need to ensure the analytical • patients are appropriately
process is; categorised
• scientifically robust
• deficiencies understood
• Work towards improving things
Berkshire & Surrey Pathology Services
A joint venture between Frimley Park Hospital, Royal Surrey County
Hospital, Royal Berkshire Hospital, Wexham Park Hospital and Ashford
and St. Peter’s Hospitals NHS Foundation Trusts