1216
Consultation Protocol
to guide the
assessment of testing
for hereditary
mutations in the
Cystic Fibrosis
conductance
Transmembrane
Regulator (CFTR)
gene
February 2014
Table of Contents
Questions for public consultation ............................................................................................ 4
MSAC and PASC ........................................................................................................................ 5
Purpose of this document ........................................................................................................... 5
Purpose of application ............................................................................................................. 6
Background .............................................................................................................................. 6
Current arrangements for public reimbursement........................................................................... 6
Regulatory status ....................................................................................................................... 7
Intervention ............................................................................................................................. 8
Clinical need and burden of disease ............................................................................................. 8
Description of the medical condition ............................................................................................ 8
Diagnosis ................................................................................................................................. 11
Impact on clinical management ................................................................................................. 11
Delivery of the proposed intervention ........................................................................................ 11
Prerequisites ............................................................................................................................ 13
Listing proposed and options for MSAC consideration ..........................................................13
Proposed MBS listing ................................................................................................................ 13
Group 1: People with a high clinical suspicion of CF.............................................................15
Co-administered and associated interventions ............................................................................ 15
Clinical place for proposed intervention ...................................................................................... 15
Comparator .............................................................................................................................. 16
Outcomes for evaluation ........................................................................................................... 17
Summary of PICO ..................................................................................................................... 18
Clinical claim ............................................................................................................................ 20
Group 2: Prenatal CF diagnosis (testing of parents and foetus) ...........................................21
2
Ethical, Legal and Social Implications (ELSI) .............................................................................. 21
Co-administered and associated interventions ............................................................................ 21
Clinical place for proposed intervention ...................................................................................... 22
Comparator .............................................................................................................................. 25
Outcomes for evaluation ........................................................................................................... 25
Summary of PICO ..................................................................................................................... 26
Clinical claim ............................................................................................................................ 28
Group 3: CFTR testing in partners of people with known CFTR mutations for the
purpose of reproductive planning ............................................................................30
Co-administered and associated interventions ............................................................................ 30
Clinical place for proposed intervention ...................................................................................... 30
Outcomes for evaluation ........................................................................................................... 32
Summary of PICO ..................................................................................................................... 32
Clinical claim ............................................................................................................................ 33
References .............................................................................................................................33
Appendix A: Classification of Class 3 in vitro diagnostic medical devices .............................37
Appendix B: MBS item descriptors for associated interventions ...........................................38
3
Questions for public consultation
Noting the limited access to clinical geneticist in Australia would it reasonable to consider restricting
the ordering of this service to clinical geneticists to ensure genetic counselling has been undertaken?
Group 1 (People with high clinical suspicion of CF):
-
What would be the best reference standard in this group? Clinical diagnosis or whole
gene sequencing?
Group 2 (Prenatal CF diagnosis):
-
HESP expert advice is that the subgroup ‘Parent with a foetus at risk of CF due to a
previous child being clinically diagnosed with CF’ (see Figure 3) normally undergoes
testing at a similar time as the child that is diagnosed.
o
Given that these children are usually identified through the Newborn
Screening (NBS) program, funded by the States/Territories, are tests done on
the parents also funded through the States/Territories? (If they are selffunded, they should be included in this assessment).
o
In case CFTR tests on the parents are funded through the States/Territories,
could this subgroup be deleted? The foetus of this couple would be included
under the third subgroup (Foetus where both parents have been diagnosed
with CFTR mutation(s)).
Group 3 (Partners of people with known CFTR mutations for the purpose of
reproductive planning):
-
The first research question would essentially be an evaluation of the safety and
effectiveness of PGD, which is already the subject of another assessment (1165:
Preimplantation Genetic Diagnosis). Could the assessment of CFTR mutation testing
in this population be restricted to an assessment of the accuracy of the test
(question 2)?
4
MSAC and PASC
The Medical Services Advisory Committee (MSAC) is an independent expert committee
appointed by the Australian Government Health Minister to strengthen the role of evidence
in health financing decisions in Australia. MSAC advises the Commonwealth Minister for
Health on the evidence relating to the safety, effectiveness, and cost-effectiveness of new
and existing medical technologies and procedures and under what circumstances public
funding should be supported.
The Protocol Advisory Sub-Committee (PASC) is a standing sub-committee of MSAC. Its
primary objective is the determination of protocols to guide clinical and economic
assessments of medical interventions proposed for public funding.
Purpose of this document
This document is intended to provide a draft protocol to guide the assessment of diagnostic
testing for hereditary mutations in the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) gene, whether for prenatal diagnosis or for in subjects suspected of Cystic
Fibrosis (CF) or CFTR related disorders. The draft protocol will be finalised after inviting
relevant stakeholders to provide input. The final protocol will provide the basis for the
assessment of the intervention.
The protocol guiding the assessment of CFTR testing has been developed using the widely
accepted “PICO” approach. The PICO approach involves a clear articulation of the following
aspects of the research question that the assessment is intended to answer:
Population – specification of the characteristics of the population in whom the
investigative intervention is to be considered for use;
Intervention – specification of the proposed investigative intervention;
Comparator – specification of the investigation most likely to be replaced by the
proposed investigative intervention; and
Outcomes – specification of the health outcomes and the healthcare resources likely
to be affected by the introduction of the proposed investigative intervention.
5
Purpose of application
An application was received from the genetics subcommittee of the Pathology Services Table
Committee (PSTC) by the Department of Health and Ageing in July 2011 requesting
Medicare Benefits Schedule (MBS) listing of diagnostic testing for hereditary mutations in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene. In July 2012, the topic
was deemed suitable for assessment. In May 2013, the PSTC body no longer existed, so the
Royal College of Pathologists of Australasia (RCPA) were approached, agreed to sponsor the
referral originally made by the PSTC, and submitted an updated application. There is
currently no Medicare Benefits Schedule (MBS) number for diagnostic testing for hereditary
mutations in the CFTR gene. The proposed new MBS item(s) would be used for three quite
distinct groups/indications:
1) In people with high clinical suspicion of CF;
2) For prenatal CF diagnosis; and
3) In partners of people with known CFTR mutations for the purpose of reproductive
planning.
Adelaide Health Technology Assessment (AHTA), in the School of Population Health,
University of Adelaide, as part of its contract with the Department of Health, has drafted this
protocol to guide the assessment of diagnostic testing for hereditary mutations in CFTR
gene in order to inform MSAC’s decision-making regarding public funding of the intervention.
Background
Current arrangements for public reimbursement
Currently, there is no MBS listing for any diagnostic tests for hereditary mutations in the
CFTR gene. CFTR gene testing is currently funded through state-wide genetics services for
patients with a clinical presentation (after a borderline or positive sweat test). CFTR
mutation testing is also current practice as part of the state-funded NBS (after an elevated
immunoreactive trypsinogen (IRT) level is detected), although the number and range of
mutations that are being tested varies by State/Territory.
As there is no Medicare rebate, only those with a family history of CF are offered free testing
through genetic counselling services, funded by some States or Territories (Massie et al.
2007). Other individuals who would like to be tested for CFTR mutations have to pay for it
themselves.
6
Regulatory status
Diagnostic genetic tests for hereditary mutations in the CFTR gene would be classified as a
Class 3 in vitro diagnostic medical device (IVD) under the 2010 regulatory framework
(Therapeutic Goods Administration 2009) (See Appendix A).
The laboratories dealing with Class 3 IVDs have to notify the TGA annually of the contact
details of the laboratory and provide the name and risk class for each (in-house) IVD
manufactured. They also have to meet the National Pathology Accreditation Advisory Council
(NPAAC) performance standard Requirements for the Development and Use of In-house In
Vitro Diagnostic Devices and be accredited as a medical testing laboratory by the National
Association of Testing Authorities (NATA) or by a conformity assessment body determined
suitable by the TGA. Furthermore, they have to meet the standard ISO 15189 Medical
laboratories – Particular requirements for quality and competence (Therapeutic Goods
Administration 2012).
Genetic and DNA mutation tests are further regulated by Laboratory Accreditation Standards
and Guidelines for Nucleic Acid Detection and Analysis (2012) (NPAAC 2012). There are two
levels of DNA testing, shown in Table 1.
Table 1 Levels of DNA testing
Type of DNA test for an inherited
genetic disorder
Explanatory notesa
Level 1 DNA test
Included here would be:
(standard)
a) DNA testing for diagnostic purposes (eg the patient has clinical indicators or a
family history of an established inherited disorder and DNA testing is being used
to confirm the disorder) or any other DNA test that does not fall into level 2.
b) Population-based screening programs.
Level 2 DNA test
(ie the test has the potential to lead to
complex clinical issues)
a
DNA testing for which specialised knowledge is needed for the DNA test to be
requested, and for which professional genetic counselling should precede and
accompany the test. Predictive or presymptomatic DNA testing, for conditions for
which there are no simple treatment would usually be included in this grouping.
Specific written consent and counselling issues are associated with this grouping.
The distinction between Level 1 (standard DNA test) and Level 2 (DNA test with potential complex issues) would usually
be made by the doctor ordering the test, since that individual will be best placed to appreciate the short-term and long-term
implications of the test for the patient and other family members
CFTR testing in newborns and patients suspected of CF and CFTR related disorders would
constitute level 1 testing, and would therefore not require formal pre-test genetic
counselling or written consent (NPAAC 2007). However, if the specimen being tested is from
an apparently unaffected foetus, child or adult, such as prenatal testing or testing for
reproductive purposes, the test would constitute level 2 testing. This means that specialised
knowledge is needed for the DNA test to be requested, and the test should be preceded by
genetic counselling and specific written consent. Prenatal CFTR mutation testing (where the
7
parents are known to be carriers or in the case of ‘echogenic gut’ identified in the foetus at
ultrasound) would therefore need to be restricted to services which can provide accredited
genetic counselling.
Intervention
Clinical need and burden of disease
Cystic Fibrosis (CF) and other CFTR-related disorders are the most common autosomal
recessive disorder in Caucasians, with a frequency of about 1 in 2500 - 2800 live births
worldwide and a carrier frequency of 1 in 25 in Australia (Bell et al. 2011; Ratjen, F. &
Doring 2003). Progressive respiratory disease is the major cause of morbidity and mortality
among young people with CF. On the 31st of December 2012 the Australian Cystic Fibrosis
Data Registry (ACFDR) held records of 3,156 people with CF (Cystic Fibrosis Australia 2013).
The actual numbers of people suffering from CF will be slightly higher, as it is estimated that
only 90 per cent of the people with CF are registered on the database (Cystic Fibrosis
Australia 2013). Based on a population of 22.7 million Australians (2012), 1 in 7193 people
in Australia was diagnosed with CF and registered with the ACFDR. In the same year 63 (out
of 309,582 births) CF cases were identified through newborn screening; i.e. 1 in 4914
newborns received a CF diagnosis and were registered with the ACFDR. Over 80 per cent of
infant diagnoses are completed by three months of age and are aided by neonatal screening
programs, but some individuals get diagnosed when they are older (ranging from early
childhood to age 35 and over, depending on disease severity). Early diagnosis is expected to
be associated with improved health outcomes, but may have adverse social and
psychological outcomes.
In Australia, the mean life expectancy of people with CF increased from 12.2 to 27.9 years
for males and from 14.8 to 25.3 years for females, between 1979 and 2005 (Reid et al.
2011). The mean age of the registry population was 19.5 years on 31 December 2012,
which is higher than previous years (19.1 in 2011, 18.8 in 2010 and 2009). The proportion
of patients who were adults (18 years and over) was 49.3 per cent in 2012, compared to 35
per cent in 2001, demonstrating improved life expectancy. Increases in life expectancy have
had a progressive impact on health care utilisation. CF in adulthood is associated with
severe lung disease, poor nutritional status and CF-related complications, leading to a high
burden of disease.
Description of the medical condition
CF and CFTR related disorders are caused by mutations in a 230 kb gene on chromosome 7,
encoding a polypeptide that is 1480 aminoacids long, called the Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) gene (Ratjen, F. & Doring 2003). CFTR
8
belongs to a family of transmembrane proteins called ATP-binding cassette (ABC)
transporters which function as a chloride channel in epithelial membranes (Ratjen, F. &
Tullis 2008). Disease expression varies by class of CFTR mutation, along with genetic
modifiers and environmental factors (Moskowitz et al. 2008). For classic CF to develop it
requires two loss-of-function mutations in the CFTR gene. The disorder is characterised by
chronic bacterial infection of the airways and sinuses, fat maldigestion due to pancreatic
exocrine insufficiency, infertility in males due to absence of the vas deferens, and high
concentrations of chloride in sweat (Knowles & Durie 2002).The most common changes are
seen in the airways, where classic CF causes chronic pulmonary infections. Non-classic CF
develops when there is at least one ‘mild’ mutation that results in partial functionality of the
CFTR protein. Some of these mutations are linked to diseases of one organ, such as late
onset pulmonary disease, congenital bilateral absence of the vas deferens (CBAVD), or
idiopathic pancreatitis (Knowles & Durie 2002). These patients are usually pancreatic
sufficient, have chloride values that are close to normal and are typically diagnosed at an
older age (Ratjen, F. & Tullis 2008).
CFTR mutations can be grouped into six classes (Rowe, Miller & Sorscher 2005):
Class 1-3 mutations are associated with classic CF – pancreatic exocrine insufficiency and
progressive lung disease 1) The absence of synthesis of the CFTR protein
2) Defective protein maturation and premature degradation
3) Disordered regulation, such as diminished ATP binding and hydrolysis
Class 4-6 mutations give a broader phenotype (and less severe disease) due to some
functionality of the CFTR protein, usually without pancreatic insufficiency 4) Defective chloride conductance or channel gating, leading to partial channel activity
5) Reduced number of CFTR transcripts due to a promotor or splicing abnormality
6) Accelerated turnover from the cell surface due to defective stability of the CFTR
protein.
Over 1600 different CFTR mutations are known. Almost all are point mutations or small
deletions (Moskowitz et al. 2008). Worldwide, the most common mutation in the CFTR gene
is a Class 2 mutation, caused by a three base-pair deletion which results in the loss of
phenylalanine at position 508 (F508del). It accounts for approximately 70 per cent of CFTR
mutations worldwide, but its frequency varies between different ethnic groups. For instance,
F508del accounts for 82% of mutations in CF patients in Denmark, but this is only 32% of
CFTR mutations in Turkey (Ratjen, F. & Doring 2003). With this mutation, CFTR is being
9
misfolded and stays trapped in the endoplasmic reticulum, where it eventually gets
degraded. The most common mutations in the CFTR gene in Australia (that are genotyped)
are shown in Figure 1. Approximately 85 per cent of CF patients have at least one copy of
the F508del mutation - 52 per cent have two copies of F508del and 33 per cent have one
copy of this mutation, in addition to another CFTR mutation.
The pathogenicity of some mutations may be influenced by other variants within the CFTR
gene. For example, the poly T mutations are abbreviated tracts of a number of thymidines in
intron 8, thereby resulting in reduced levels of functional CFTR protein (Groman et al. 2004).
The best correlation between genotype and phenotype in CF is seen in the context of
pancreatic function. Prognosis in classical CF largely depends on whether the affected
individual is pancreatic sufficient or insufficient (most are insufficient). Different genotypephenotype correlations are shown in Table 2.
Figure 1 Genotypes CFTR mutations in Australia, 2012 (Cystic Fibrosis Australia 2013)
Table 2 CFTR genotype-phenotype correlations (Moskowitz et al. 2008)
Allele 1
Allele 2
Range of phenotypes
Classica
Classic
Classic >> non classic
Mildb
Classic or mild
Non classic > classic
R117H/5T
Classic or mild
Non classic > classic
R117H/7T
Classic or mild
Asymptomatic female or CBAVD
>
non classic CF
5T/TG11
Classic or mild
Asymptomatic > CBAVD
10
Allele 1
Allele 2
Range of phenotypes
7T or 9T
Classic or mild
Asymptomatic
7T or 9T
7T or 9T
Asymptomatic
a Classic
refers to Class I, II and III mutations
Mild refers to Class IV, V and VI mutations, exclusive of R117H and 5T alleles
CBAVD = Congenital Bilateral Absence of the Vas Deferens
CF = Cystic Fibrosis
b
Diagnosis
CF is clinically diagnosed with supporting evidence of a CFTR abnormality, either by sweat
chloride measurement or mutations in the CFTR gene known to cause CF. An elevated
immunoreactive trypsinogen (IRT) level during the newborn screening test can replace
clinical features as a diagnostic criterion in newborns. Diagnosis is usually simple, following
newborn screening or clinical presentation with an elevated sweat chloride level, but in
some situations the combined information makes the diagnosis difficult (e.g. mild symptoms
and a (borderline) positive sweat test and a new CFTR sequence variation of unknown
significance) (Farrell et al. 2008).
Impact on clinical management
The identification of CFTR mutations in affected individuals could lead to:
1) Additional diagnostic surety for a lifelong, expensive and complex condition.
2) Changed family planning options (e.g. if the parents of the CF patient want more
children).
3) More treatment options. Currently most CF treatment is not mutation specific,
however there are therapies currently available (and more in development) that are
tailored to a specific CFTR gene mutation (e.g. Ivacaftor for the G551D mutation
(O'Reilly & Elphick 2013)).
Ruling out CFTR mutations in (unaffected) individuals would not lead to a change in
management.
Delivery of the proposed intervention
Multiple pathways
As stated previously, diagnostic testing for hereditary mutations in the CFTR gene occurs in
three distinct groups/indications:
1) In people with a high clinical suspicion of CF;
2) For prenatal CF diagnosis; and
11
3) In partners of people with known CFTR mutations for the purpose of reproductive
planning.
The first group includes individuals presenting with classic or non-classic CF symptoms
(including men with CBAVD). Prenatal diagnosis would be indicated for couples who have
had a previous child with CF or a CFTR related disorder or who have been identified by other
means to both be carriers of a CFTR mutation. It could also be used in cases where the
foetus is found to have an ‘echogenic gut’. In this scenario, the foetus’ parents would
undergo CFTR mutation testing to determine if they are carriers, prior to the foetus being
tested (and only if both parents are carriers). The third group includes the testing of a
partner of someone with known CFTR mutations, which would influence their reproductive
planning (allowing an additional option of Preimplantation Genetic Diagnosis (PGD) if both
partners have at least one CFTR mutation).
Each person or foetus being tested for hereditary mutations in the CFTR gene would only
need to be tested once in their lifetime.
The different clinical pathways are shown in ‘Clinical place for the proposed intervention’ for
each population ‘Group’ chapter. In every proposed pathway the new intervention is used in
addition to the already available interventions. Most CF patients would be diagnosed through
newborn screening, whereas the ultrasound examination showing ‘echogenic gut’ leads to
approximately 11% of CF diagnoses (Scotet et al. 2002). A small percentage of patients get
diagnosed when older, as these patients often have a milder form of the disease (such as
men with CBAVD).
Different gene tests
The common CFTR tests are:
-
F508del mutation test
-
Single mutation test
-
Common mutation test
-
Poly-T test (for mild disease and infertility)
-
Total gene and rare mutation test
-
Prenatal test
Different CFTR gene tests would be conducted according to the different groups:
-
Group 1 (High clinical suspicion of CF): common mutation analysis is conducted in
symptomatic patients, followed by an expanded mutation panel and then total gene
sequencing if the clinical situation demands and common mutation analysis is unable
to identify both mutations. In men with CBAVD, common mutation analysis is done
12
with the addition of R117H and intron 8 plus possibly poly T testing. Neonates with a
positive sweat test after having one mutation identified through newborn screening
would get total gene sequencing, as they are already tested for the most common
mutations.
-
Group 2 (Prenatal diagnosis): In the parents of the foetus common mutation analysis
would be done. If a mutation is found in both parents, a single mutation analysis
would be performed, as the test would specifically target the previously identified
(specific) parents’ mutations.
-
Group 3 (Reproductive planning): If a person has CFTR mutations identified, and is
planning on having children, their partner would be undergo common mutation
analysis for carrier screening. No additional testing would be done in this group if the
initial tests are negative.
Prerequisites
Due to the specialised nature of the counselling requirements and interpretation of the
genetic data generated by genetic testing, CFTR mutation analysis should be conducted in
the context of a close working relationship between specialist clinical services and the
laboratory (Royal College of Pathologists of Australasia 2013). The ordering of CFTR
mutation tests in symptomatic patients should be restricted to consultant physicians with
expertise in the care of patients with CF (e.g. paediatricians, respiratory physicians and
clinical geneticists) and reproductive medicine specialists specialising in areas related to
CFTR-related disorders. Information should be made available for parents advising of
residual risks in atypical cases (if no mutation identified) and they should have access to up
to date information about genotype-phenotype correlations where this is available.
For parents undergoing prenatal genetic testing for cystic fibrosis, it is recommended that
they should undergo genetic counselling. Therefore prenatal genetic CFTR testing should be
restricted to specialist medical services which provide accredited genetic counselling.
Obstetricians specialising in prenatal diagnosis or clinical geneticists should provide the
service.
Listing proposed and options for MSAC consideration
Proposed MBS listing
The MBS item descriptors were not proposed in the original application and were therefore
developed by the evaluator and the HESP members. It is proposed that there would be at
least three different forms of CFTR mutation testing listed on the MBS:
1. The detection of one or two specific mutation(s) on the CFTR gene;
13
2. An extended CFTR mutation panel covering the most common mutations in the
general population (PCR based technology, minimum of 10 mutations)
3. The analysis of the entire CFTR gene for rare mutations
The proposed MBS items are shown in Table 3. Fees have not been proposed, but vary per
test: single mutation testing normally costs between $50 and $90, but whole-gene and rare
mutation screening can cost up to $1000 (Royal College of Pathologists of Australasia). Full
gene sequencing should only be offered if an extended panel testing has previously been
ordered, and especially for this item number there should be a requirement for referral by a
qualified CF physician or clinical geneticist service.
Under current MBS rules, prenatal testing of a foetus is currently described as testing of
“blood or other fluid or tissue” of the mother. The suggested wording for prenatal testing is
currently listed under proposed MBS item 1 below, part (a).
Table 3: Proposed MBS item descriptors for CFTR mutation testing
Category 6 – Pathology services
MBS [proposed MBS item number 1]
Detection of one or two known genetic mutation(s) of the CFTR gene in sample of blood or other fluid or tissue,
in the following situation:
(a) Pregnant woman whose foetus is at 25% or more risk of CF
Fee: $[fee]
Prior to ordering these tests the ordering practitioner should ensure the patient has given informed consent. Testing can
only be performed after genetic counselling. Appropriate genetic counselling should be provided to the patient either by the
treating practitioner, a genetic counselling service or by a clinical geneticist on referral. Further counselling may be
necessary upon receipt of the test results.
MBS [proposed MBS item number 2]
Simultaneous detection of multiple mutations (minimum of 10 mutations) in the CFTR gene in blood or other
fluid / tissue sample in a:
(a) Prospective parent whose foetus is suspected of having a CFTR related disorder
(b) Patient suspected of cystic fibrosis or a CFTR related disorder (with the exception of newborns
suspected of cystic fibrosis through newborn screening);
(c) Man with congenital bilateral absence of the vas deferens (CBAVD); or
(d) Partner of someone with a known CFTR mutation, for reproductive planning purposes
Fee: $[fee]
Prior to ordering these tests the ordering practitioner should ensure the patient (or their parent/guardian in the case of
children) has given informed consent. Testing can only be performed after genetic counselling. Appropriate genetic
counselling should be provided to the patient either by the treating practitioner, a genetic counselling service or by a clinical
geneticist on referral. Further counselling may be necessary upon receipt of the test results.
MBS [proposed MBS item number 3]
Sequencing analysis of the entire CFTR gene for constitutional genetic abnormalities causing CFTR related
disorders, where the results in item [proposed MBS item number 2] or newborn screening common mutation
14
analysis (funded by the State / Territory) are inconclusive, either as:
(a) Diagnostic studies of a CF affected person; or
(b) Identification of the second mutation in a newborn with one identified mutation and a positive result
from item 66686 (sweat test)
Fee: $[fee]
Prior to ordering these tests the ordering practitioner should ensure the patient (or their parent/guardian in the case of
children) has given informed consent. Testing can only be performed after genetic counselling. Appropriate genetic
counselling should be provided to the patient either by the treating practitioner, a genetic counselling service or by a clinical
geneticist on referral. Further counselling may be necessary upon receipt of the test results.
Group 1: People with a high clinical suspicion of CF
Group 1 consists of the patients with signs or symptoms consistent with CF or CFTR related
disorders. This includes people with clinical signs of CF such as neonates with a positive
sweat test after one mutation has been found through newborn screening and people
visiting their health care provider with symptoms consistent with typical or atypical CF. Since
most patients are currently identified through newborn screening, older patients in group 1
are those who did not have the newborn screening test (e.g. born outside Australia, born
before CF screening was introduced, discharged from hospital early or were missed by
screening); had an uncertain diagnosis after NBS (e.g. because of a rare mutation that did
not get picked up by newborn screening), or would have a milder or non-classic form of the
disease which did not get detected during NBS. An example is males with CBAVD: CF
symptoms could develop at a later stage or symptoms could be mild, leading to a normal
IRT- or sweat test result (and therefore remains undiagnosed), or the absence of the vas
deferens may be the only symptom present (Grzegorczyk et al. 2012).
Co-administered and associated interventions
In the absence of genetic CFTR testing in patients with CF symptoms, other diagnostic
testing would be performed in the form of a sweat test. Sweat testing is listed on the MBS
(see Appendix B, Table 11). In most cases the sweat test provides a conclusive result.
However, in some cases the clinical features are suggestive and a CFTR mutation analysis
will be requested. Neonates would have had an IRT-test, sweat test and a genetic test to
test for the most common CFTR mutations.
Clinical place for proposed intervention
CFTR mutation testing is conducted in patients with a wide range of typical and atypical CF
symptoms to determine whether their symptoms are caused by mutations in the CFTR gene.
This could affect treatment and prognosis. Another reason for CFTR testing would be to
determine the patient’s carrier status if they wish to have children. For instance, CBAVD
patients are infertile due to having obstructive azoospermia, and often only find out about
15
their condition when they are trying to have children. These men still produce sperm and
may father children through using IVF. With CFTR mutation testing in these patients and
their partners, they would have a better indication of the risk of their children having CF or
CFTR related disorders. This could help with deciding whether the couple is eligible for PGD,
which is subject of another MBS application, or prenatal diagnostic CF testing.
The pathway of symptomatic patients undergoing diagnostic genetic CFTR mutation testing
is demonstrated in Figure 2. Before CFTR mutation testing, the patient would have to be
referred to a CF clinic for sweat testing or mutation testing. The grey boxes show current
clinical practice (currently reimbursed through the MBS), without the diagnostic genetic
CFTR mutation testing. The blue boxes show proposed clinical practice (additional coverage
by the MBS), which includes the use of genetic testing. Two different diagnostic genetic
CFTR mutation tests are presented. First a common mutation analysis is done (proposed
MBS item number 2), and when only one mutation is identified a second genetic CFTR
mutation test would be conducted (proposed MBS item number 3), to identify a possible
second (rare) mutation.
Comparator
Comparators are usually selected by determining the technology most likely to be replaced
by or added to the technology submitted for a new MBS item number. In the case of genetic
CFTR testing in neonates with a positive sweat test after having one mutation identified
through newborn screening, the whole gene screen is already standard practice (paid for by
the States and Territories), and it does not change the clinical management or health
outcomes of the affected individual. Therefore the comparator for neonates would be
genetic testing paid for by the States/Territories. For other patients with high clinical
suspicion of CF, the comparator would be no CFTR mutation testing.
16
Figure 2 Clinical pathway for use of a genetic CFTR test to identify mutations people with a high clinical suspicion
of CF
Outcomes for evaluation
As the comparator chosen is the hypothetical situation of what would be done in the
absence of prenatal genetic testing (i.e. no testing), the health outcomes, upon which the
comparative clinical performance of diagnostic genetic CFTR mutation testing for people
with classic or non-classic CF symptoms, are:
Effectiveness outcomes:
Primary:
-
Mortality
Quality of life
17
Secondary:
-
Incidence of symptoms arising from CF or CFTR related disorders
-
Age at diagnosis
-
Psychological health
Safety outcomes:
-
Physical harms from testing / no testing
-
Psychological harms from testing / no testing
In the absence of sufficient direct evidence, evidence from comparative studies evaluating
the treatment, linked with applicable evidence of the accuracy of CFTR mutation testing will
be used (linked evidence) to assess the clinical evidence.
As the comparator for neonates with a positive sweat test after having one mutation
identified through newborn screening is testing paid for by the States/Territories, the only
outcome would be financial implications on the MBS and health care system.
Summary of PICO
Table 4 provide a summary of the PICO used to:
(1) define the questions for public funding,
(2) select the evidence to assess the safety and effectiveness of CFTR mutation testing
in people with signs or symptoms of classic or non-classic CF, and
(3) provide the evidence-based inputs for any decision-analytical modelling to determine
the cost-effectiveness of CFTR mutation testing for diagnostic testing in people with
signs or symptoms of classic or non-classic CF.
18
Table 4 PICO criteria for evidence assessing the safety, effectiveness, cost-effectiveness and financial
implications of CFTR mutation testing, compared to no CFTR mutation testing, in people with a high
clinical suspicion of CF.
Patients
Intervention
Comparator
Reference
standard/
evidentiary
standard
Outcomes to be assessed
1. Patients with
classical CF
symptoms
Diagnostic
CFTR mutation
testing
(common
mutation
analysis, if
necessary
followed by
whole gene
screen)
No diagnostic
genetic CFTR
mutation testing
Whole gene
sequencing
Neonates with a Genetic CFTR
positive sweat
mutation testing
test after having (whole gene
one mutation
screen) paid for
found through
by the MBS
newborn
screening
N/A=not applicable
Genetic CFTR
mutation testing
(whole gene
screen) paid for
by the
States/Territorie
s
N/A
Safety
Physical / psychological harms from
testing or no testing,
Analytic validity
Test-retest reliability
Sensitivity*
Specificity*
(*by reference to the reference
standard)
Clinical validity
Test-retest reliability
Sensitivity*
Specificity*
Negative Predictive Value*
Positive Predictive Value*
(*by reference to the reference
standard)
Change in management
% change in management plan (e.g.
changes in medication, monitoring, etc.)
Effectiveness
Primary:
Mortality, quality of life
Secondary:
Incidence of symptoms arising from CF
or CFTR related disorders, age at
diagnosis,
psychological health
Cost-effectiveness
Cost, cost per life year gained, cost per
quality adjusted life year or disability
adjusted life year, incremental costeffectiveness ratio, cost per case
identified
Financial implications
2. Patients with
non-classic CF
symptoms
(CBAVD,
bronchitis /
bronchiectasis,
chronic
pancreatitis,
salt-losing
syndromes etc.)
Questions
1. What is the safety, effectiveness and cost-effectiveness of CFTR mutation testing in patients
with a high clinical suspicion of CF, compared no CFTR mutation testing?
19
2. What is the financial impact to the MBS and health care system of listing CFTR mutation testing
for neonates with a positive sweat test identified as having one mutation through newborn
screening, for the purposes of identifying the second (rare) mutation?
Clinical claim
The applicant claims that identification of CFTR mutations is important for providing
information at a molecular level about prognosis as a result of genotype-phenotype
correlation. Furthermore, identification of CFTR mutations in an individual with CF or another
CFTR related disorder is essential if prenatal diagnosis or PGD is to be offered to prospective
parents within extended family.
It is expected that this test would result in non-inferior safety outcomes, and non-inferior or
superior effectiveness versus no genetic testing, as management options may differ for
those with non-classic symptoms, based on the results of genetic testing. As shown in Table
5, a cost-effectiveness, cost-utility, or cost-minimisation analysis would be performed under
these conditions.
Table 5: Classification of an intervention for determination of economic evaluation to be presented
Abbreviations: CEA = cost-effectiveness analysis; CUA = cost-utility analysis
* May be reduced to cost-minimisation analysis. Cost-minimisation analysis should only be presented when the
proposed service has been indisputably demonstrated to be no worse than its main comparator(s) in terms of
both effectiveness and safety, so the difference between the service and the appropriate comparator can be
reduced to a comparison of costs. In most cases, there will be some uncertainty around such a conclusion
(i.e., the conclusion is often not indisputable). Therefore, when an assessment concludes that an intervention
was no worse than a comparator, an assessment of the uncertainty around this conclusion should be
provided by presentation of cost-effectiveness and/or cost-utility analyses.
^ No economic evaluation needs to be presented; MSAC is unlikely to recommend government subsidy of this
intervention
20
Group 2: Prenatal CF diagnosis (testing of parents and foetus)
Group 2 consists of pathways that are associated with prenatal diagnosis, where there is a
foetus at risk of having CF. This includes the testing of parents where an earlier child has
been diagnosed with CF, or where the foetus is found to have an ‘echogenic gut’ on
ultrasound during the second trimester. If both parents are found to be carriers, then the
foetus may be tested to determine whether it has inherited the CFTR mutations or not.
Because these children have a higher chance of CF and CFTR related disorders (25% when
both parents are carriers), prenatal diagnosis for CFTR related disorders is indicated, to
enable an early diagnosis and provide the parents with a choice regarding whether to
terminate the pregnancy if the foetus tests positive for CF.
Ethical, Legal and Social Implications (ELSI)
As the option arises to terminate the pregnancy after a prenatal CF diagnosis is made,
ethical and legal implications should be considered when assessing prenatal CFTR testing.
Abortion is state regulated and is subject of criminal law in almost all states and territories,
except the Australian Capital Territory. Victoria, South Australia, Western Australia,
Tasmania and the Northern Territory have legislation in place that provides a statutory
explanation of when an abortion is legal, with respect to personal circumstances and timing.
In New South Wales and Queensland, the common law recognises exceptions to the Crimes
Act and Criminal Code that enable the lawful termination of pregnancy in a large number of
women who meet certain criteria. However, it could differ by state regarding whether
termination of pregnancy is lawful when CF is prenatally diagnosed, since the life expectancy
of CF patients is increasing. This should be considered in the decision making process
regarding prenatal CF diagnosis, as the usefulness of prenatal CF diagnosis is questionable
in circumstances where lawful termination of pregnancy would not be available.
Co-administered and associated interventions
Prior to prenatal foetal CFTR testing, most parents would have undergone carrier testing
(see Table 6). Carrier testing is currently not listed on the MBS. Only those people with a
family history of CF are currently offered testing through genetic counselling services. This is
sometimes funded by the State or Territory or self-funded (Massie et al. 2007). In cases
where couples already have a child with CF, this child would most likely have been identified
through newborn screening. In this case the couple also knows that they are likely to be
carriers, and could decide to undergo a CFTR mutation test themselves.
When an echogenic gut is detected, patient counselling is offered to assist with the decision
about whether to undergo invasive diagnostic testing for aneuploidy, congenital infection
and prenatal CF carrier status determination. Echogenic gut is identified on mid trimester
ultrasound in 0.3 – 0.8 per cent of pregnancies and is a marker for poor foetal outcome
21
(e.g. intra uterine growth restriction (IUGR)) and foetal demise (Mailath-Pokorny et al.
2012). CF may be the cause in 3 – 4 per cent of these cases and is usually associated with a
favourable outcome (Goetzinger et al. 2011). Other causes, including intrauterine infection
(CMV) or chromosome aneuploidy, may also be detected on amniocentesis and usually have
unfavourable outcomes. This means amniocentesis is often indicated not just for CFTR
testing. The pathway followed will be dictated by assessment of several factors including
gestational age (+/- 20 weeks), associated features such as IUGR and parental
preferences.1
If the parents are diagnosed as being CF carriers, and consent for invasive testing is given,
amniocentesis is performed and tests are conducted on the amniotic fluid cells (see
Appendix B). With the implementation of MBS funded prenatal CFTR mutation testing, the
change expected is an increase in the termination rate of pregnancies.
Table 6 Prior and co-administered interventions in group 3
Population
Prior and co-administered tests or interventions
Pregnant women known to be carriers
Prior:
- Carrier testing in woman and partner
Co-administered:
- Possible termination of current pregnancy
Pregnant women with a child with CF
Prior:
- IRT test in other child
- Sweat test in other child
- CFTR mutation testing in other child
Co-administered:
- Possible termination of current pregnancy
Pregnant women whose child shows an ‘echogenic Prior:
gut’ on ultrasound
- Ultrasound
- Patient counselling
Co-administered:
- Carrier testing in woman and partner
- Amniocentesis
- Karyotyping
- Congenital infection testing
- Termination of current pregnancy
Clinical place for proposed intervention
1
HESP Expert advice received via email on 26-10-2013
22
Foetuses with echogenic bowel and foetuses with a family history of CFTR related disorders
both have increased risks of CF or CFTR related diseases. This risk is around 25 per cent
when both parents are CF carriers, as compared to approximately 0.004 per cent in the
general population. However, when a foetus with echogenic bowel has parents that are
known to be carriers, the risk of a CF affected baby is significantly greater than 25 per cent.
Figure 3 shows that with MBS funded prenatal genetic CFTR mutation testing available,
parents may be able to establish a reliable diagnosis prior to the birth of their child. Some
parents may consider terminating the pregnancy. Furthermore, if the child has CF and the
parents decide to proceed with the pregnancy, they would be better prepared for managing
the CF once the child is born. The red boxes show the populations included in this clinical
pathway.
The grey box shows historical clinical practice, without the diagnostic genetic CFTR mutation
testing. The blue boxes show proposed clinical practice (additional coverage by the MBS),
which includes the use of genetic testing.
Questions for PASC/Public consultation: HESP expert advice is that the subgroup ‘Parent
with a foetus at risk of CF due to a previous child being clinically diagnosed with CF’ (see
Figure 3) normally undergoes testing at a similar time as the child that is diagnosed. Given
that these children are usually identified through the Newborn Screening (NBS) program,
funded by the States/Territories, are tests done on the parents also funded through the
States/Territories? This includes self funded testing. In cases where CFTR tests on the
parents are funded through the States/Territories, these subgroups can be identified in the
application. The foetus of this couple would be included under the third subgroup (Foetus
where both parents have been diagnosed with CFTR mutation(s)).
23
Figure 3 Clinical pathway for use of a genetic CFTR test for parents of foetus at high risk of having CF and foetus of
parents who are carriers
24
Comparator
Comparators are normally chosen based on what the proposed technology is likely to
replace. As with the previous patient group, CFTR mutation testing in the parents of a foetus
at risk of having CF, and in foetuses where the parents are both carriers, is currently
standard practice, and some patients would have this test funded by the States and
Territories. However, there is a sizeable proportion of the population who would be receiving
their prenatal care in the private health system, and would currently be paying for the CFTR
mutation tests themselves. As such, PASC suggested that the comparator should be no
prenatal CFTR testing, and diagnosis of the child via newborn screening after the child is
born.
Outcomes for evaluation
As the comparator chosen is the hypothetical situation of what would be done in the
absence of prenatal genetic testing (i.e. newborn screening), the health outcomes, upon
which the comparative clinical performance of diagnostic genetic CFTR mutation testing for
foetuses versus newborns will be measured, are:
Effectiveness outcomes:
Primary:
-
Rate of births without CF
-
Parental psychological health benefits
-
Child’s quality of life
-
Child’s life expectancy
-
Parental quality of life
-
Child’s functional status
Secondary:
-
Termination rate due to presence of specific CFTR mutations
-
Psychological health of the parent
-
Pregnancy termination rate
-
Miscarriage rate
-
Live birth rate
Safety outcomes:
-
Physical harms from DNA sampling procedures in the parent
-
Psychological harms from decision making or other aspects of the procedures (in the
parent), such as:
25
-
o
Depression
o
Post traumatic stress symptoms
o
Harms resulting from misdiagnosis
o
Psychological and physical harms from not achieving a pregnancy
Adverse events from the amniocentesis (for the child), such as:
o
Physical disability
o
Intellectual disability
o
Developmental delay
o
Peri-natal mortality (e.g. still-birth)
In the absence of sufficient direct evidence, evidence on the change in management, linked
with applicable evidence of the accuracy of CFTR mutation testing will be used (linked
evidence) to assess the clinical evidence (see Table 7 and Table 8).
Summary of PICO
Table 7 and Table 8 provide a summary of the PICO used to:
(4) define the questions for public funding,
(5) select the evidence to assess the safety and effectiveness of CFTR mutation testing
for prenatal diagnosis, and
(6) provide the evidence-based inputs for any decision-analytical modelling to determine
the cost-effectiveness of CFTR mutation testing for prenatal diagnosis.
26
Table 7 PICO criteria for testing parents of foetus at risk of having CF
Patients
Intervention
Comparator
Parent with a
foetus showing
echogenic gut
on second
trimester
ultrasound
CFTR mutation
testing
(common
mutation
analysis) in the
parents
and if parents
are both
carriers:
amniocentesis
+ CFTR
mutation testing
(known
mutation
analysis) in the
foetus
No CFTR
mutation testing
Parent with a
foetus at risk of
CF due to a
previous child
being clinically
diagnosed with
CF
Reference
standard
Clinical
diagnosis
(newborn
screening +
symptoms) at
birth
Outcomes to be assessed
Safety
Physical harms from DNA sampling
procedures
Physical harms from TOP
Psychological harms from decision
making or other aspects of the
procedures
Depression
Post-traumatic stress symptoms
Harms resulting from misdiagnosis
Physical and psychological harms
from not achieving a pregnancy
Analytic validity
Test-retest reliability
Sensitivity*
Specificity*
(*by reference to the reference
standard)
Change in management
% change in patients proceeding to
amniocentesis
% change in method of CF diagnosis in
child/foetus
Effectiveness
Primary
Rate of live births without CF
Parental psychological health benefits
Parental quality of life
Secondary
Termination rate due to presence of
specific CFTR mutation
Cost-effectiveness
Cost, cost per case identified, cost per
CF birth averted
Question
What is the safety, effectiveness and cost-effectiveness of genetic CFTR testing on parents with a foetus
with a high clinical suspicion of CF, compared to clinical diagnosis of the child after birth?
27
Table 8 PICO criteria for testing foetuses at risk of having CF
Patients
Intervention
Comparator
Foetuses where
both parents
have been
identified as CF
carriers
(parents
identified due
to:
signs/symptoms
of CF, or
previous child
with CF, or
foetus showing
an echogenic
gut on second
trimester
ultrasound)
Amniocentesis
followed by
CFTR mutation
testing
(common
mutation
analysis for
foetuses with
echogenic gut
and known
mutation
analysis for
foetuses whose
parents are
carriers) with
the option of
TOP if the
foetus is
affected
No prenatal
CFTR mutation
testing followed
by newborn
screening or
clinical
diagnosis
Reference
standard
Clinical
diagnosis
(newborn
screening +
symptoms) at
birth
Outcomes to be assessed
Safety
Adverse events from the amniocentesis
Physical disability
Intellectual disability
Developmental delay
Peri-natal mortality (eg still-birth)
Analytic validity
Test-retest reliability
Sensitivity*
Specificity*
(*by reference to the reference
standard)
Clinical validity
Test-retest reliability
Sensitivity*
Specificity*
Negative Predictive Value*
Positive Predictive Value*
(*by reference to the reference
standard)
Change in management
% change in termination of pregnancy
rate
Effectiveness
Live birth rate, miscarriage rate, life
expectancy of child, morbidity in child,
quality of life of the child, functional
status
Cost-effectiveness
Cost, cost per case identified, cost per
CF birth averted
Question
What is the safety, effectiveness and cost-effectiveness of diagnostic genetic CFTR testing on foetuses
where both parents are CF carriers, compared to clinical diagnosis after birth?
Clinical claim
The applicant claims that identification of CFTR mutations as a result of CFTR diagnostic
testing is important for providing information about prognosis at a molecular level as a result
of genotype-phenotype correlation. Identification of CFTR mutations in a foetus could also
aid the decision regarding whether to terminate the pregnancy. In cases where the
pregnancy is not terminated despite two CFTR mutations, the foetus would be diagnosed
before birth, so his/her parents could be better prepared for the possible complications and
symptoms that arise after birth, optimising treatment options and prognosis.
It is expected that this test would result in inferior safety outcomes, as there is some risk in
performing amniocentesis, and superior or non-inferior effectiveness versus clinical diagnosis
28
for CF. As shown in Table 9, a cost-effectiveness or cost-utility analysis would be performed
under these conditions.
Table 9: Classification of an intervention for determination of economic evaluation to be presented
Abbreviations: CEA = cost-effectiveness analysis; CUA = cost-utility analysis
* May be reduced to cost-minimisation analysis. Cost-minimisation analysis should only be presented when the
proposed service has been indisputably demonstrated to be no worse than its main comparator(s) in terms of
both effectiveness and safety, so the difference between the service and the appropriate comparator can be
reduced to a comparison of costs. In most cases, there will be some uncertainty around such a conclusion
(i.e., the conclusion is often not indisputable). Therefore, when an assessment concludes that an intervention
was no worse than a comparator, an assessment of the uncertainty around this conclusion should be
provided by presentation of cost-effectiveness and/or cost-utility analyses.
^ No economic evaluation needs to be presented; MSAC is unlikely to recommend government subsidy of this
intervention
29
Group 3: CFTR testing in partners of people with known CFTR mutations for the
purpose of reproductive planning
Parental carrier screening where there are no clinical indications for testing is considered
outside the scope of the application. However, PASC agreed that where one partner had CF
or was a known carrier, that their partner should be tested, if the couple are planning on
having children.
CFTR mutation testing of the partner prior to conception could help with deciding whether
the couple is eligible for Pre-implantation Genetic Diagnosis (PGD), which is subject of
another application for Commonwealth funding. Potential funding for PGD would only be
available to couples where the causative gene mutations have already been identified.
Co-administered and associated interventions
It is envisaged that where a partner of someone with a confirmed CFTR mutation is also
found to have a CFTR mutation, the couple would either proceed to using PGD, or to natural
conception or IVF, followed by prenatal testing and possible termination of pregnancy. The
MBS items for IVF are listed in Table 13, Appendix B. PGD is currently being considered
under another application for Commonwealth funding.
Clinical place for proposed intervention
The key benefit of pre-conception testing for CFTR mutations, is that the prospective
parents may make more informed decisions regarding their reproductive choices. If both
parents have CFTR mutations, then the couple would likely be eligible for PGD. If they
choose not to proceed with PGD, and prefer the option of natural conception or IVF without
PGD, then they know that the child has a 25% chance of having CF. Upon pre-natal testing
of the foetus (as per Group 2), if two mutations are identified, they may decide to terminate
the pregnancy.
If the partner does not have a CFTR mutation, then the couple may proceed with a natural
pregnancy (if possible) or IVF, without concern regarding the CF status of the child.
Thus, pre-conception CFTR mutation testing would be used as a replacement for pre-natal
CFTR mutation testing in a proportion of cases, and in addition to pre-natal testing in the
remainder of cases.
The clinical pathway for the use of CFTR mutation testing to screen the partner of someone
with at least one CFTR mutation is shown in Figure 4.
30
Figure 4 Clinical pathway for use of a genetic CFTR test for reproductive planning, prior to conception (plus PGD or pre-natal CFTR testing) versus pre-natal CFTR testing
Comparator
It is possible that some couples at risk of having a child with CF may choose not to have
biological children, or may choose to conceive without either pre-conception or prenatal
CFTR mutation testing. However PASC suggested that when prospective parents are being
tested for CFTR mutations for reproductive purposes prior to conception, the comparator
should be prenatal CFTR mutation testing and possible termination of pregnancy. A
comparison of prenatal testing versus no prenatal testing is proposed to be assessed under
Group 2 (Prenatal CF diagnosis).
Outcomes for evaluation
The outcomes for evaluation are the direct safety and effectiveness of pre-conception CFTR
mutation testing, plus downstream implications of PGD or pre-natal testing and possible
termination of pregnancy, versus pre-natal testing and possible termination of pregnancy.
For the sake of simplicity, the health outcomes of those who proceed to pregnancy and prenatal testing in the intervention arm could be considered to be the same as those who
proceed to pregnancy and pre-natal testing in the comparator arm. The key comparison of
interest is therefore pre-conception testing (allowing PGD) versus pre-natal testing.
However, this comparison is the subject of another assessment (MSAC application 1165),
and therefore it does not need to be duplicated in this assessment.
The assessment group proposes that a fit-for-purpose evaluation for Group 3 be restricted
to an assessment of the accuracy of CFTR testing in an asymptomatic population
(sensitivity, specificity, positive predictive value, negative predictive value and test-retest
reliability).
Summary of PICO
A summary of the suggested PICO criteria may be found in Table 10.
It shows the PICO criteria for an assessment of the accuracy of CFTR in a partner of
someone with a CFTR mutation. The accuracy of CFTR testing in this population, would be
the same as carrier testing within the general population. If the parents of a child with CF
are also included in this assessment (prior to conception of a subsequent child, not only
prenatally, as in Group 2), then the accuracy of CFTR mutation testing in this population
should also be assessed.
Table 10 PICO criteria for the assessment of pre-conception versus pre-natal testing CFTR mutation testing
Population
Intervention
Comparator
Reference
standard
Outcomes to be assessed
1. General
screening
population
CFTR mutation
testing (common
mutation analysis)
N/A
Whole gene
sequencing
Accuracy
Test-retest reliability
Sensitivity*
Specificity*
Negative Predictive Value*
Positive Predictive Value*
(*by reference to the reference
standard)
Question
1. What is the accuracy of CFTR mutation screening in the general population?2
Clinical claim
No clinical claim regarding CFTR testing for reproductive planning was made by the
applicant. However, according to the Human Genetics Society of Australia (HGSA), prepregnancy testing is preferable because it allows more options for carrier couples, including
PGD, donor gamete/embryo and prenatal diagnosis with the option of terminating the
pregnancy, leading to a decreased incidence of CF.
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36
Appendix A: Classification of Class 3 in vitro diagnostic medical devices
Box 1 Classification of Class 3 in vitro diagnostic medical devices
From Therapeutic Goods (Medical Devices) Regulations 2002 - Schedule 2A
1.3 Detection of transmissible agents or biological characteristics posing a moderate public health risk or high personal risk
1.
An IVD is classified as Class 3 IVD medical devices or a Class 3 in-house IVD if it is intended for any of the
following uses:
a. detecting the presence of, or exposure to, a sexually transmitted agent;
b. detecting the presence in cerebrospinal fluid or blood of an infectious agent with a risk of limited
propagation;
c. detecting the presence of an infectious agent where there is a significant risk that an erroneous result
would cause death or severe disability to the individual or foetus being tested;
d. pre-natal screening of women in order to determine their immune status towards transmissible agents;
e. determining infective disease status or immune status where there is a risk that an erroneous result will
lead to a patient management decision resulting in an imminent life-threatening situation for the patient;
f. the selection of patients;
i.
for selective therapy and management; or
ii.
for disease staging; or
iii.
in the diagnosis of cancer;
g. human genetic testing;
h. to monitor levels of medicines, substances or biological components, when there is a risk that an
erroneous result will lead to a patient management decision resulting in an immediate life-threatening
situation for the patient;
i. the management of patients suffering from a life-threatening infectious disease;
j. screening for congenital disorders in the foetus.
Note: For paragraph (f) An IVD medical device would fall into Class 2 under clause 1.5 if:
2.
k. a therapy decisions would usually be made only after further investigation; or
l. the device is used for monitoring.
Despite subsection (1) an IVD is classified as a Class 3 IVD medical device or a Class 3 in-house IVD if it is used
to test for transmissible agents included in the Australian National Notifiable Diseases Surveillance System
(NNDSS) list as published from time to time by the Australian government.
Source: http://www.tga.gov.au/industry/ivd-classification.htm [accessed August 2013]
37
Appendix B: MBS item descriptors for associated interventions
Table 11 MBS item descriptor for sweat testing
Category 6 – Pathology services
MBS 66686
Performance of 1 or more of the following procedures:
(a)
(b)
(c)
(d)
(e)
Growth hormone suppression by glucose loading;
Growth hormone stimulation by exercise;
Dexamethasone suppression test
Sweat collection by iontophoresis for chloride analysis
Pharmacological stimulation of growth hormone
Fee: $50.65 Benefit: 75% = $38.00 85% = $43.10
Table 12 MBS item descriptor for interventions associated with CFTR mutation testing in group 2
Category 5 – DIAGNOSTIC IMAGING DEVICES
MBS 55706
PELVIS OR ABDOMEN, pregnancy related or pregnancy complication, fetal development and anatomy,
ultrasound scan (not exceeding 1 service in any 1 pregnancy) of, by any or all approaches, with measurement
of all parameters for dating purposes, if:
(a) the patient is referred by a medical practitioner or participating midwife; and
(b) the dating for the pregnancy (as confirmed by ultrasound) is 17 to 22 weeks of gestation; and
(c) the service is not associated with a service to which an item in Subgroup 2 or 3 of this group applies; and
(d) if the patient is referred by a medical practitioner - the referring medical practitioner is not a member of a
group of practitioners of which the providing practitioner is a member; and
(e) if the patient is referred by a participating midwife - the referring midwife does not have a business or
financial arrangement with the providing practitioner; and
(f) the service is not performed in the same pregnancy as item 55709 (R)
Bulk bill incentive
Fee: $100.00 Benefit: 75% = $75.00 85% = $85.00
(See para DIQ of explanatory notes to this Category)
Category 3 – THERAPEUTIC PROCEDURES
MBS 20842
INITIATION OF MANAGEMENT OF ANAESTHESIA for amniocentesis
(4 basic units)
38
Fee: $79.20 Benefit: 75% = $59.40 85% = $67.35
MBS 16600
INTERVENTIONAL TECHNIQUES
AMNIOCENTESIS, diagnostic
Fee: $63.50 Benefit: 75% = $47.65 85% = $54.00
(See para T4.11 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $32.95
Category 6 – PATHOLOGY SERVICES
MBS 73287
The study of the whole of every chromosome by cytogenetic or other techniques, performed on 1 or more of
any tissue or fluid except blood (including a service mentioned in item 73293, if performed) - 1 or more tests
Fee: $394.55 Benefit: 75% = $295.95 85% = $335.40
MBS 73289
The study of the whole of every chromosome by cytogenetic or other techniques, performed on blood (including
a service mentioned in item 73293, if performed) - 1 or more tests
Fee: $358.95 Benefit: 75% = $269.25 85% = $305.15
Table 13 Current MBS items for IVF services (relevant to group 3)
Category 3 – THERAPEUTIC PROCEDURES
MBS 13200
ASSISTED REPRODUCTIVE TECHNOLOGIES SUPEROVULATED TREATMENT CYCLE PROCEEDING TO
OOCYTE RETRIEVAL, involving the use of drugs to induce superovulation, and including quantitative
estimation of hormones, semen preparation, ultrasound examinations, all treatment counselling and embryology
laboratory services but excluding artificial insemination or transfer of frozen embryos or donated embryos or
ova or a service to which item 13201, 13202, 13203, 13206, 13218 applies - being services rendered during 1
treatment cycle - INITIAL cycle in a single calendar year
Fee: $3,110.75 Benefit: 75% = $2,333.10 85% = $3,036.25
(See para T.1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $1,675.50
MBS 13201
ASSISTED REPRODUCTIVE TECHNOLOGIES SUPEROVULATED TREATMENT CYCLE PROCEEDING TO
OOCYTE RETRIEVAL, involving the use of drugs to induce superovulation, and including quantitative
estimation of hormones, semen preparation, ultrasound examinations, all treatment counselling and embryology
laboratory services but excluding artificial insemination or transfer of frozen embryos or donated embryos or
ova or a service to which item 13200, 13202, 13203, 13206, 13218 applies - being services rendered during 1
treatment cycle - each cycle SUBSEQUENT to the first in a single calendar year
Fee: $2,909.75 Benefit: 75% = $2,182.35 85% = $2,835.25
(See para T1.4 of explanatory notes to this Category)
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Extended Medicare Safety Net Cap: $2,432.15
MBS 13202
ASSISTED REPRODUCTIVE TECHNOLOGIES SUPEROVULATED TREATMENT CYCLE THAT IS
CANCELLED BEFORE OOCYTE RETRIEVAL, involving the use of drugs to induce superovulation and
including quantitative estimation of hormones, semen preparation, ultrasound examinations, but excluding
artificial insemination or transfer of frozen embryos or donated embryos or ova or a service to which Item
13200, 13201, 13203, 13206, 13218, applies being services rendered during 1 treatment cycle
Fee: $465.55 Benefit: 75% = $349.20 85% = $395.75
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $64.95
MBS 13206
ASSISTED REPRODUCTIVE TECHNOLOGIES TREATMENT CYCLE using either the natural cycle or oral
medication only to induce oocyte growth and development, and including quantitative estimation of hormones,
semen preparation, ultrasound examinations, all treatment counselling and embryology laboratory services but
excluding artificial insemination, frozen embryo transfer or donated embryos or ova or treatment involving the
use of injectable drugs to induce superovulation being services rendered during 1 treatment cycle but only if
rendered in conjunction with a service to which item 13212 applies
Fee: $465.55 Benefit: 75% = $349.20 85% = $395.75
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $64.95
MBS 13209
PLANNING and MANAGEMENT of a referred patient by a specialist for the purpose of treatment by assisted
reproductive technologies or for artificial insemination payable once only during 1 treatment cycle
Fee: $84.70 Benefit: 75% = $63.55 85% = $72.00
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $10.90
MBS 13212
OOCYTE RETRIEVAL for the purposes of assisted reproductive technologies - only if rendered in conjunction
with a service to which Item 13200, 13201 or 13206 applies
(Anaes.)
Fee: $354.45 Benefit: 75% = $265.85 85% = $301.30
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $70.35
MBS 13215
TRANSFER OF EMBRYOS or both ova and sperm to the female reproductive system, excluding artificial
insemination - only if rendered in conjunction with a service to which item 13200, 13201, 13206 or 13218
applies, being services rendered in 1 treatment cycle (Anaes.)
Fee: $111.10 Benefit: 75% = $83.35 85% = $94.45
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $48.70
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MBS 13218
PREPARATION of frozen or donated embryos or donated oocytes for transfer to the female reproductive
system, by any means and including quantitative estimation of hormones and all treatment counselling but
excluding artificial insemination services rendered in 1 treatment cycle and excluding a service to which item
13200, 13201, 13202, 13203, 13206, 13212 applies
(Anaes.)
Fee: $793.55 Benefit: 75% = $595.20 85% = $719.05
(See para T1.4 of explanatory notes to this Category)
Extended Medicare Safety Net Cap: $702.65
41