Download UKGTN_IVDD_Sept_10 - UK Genetic Testing Network

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RESPONSE TO THE PUBLIC CONSULTATION OF THE REVISION OF DIRECTIVE 98/79/EC OF THE
EUROPEAN PARLIAMENT AND OF THE COUNCIL OF 27 OCTOBER 1998 ON IN VITRO DIAGNOSTIC
MEDICAL DEVICES
Submission by:
UKGTN Scientific Advisor (author):
Project Team:
Programme Director
Clinical Advisor:
Scientific Advisor:
Molecular
Scientific Advisor:
Cytogenetics
Public Health Advisor
Communications Specialist
Service Development Manager
Business & Corporate Support Officer
Contact:
UK Genetic Testing Network (UKGTN) Project Team
Su Stenhouse
Jacquie Westwood
Dr Shehla Mohammed
(Consultant Geneticist and Head of Service Guys & St Thomas’
Hospital)
Su Stenhouse
(Head of Laboratory, South West Scotland Regional Genetics
Centre, Glasgow)
Val Davison
(Head of Laboratory, Birmingham Regional Genetics Centre)
Dr Mark Kroese
(Consultant Public Health, Peterborough PCT)
Dr Jacqui Hoyle
Jane Deller
Tarita Turtiainen
UKGTN, c/o National Specialised Commissioning Group, NHS London, 2nd Floor Southside,
105 Victoria Street, London, SW1E 6QT
Tel: 020 7932 3969, email: [email protected]
The United Kingdom Genetic Testing Network: Background
The UKGTN Steering Group was established in 2002 and is part of the National Specialised Commissioning
Team in NHS London. It is a collaborative group of NHS laboratory scientists, clinical geneticists, genetics
commissioners and patient representatives and the Steering Group is Chaired by Professor Peter Farndon. It
aims to promote the provision of high quality equitable genetic testing services for NHS patients across the
UK. This involves evaluating new tests and recommending to specialised services commissioners (procurers
of genetic services for patients in the NHS) those appropriate for service. There are 50 member laboratories
from regional genetics and other specialist laboratories. Membership is conditional on the laboratory meeting
the required quality criteria (e.g. CPA) and participating in External Quality Assurance schemes. A small
project team and four working groups carry out the work on behalf of the Steering Group. The working group
members are nominated representatives from healthcare professionals and patient representatives from
across the UK.
The UKGTN has an internationally recognised process (commonly referred to as the “Gene Dossier process”)
to evaluate new genetic tests (within its scope) being proposed for NHS service nationally from its member
laboratories. Tests that pass the UKGTN evaluation process are recommended to commissioners for
funding. A Directory1 is produced annually listing all the tests that have been through this process and the
associated testing criteria to promote appropriate referrals. Currently there are 487 diseases on Directory
which equates to 659 tests (i.e. disease/gene pairs). The Genetic Alliance UK (formerly the Genetic Interest
Group) reports that patients have recognised the increased availability of genetic tests because of the
UKGTN system. Different approaches are used internationally2, but the UK is seen as a world leader.
1.
2.
The Directory of genetic tests that have been evaluated and are available from UKGTN member laboratories is
available from the UKGTN website at www.ukgtn.nhs.uk
The evaluation of clinical validity and clinical utility of genetic tests (September 2007), authors Dr Mark
Kroese, UKGTN Public Health advisor; Dr Rob Elles, Director NGRL Manchester; Dr Ron Zimmern,
Executive Director PHG Foundation.
www.ukgtn.nhs.uk
This response is particularly targeted at section 3 of the consultation document.
Question 7.
We believe that it is absolutely essential to maintain the ‘in-house’ exemption for a variety of
reasons:
1) Rare Disease Testing. Rare diseases may be defined as conditions affecting fewer than 5 in
10,000 people and clearly testing for these is performed infrequently and usually only
available from specialist centres. CE marking of every test offered in these centres is
impractical both scientifically and economically. The quality of such testing must be of a high
standard but requiring CE marking would result in the loss of currently available tests for
rare diseases due to the burden of regulation.
2) Rare tests for common disorders. Some inherited disorders such as familial breast cancer
are quite common but the causative mutations are individually very rare and may be found
in only one family. This means that each test has to be individually tailored to that familial
mutation. Furthermore such testing is often required within a very narrow time frame
following the diagnosis of breast cancer to inform and optimise treatment and management
options and CE marking of each rare test would not be possible.
Similarly, prenatal tests often involve testing for a ‘private’ family mutation and the test may
have to be developed very quickly to provide appropriate information to the parents. This
could not be accomplished if CE marking of the test were to be required.
3) Seldom used tests for common analytes. Very few genetic disorders have CE marked kits
available. However even for those which do have an available kit, follow on tests are often
required. For example CF has a variety of CE marked testing kits but none of these can
provide testing for every possible mutation in the CFTR gene. In order to produce a full
result further bespoke testing has to be performed in a substantial minority of patients using
in-house methods. The existing exemption ensures such testing is available.
4) Population specific tests. Where CE marked kits are available they may not be appropriate
for every population. The newest CF kit comes in a US and European format but even so,
sub-populations and more isolated countries are unlikely to be well served by such a generic
kit and must rely on in-house customised assays to ensure the detection of ‘local’ mutations.
5) Rapid response to new health threats. In recent years there have been a number of health
threats such as H5N1 or SARS which have required a rapid response in the development of
tests for diagnosis, monitoring and vaccine development. The urgent nature of these tests
means that CE marking would introduce an unacceptable delay in implementation which
could exacerbate the situation.
6) Safety benefits of alternative testing methods. Whilst harmonisation of testing standards and
comparability of results is essential there are also benefits to be gained from a variety of
testing methods. Undue reliance on a single method can mask systematic deficiencies in
that method. A variety of validated in-house methods used within a network of laboratories
ensures that any systematic weaknesses are picked up and can be rectified. An example of
this is a group of laboratories using the same PCR primers for a breast cancer test all of
which missed a mutation in a quality assessment exercise due to a deficiency in one of the
primers. Had no other assay been in use this would not have been identified.
7) Cytogenetic and other whole genome testing. Conventional chromosome analysis involves
the culturing of cells from the patient and the examination of fixed metaphase spreads using
either a microscope or more commonly digital analysers. These sophisticated image
analysis systems are not specifically CE marked and it would be impossible to do this as
each is configured to a specific department’s requirements. Similarly any attempt to CE
mark any of the culture systems would be impossible and not cost effective.
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In the UK over 35,000 cytogenetic investigations are carried out in patients referred for
prenatal diagnosis using samples from the fetus at either 12 weeks gestation (chorionic
villus samples), or 16 weeks (amniotic fluid samples). These patients are referred for a
variety of reasons but all with a high risk of a genetic disorder. Timing of the results is hugely
important and each individual biological system may need a slight variation to maximise the
growth of cells. If CE marking were required for such tests the service would not be viable.
8)Array Comparative Genome Hybridisation and next generation sequencing These
technologies are increasingly replacing some of the functions of karyotyping and broaden
the range of analysis which is possible but karyotyping will still play a role for many patients.
All of these new techniques will also share with karyotyping the possibility of producing
results unrelated to the clinical question and requiring expert interpretation in the context of
the patient’s phenotype. Such testing is not amenable to CE marking and is best delivered
by a specialist laboratory accredited to perform and interpret the results of such complex
testing in conjunction with specialist clinical advice.
In the UK in 2008-09 postnatal testing was provided for over 400 disorders. Over 300 of these
(74%) had a test volume of fewer than 100. Only 16 (4%) had a test volume of greater than 1000.
The chance of any commercial provider supplying CE marked kits for such low volumes is slim.
There is therefore little evidence in the UK to support the claim of unfair competition between CE
marked devices and ‘in-house’ tests.
In conclusion, the use of validated in-house tests devised by accredited diagnostic laboratories
need not pose an increased risk to patients and abolition of the exemption would certainly result in
the loss of many tests for rare disorders which are currently available.
Question 8.
Item 1:
Better definitions are required. For ‘in-house test’ there should be a requirement for any laboratory
developing such tests to be accredited to ISO 15189/CPA or equivalent and to provide evidence of
validation of the test.
There is a risk of narrowing the definitions too much so that no existing institution fulfils the criteria.
Item 2:
No. Requiring ‘in-house’ tests to fulfil the essential criteria even without formal CE marking would
still place an unacceptable burden on laboratories.
Item 3:
No. Many of the most important testing for patients with rare diseases such as pre-symptomatic
testing might be construed as high risk. If they were to be excluded from the exemption they would
cease to be provided which would have adverse effects on families with these conditions.
Item 4:
Yes. The restriction of the ‘in-house’ exemption to laboratories which are accredited to ISO 15189
or equivalent would provide an important safeguard for patients who rely on these tests. Given that
in general these are very rare disorders, this proposal provides a proportionate response which
balances the risks and benefits.
It should be noted that the ISO definition of accreditation should be used and should not be
confused with certification or licensing, neither of which provide the same assurance of quality and
competence.
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Question 9.
No. Patients with rare diseases deserve the same quality of diagnostic testing as those with more
common conditions. To remove the ‘in-house’ exemption except for rare diseases would
discriminate against those suffering from those conditions. This is in direct contradiction of the EC
initiative on improved services for rare diseases.
In addition, such an exemption would allow the marketing of test kits for rare diseases with no
regulatory oversight to ensure their quality, suitability or effectiveness. These kits could be used in
laboratories not expert in their use or interpretation of the results putting families with rare diseases
at risk.
Retention of the ‘in-house’ exemption with the safeguard of its use only in accredited laboratories
provides security, assurance of a high quality test and equity of access for those with rare
disorders. In addition, the rarity of a disorder depends to some extent on the population and a rare
disease in one country may be relatively common in another.
The removal of the ‘in-house’ exemption would not just affect the availability of rare disease tests
but also other types of specialized test where no CE marked test is available and this would do
nothing to preserve those tests for patients.
Question 10.
Yes, this would be useful clarity.
Item1:
Not all genetic tests require ‘results obtained by analysis of the genome’ as some will use RNA
analysis or protein tests and that wording would be likely to cause confusion as to which tests are
included.
There are also occasions when paternity testing or DNA comparison is employed for medical
reasons.
Item 2:
This is preferable to item 1 but may require clarification of ‘direct’ and indirect’ medical purposes.
In conclusion, the ‘in-house’ exemption is required to maintain the safety provided by
alternatives in test methodology and to ensure the continued availability of tests that are not
suitable for CE marking. These will include:
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Rare disease testing
Customised tests for common disorders
Cytogenetic and other whole genome analysis
Seldom used tests for common analytes
Rapid response to changing health threats
Population specific tests and test panels