1. Case Study: The Binding Site. Working with the Recast/Revision of the IVD Directive - the Impact on a Medium- sized Diagnostics Company Dr Kirk Buller Head of Regulatory Affairs

2. My Background: 1964-1977:Educated in London and Northern Ireland. 1980: BSc Biochemistry (University of Bristol) 1984: PhD Biochemistry (Meat Research Institute/ University of Bristol) 1984-6: Post-doc studying duodenal ulcers (Southampton General Hospital/University of Southampton)

3. My Background (cont’d): 1986: Joined Binding Site. 1986-2012: Worked in R+D and Production. Managed Quality Assurance, Technical Services, UK Sales Office, Instrument Support. Since 1988 I have run the Regulatory Affairs function, which now consists of 8 staff.

4. Binding Site – a Short History. Early 1980’s: Formed as spin-off company from Birmingham University, selling OEM antibodies & RID kits. 1987/8: Selling IVD kits under Binding Site label. Main products in-vitro tests measuring human serum immunoglobulins, incl. IgG subclasses. 1987: First FDA-cleared product - IgG radial immunodiffusion (RID) kit. 1988: US office opened in San Diego. 1992: BS 5750 certification (now ISO 9000) received.

5. Binding Site – a Short History cont’d. 2000: Registered under the IVD Directive with the MHRA. 2001: IVD test for free light chains (Freelite) launched – a new cancer marker. 2009: Autoimmune product business sold. 2012: Company has 500 employees, based in 12 countries. Manufacturing site in Birmingham, production unit in US. Distributors cover an additional 60 countries.

6. Recast of the IVD Directive -Biggest change since the directive was introduced in 2000. -Exact details are not yet confirmed – though the main proposed changes have been known since end 2011. -The proposed changes have been discussed at BIVDA and EDMA meetings and feedback has been given..

7. Four Key Impacts: 1. Clinical Evidence 2. Classification of Medical Devices 3. Conformity Assessment 4. UDI/Barcoding. (Based upon the version reviewed by the Medical Device Expert Group on 13 th February 2012)

8. 1. Clinical Evidence “The demonstration of conformity… shall be based upon clinical evidence.” “The clinical evidence report shall contain a scientific validity report, an analytical performance evaluation report and where appropriate, a clinical performance report.” “Clinical performance means the ability of a device to yield results that are correlated with a particular clinical condition...”

9. Why does this pose a significant impact? 1. This is a new requirement. 2. Clinical evidence reports will be needed for 200+ IVD products. 3. No “grandfathering” – existing products are not exempt. Cont’d

10. Why does this pose a significant impact? 4. Generating the necessary data with patient groups would be very time-consuming and expensive. Unclear how much existing literature/publications can be used. 5. The use of positive/negative predictive values and likelihood ratios have been suggested previously - may be impossible to define for many IVD tests which are used as part of a panel rather than stand-alone.

11. 2. Classification of IVD Medical Devices Reminder of current classification: 1. Annex II A – Very high risk (HIV, Hepatitis, ABO, Rhesus Blood grouping). 2. Annex II B – High risk (anti-Duffy, Kidd blood grouping, erythrocytes, rubella, toxoplasmosis, PKU, CMV, chlamydia, HLA tissue groups, PSA, trisomy 21, blood glucose self-test). 3. Self Test Devices. 4. “The rest” (also known as Annex III) – Low risk, self- certification

12. New Classification – based on the GHTF system. Already adopted/adapted by several countries – Australia, China, Canada, Singapore. Class A: Instruments (except self & near patient testing), specimen receptacles, reagents with specific characteristics intended to make them suitable for IVD procedures related to a specific examination. Class B: All non-class A, C and D. Class C: Sexually transmitted agents, infectious agents in blood, CSF, infective disease/immune states which would lead to patient- management decisions resulting in life-threatening situations. Devices used in companion diagnostics for disease staging, used in screening or diagnosis of cancer, genetic testing. Class D: Detect transmissible agents in blood components, blood cells, tissues for transplantation, transmissible agents causing life-threatening diseases..

13. Why does this pose a significant impact? Several tests have gone “up a class”, including cancer diagnosis/screening tests. The concern over this becomes apparent when considering Conformity Assessment.

14. 3. Conformity Assessment Under current system, the large majority of IVDs on the market are the low-risk “Annex III” products which are self- certified as compliant with the IVD Directive by their manufacturers, usually supported by an externally inspected ISO9001/ISO13485 quality system. This allows companies to bring new products quickly to the market, also to manufacture, release and modify products without time-consuming external approvals.

15. New Conformity Assessment Under the new system: “Manufacturers of Class C devices…shall be subject to conformity assessment based on product quality assurance and design dossier examination”.

16. Why does this pose a significant impact? Binding Site would have to appoint a Notified Body for its Freelite product range, since these tests are used in the diagnosis of multiple myeloma, a type of cancer. This would add a significant annual cost and potentially restrict development and time-to-market for this product area. But there is more….

17. New Conformity Assessment Under the new system: “Manufacturers of Class B devices…shall be subject to conformity assessment based on full quality assurance” This is essentially a level of Notified Body involvement for by far the largest group of IVDs (affecting all Binding Site’s diagnostic products). A very significant extra workload and expense.

18. There is also concern about the availability of enough suitably-experienced Notified Body staff to handle this considerably increased workload across the industry!

19. 4. UDI/Barcoding New EU and US guidance has been recently published: 1. European Commission recommendation on a common framework for a unique device identifier system in the EU. 2. FDA (USA) Proposed Rule…to establish a unique device identification system…

20. The main driver for UDI/barcoding is product safety – by better product identification and traceability, recalls will be more effective, incident reporting will be improved etc. Other benefits related to stock management, anti- counterfeiting and distribution control are anticipated.

21. There has been collaboration between the EU and US authorities to try to ensure the two sets of requirements are compatible. Other countries that are also currently looking at UDI/barcoding (China, Australia) will be watching with interest….

22. It is important to emphasize that the UDI/barcoding requirements will almost certainly come into force before the other requirements of the recast IVD Directive.

23. Key Requirements of the UDI/Barcoding guidelines: 1. National databases will need to be set up to hold the product data. It is hoped that a single database can be used to cover the whole of the EU.

24. Key Requirements of the UDI/Barcoding guidelines: 2. Manufacturers will need to provide a UDI/barcode on the label of each medical device comprising a “static” part and a “dynamic” part.

25. Key Requirements of the UDI/Barcoding guidelines: 3. Manufacturers will supply “fixed” data to each national database linked to the “static” part of the UDI. This fixed data is likely to include product code, product name, storage temperature, national registration number etc.

26. Key Requirements of the UDI/Barcoding guidelines: 4. The “dynamic” part of the UDI, comprising lot number or serial number or expiry date, will be added by the manufacturer at the time of production. This information will not be supplied to national databases.

27. Why does this pose a significant impact for Binding Site? 1. An internal database to collate all of the “static” information will need to be set up – in a format that can be easily submitted to national databases. 2. Barcoding technology will need to introduced across the product range (Binding Site does not currently barcode its products). This will include new printers, readers and additional quality control checking. Cont’d

28. Why does this pose a significant impact for Binding Site? 3. All outer product labels will need to be redesigned to incorporate the barcode. This could cause problems for smaller products where space on the label is severely limited. 4. A decision must be taken on whether to adopt the old 1-dimensional the newer 2-dimensional barcode format.

29. The US UDI proposal is currently out for comment, but is expected to be in place by May 2013. Medium risk products (most IVDs) will then need to comply by May 2016. (High risk products earlier). The European requirements are expected to be in place by the same time as the US requirements or shortly afterwards.

30. What’s Next? Binding Site have fed back their comments through BIVDA and EDMA, so now we await the publication of the proposed IVD Directive when it is passed to the European Parliament this autumn. Updates on the UDI requirements are expected before the end of 2012.

31. Thank you for listening. Any Questions?