The Challenges in Developing and Commercializing HIV Tests that are Useful in Differentiating VISP/R VISP/R Workshop Bethesda, MD March 2013

Transcription

1 The Challenges in Developing and Commercializing HIV Tests that are Useful in Differentiating VISP/R VISP/R Workshop Bethesda, MD March 2013 Christopher Bentsen, M.S.,RAC, FRAPS Bio-Rad Laboratories, Redmond, WA

2 The Challenges in Developing and Commercializing HIV tests Bio-Rad HIV assays has been used for the testing of HIV vaccine recipients for many years with variable VISP/R reactivity, depending on the generation of HIV assay used. In my opinion, developing a specialized HIV antibody test for VISP/R is not cost effective for large diagnostic companies. The costs for facility overhead and FDA regulations falls equally on all products being manufactured, which makes low volume HIV tests typically un-economical. Currently available HIV diagnostic test designs have changed significantly in the past 5-10 years to move toward highly specific and high purified peptide and recombinant proteins and appear to show improved specificity in testing HIV vaccine recipients C. Bentsen VISP/R Meeting March 14,

3 Food and Drug Administration Food and Drug Administration is made up of different Offices and Centers. In the Office of Medical Products and Tobacco are: Center for Devices and Radiological Health (CDRH) Center for Biological Evaluation and Research (CBER) Center for Drug Evaluation and Research (CDER) Center for Tobacco Products C. Bentsen VISP/R Meeting March 14,

4 FDA Regulations FDA Regulations affecting HIV tests HIV in vitro diagnostic (IVD) test kits are medical devices under Section 210(h) of the FD&C Act and also regulated under Section 351 of the Public Health Services Act as a biological. FDA considers HIV tests to be in Class III as a high risk medical device. Most other IVD kits are either in Class I or Class II. FDA approves HIV tests for diagnostic use by approval of a Pre-Market Approval Application (PMA). FDA licenses HIV tests used for blood screening approval of a Biological License Application (BLA). HIV blood screening assays are also subject to lot release testing C. Bentsen VISP/R Meeting March 14,

5 FDA Laws and Amendments FDA Laws or Amendments to the FD&C Act that affect IVD tests Medical Device Amendments of 1976 Safe Medical Device Amendments of 1990 Medical Device Amendments of 1992 F&D Administration Modernization Act of 1997 Medical Device User Fee and Modernization Act of 2002 (MDUFMA I) F&D Administrative Amendments Act of 2007 Medical Device User Fee and Modernization Act of 2007 (MDUFMA II) FDA Safety and Innovation Act of 2012 Medical Device User Fee Amendments of 2012 (MDUFA III) C. Bentsen VISP/R Meeting March 14,

6 Additional FDA Regulations Establishment Registration [21 CFR 807] Medical Device Listing [21 CFR 807] Quality Systems Regulation [21 CFR 820] Medical Device Reporting [21 CFR 803] Medical Device Recall Authority [21 CFR 810] C. Bentsen VISP/R Meeting March 14,

7 FDA User Fee Schedule 2013 FDA User Fee Schedule Annual Registration Fee $ 2,575 ($2,575)* PMA Annual Report (each) $ 8,680 ($2,170)* PMA 30 day Notice $ 3,968 ($1,984)* PMA Real Time Supplement $ 17,360 ($4,340)* PMA 180-day Supplement $ 37,200 ($9,300)* PMA Panel Track Supplement $186,000 ($46,500)* PMA Application $248,000 ($62,000)* * Small business fee schedule (<$100 million in sales) C. Bentsen VISP/R Meeting March 14,

8 Bio-Rad HIV Tests Worldwide C. Bentsen VISP/R Meeting March 14,

9 Bio-Rad FDA approved HIV tests FDA approved or FDA licensed HIV tests from Bio-Rad (originally Genetic Systems Corporation) LAV (HIV-1) EIA (VL) (1 st gen) 1986 HIV-2 EIA (VL) (1 st gen) 1990 HIV-1/HIV-2 EIA (VL) (1 st gen) 1991 HIV-1/HIV-2 Peptide EIA (2 nd gen) 1997 GS rlav (VL and recombinant) (2 nd gen) 1998 GS HIV-1 Western blot (VL) (1 st gen) 1998 GS HIV-1/HIV-2 PLUS O EIA (3 rd gen) 2003 Multispot HIV-1/HIV-2 (rapid differentiation) 2004 GS HIV Combo Ag/Ab EIA (4 th gen) 2011 Bolded tests are currently being manufactured and sold C. Bentsen VISP/R Meeting March 14,

10 GS HIV-1/HIV-2 PLUS O EIA 3 rd Gen GS HIV-1/HIV-2 PLUS O EIA microplates and reagents 3 rd generation test using peptides and recombinant proteins including p24 recombinant antigen. FDA licensed test every lot undergoes FDA lot release testing C. Bentsen VISP/R Meeting March 14,

11 GS HIV COMBO Ag/Ab EIA 4 th Gen Microwell schematic for simultaneous detection of HIV Antigen and Antibodies. FDA PMA approved. Detects p24 antigen and not p24 antibodies. Antigen Detection Conjugates: Antibody Detection Conjugates: Conj 2 Streptavidin-HRP SA-HRP biotin HRP Pep gp41 (HIV-1 M)-HRP Pep gp41 (HIV-1 O)-HRP Pep gp36 (HIV-2)-HRP Conj 1 Sheep anti-p24 biotin HIV p24 Ag MAbs (3) anti-p24 Pep gp41 (HIV-1 O) Rec gp160 (HIV-1 M) gp36 Pep (HIV-2) HIV-1 Antibody C. Bentsen VISP/R Meeting March 14,

12 The Bio-Rad Automated Systems HIV testing can be performed manually or with FDA approved automated instruments based on annual testing volumes. C. Bentsen VISP/R Meeting March 14,

13 Bio-Rad HIV-1 Western Blot Assay GS HIV-1 Western blot trays and reagents and controls FDA licensed assay every lot undergoes FDA lot release testing C. Bentsen VISP/R Meeting March 14,

14 Bio-Rad HIV-1 Western Blot Assay GS HIV-1 Western blot nitrocellulose strip utilizes native HIV- 1 (LAV Group B strain) viral lysate proteins. C. Bentsen VISP/R Meeting March 14,

15 Bio-Rad Multispot HIV-1/HIV-2 Rapid Test Multispot HIV-1/HIV-2 Rapid Test cubes and reagents for differentiation of HIV-1 and HIV-2 antibodies utilizes: FDA PMA approved as a diagnostic assay. HIV-1 gp41 recombinant HIV-1 gp41 peptide HIV-2 gp36 peptide C. Bentsen VISP/R Meeting March 14,

16 Bio-Rad Multispot HIV-1/HIV-2 Rapid Test The Bio-Rad Multispot assay package insert is undergoing significant changes to support the new HIV Diagnostic Algorithm. A new interpretation recommendation of requiring both HIV-1 spots to be present will be recommended for a positive result when used in the algorithm. Results will be Negative, HIV-1 Indeterminate (1 spot reactive), HIV-1 Positive (2 spot reactive) and HIV-2 Positive. C. Bentsen VISP/R Meeting March 14,

17 The Challenges in Developing and Commercializing HIV Tests- Facilities and FDA Production facilities for producing HIV test kits Manufacturing of high volume HIV tests is automated and is typically performed in Class 10,000 controlled facilities Manufacturing of lower volume HIV tests can be semi-automated or produced manually in same controlled facilities FDA CBER typically performs 3 inspections of the manufacturer of a new HIV PMA approval 1. PMA pre-approval inspection of facility and manufacturing records 2. BIMO inspection of clinical trial site(s) and sponsor facility clinical trial data 3. PMA one year post approval inspection of facility and manufacturing records Facilities producing high risk HIV devices are inspected by FDA at least every two to four years C. Bentsen VISP/R Meeting March 14,

18 The Challenges in Developing and Commercializing HIV Tests- Economy of Scale HIV Test Production Volumes per year- Economy of Scale by a manufacturer HIV EIA tests, random access HIV tests and rapid HIV tests used for diagnostic screening are typically manufactured in the millions or tens of millions of tests per year. HIV differentiation and supplemental or confirmatory tests have a smaller market but are still typically manufactured in the tens or hundreds of thousands of tests per year. C. Bentsen VISP/R Meeting March 14,

19 The Challenges in Developing and Commercializing HIV Tests-Adaptations Examples of adaptations of existing HIV test kits to include a new intended use or a new sample type HIV blood screening test claims for cadaveric and living organ donor testing HIV diagnostic screening tests adapted for use with oral fluid, dried blood spots (DBS) or urine samples HIV confirmatory tests adapted for use with oral fluid, urine or DBS (dried blood spot) samples HIV diagnostic test kits modified to perform HIV antibody avidity testing for determining HIV recency C. Bentsen VISP/R Meeting March 14,

20 The Challenges in Developing and Commercializing HIV Tests-Vaccine Trial Data HIV EIA and WB assays have been used to test HIV DNA vaccine recipients with variable results*. Cumulative results from vaccine recipients at one or more time points were: GS rlav EIA reactivity (37/38 or 97%) GS Peptide EIA reactivity ( 6/38 or 16%) GS PLUS O EIA reactivity ( 4/38 or 11%) GS PLUS O modified-p24 ( 1/38 or 3%) GS Western blot was HIV-1 positive (40%) or HIV-1 indeterminate (60%) in EIA reactive samples. None were WB negative. *S Peel 1, J Malia 1, K Shriver 3, R Bailer 2, B Graham 2, N Michael 1 and R O Connell 1 1 WRAIR, 2 Vaccine Research Center, NIH and 3 Bio-Rad Laboratories, Keystone Meeting Poster, Banff Canada, 2008 C. Bentsen VISP/R Meeting March 14,

21 «NEW» Geenius HIV-1/2 Supplemental Assay Geenius Cassette, Reader Software for interpretation IgG antibody test using colloidal gold conjugate 5 ul serum, plasma or 15 ul whole blood or finger stick Under development, Not FDA approved. C. Bentsen VISP/R Meeting March 14,

22 «New» Geenius HIV-1/2 Assay : Kit Controls Built-in assay Control Line to demonstrate assay validity HIV Negative Control and combined HIV-1/2 Positive Control Under Development Not FDA approved Negative Control Positive Control C. Bentsen VISP/R Meeting March 14,

23 «NEW» Geenius HIV-1/2 Supplemental Assay Geenius HIV Supplemental assay 6 assay lines and control line. Under development. Not FDA approved. C. Bentsen VISP/R Meeting March 14,

24 «NEW» Geenius HIV-1/2 Supplemental Assay The Geenius HIV 1/2 Supplemental Assay contains six (6) lines which are numbered on the test cassette corresponding to the following antigens: Test line 1: gp36 (HIV-2, envelope peptide), peptide mimicking the first immunodominant epitope from the gp36 region Test line 2: gp140 (HIV-2, envelope peptide), peptide mimicking the second immunodominant epitope from the gp36 region + peptides mimicking the gp105 region Test line 3: p31 (HIV-1, polymerase peptide), peptide mimicking the immunodominant epitope of the p31 region Test line 4: gp160 (HIV-1, envelope recombinant protein), recombinant protein mimicking the immunodominant epitope of the gp160 region Test line 5: p24 (HIV-1, core recombinant protein), recombinant protein mimicking the immunodominant epitope of the p24 region Test line 6: gp41 (Group M & O) (HIV-1, envelope peptides), peptides mimicking the immunodominant epitope of the gp41 region Test line C: Control band (Protein A) Under development. Not FDA approved. C. Bentsen VISP/R Meeting March 14,

25 The Challenges in Developing and Commercializing HIV Tests- Summary Screening of HIV vaccine recipients it appears can be done economically with some existing commercially available HIV 3 rd and 4 th generation assays. Newer HIV screening tests using recombinant proteins and peptides appear to have better VISP specificity than older HIV viral lysate (VL) based 1 st or 2 nd gen assays. We plan to keep the GS HIV-1 Western blot assay on the market, after it is replaced by Multispot in the new diagnostic algorithm. Newer peptide and recombinant based HIV supplemental tests like Geenius will likely have better VISP specificity. Thank you. C. Bentsen VISP/R Meeting March 14,