Critical Issues in Product Development

Transcription

1 Critical Issues in Product Development Partnership for Dengue Control Workshop 4 May 2017 Fondation Mérieux Annecy Courtesy of FIND

2 Five Lessons in Product Development 1 The easy problems have been solved. 2 Plans are useless, planning is essential. 3 Concepts are not products. 4 No one is great at this (yet). 5 There is plenty to be done.

3 Bill Brieger Global attention* drives impact Estimated Changes in Plasmodium falciparum Mortality in Sub-Saharan Africa. * G-20 funding support Prevention plus treatment Measurement Cross-disciplinary collaboration Leveraging market forces Gething PW et al. N Engl J Med 2016; 375:2435-

4 Five inflection Points in Diagnostic Product Development for Impact 1 The perfect and the good. 2 The difficulty of clinical validation. 3 The volume price curve in manufacturing. 4 Market dynamics. 5 The hidden costs of product support. 4

5 Inflection Point 1. The perfect and the good. Courtesy of Iveth Gonzalez, MD, FIND

6 Inflection Point 1. The perfect and the good. Estimated diagnostic accuracy of RDT for malaria attributable fever during the low and high transmission seasons Age Febrile Malaria attributable Not malaria attributable SE SP PPV NPV (years) N TP (a) FN (b) FP (c) TN (d) Low transmission (dry) season < All High transmission (rainy) season < All Biosffi Z et al. Malaria J 2010; 9:192 ia diagnosis among the N febrile cases in each age parasite density combination. Estimates obtained from N, AF and Prob RDT + (see methods). Numbers presented are rounded to 1 decimal place; actual calculations based on a better numerical

7 Ebola Control line Test line Broadhurst et al, Lancet 2015

8 Ebola Positive predictive value of RDT increases with positivity score Broadhurst et al, Lancet 2015

9 Inflection Point 2. The challenges of clinical validation. Timeline: Clinical validation of centralized TB assays Title Effort15 Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr 1 1) Study Conception 22w 1.1) Design study 14w 1.2) Site selection 2w 1.3) Protocol & statistical analysis plan 6w 1.4) Study plan approved 2) Study Preparation 36w 2.1) Site assessments & contracts 6w 2.2) Preparation of study documents 8w 2.3) IRB approvals 16w 2.4) Import permits 6w 2.5) Sites ready to start 3) Study Conduct 73w 3.1) Phase 1: External Laboratory Evaluation 15w 3.1.1) Import permits 4w 3.1.2) Shipment (panels, reagents, equipment) 4w 3.1.3) Site training & initiation visit 1w 3.1.4) Testing, data entry & cleaning 4w 3.1.5) Preliminary analysis 2w 3.2) Phase 2: Clinical Trial 58w 3.2.1) Shipment (reagents, equipment) 4w 3.2.2) Training & site initiation 2w 3.2.3) Recruitment & testing of samples 40w 3.2.4) Completion of culture/dst/sequencing 10w 3.2.5) Data entry & cleaning 2w 3.3) Study complete 4) Reporting 26w 4.1) Data analysis 6w 4.2) CEA 8w 4.3) WHO dossier preparation 4w 4.4) WHO data review 4.5) Preparation of publication 8w 9

10 Inflection Point 2. The challenges of clinical validation. The pathway to obtain FDA clearance for a single product with multiple fever analytes will be complex. The agency indicated that the simplest approach would be, if the system is able to report results selectively, then each individual analyte could be submitted for approval as a separate clearance, through a De Novo 510(k) for Ebola, Lassa fever, and Marburg, and through either a De Novo, or a standard 510(k) for chikungunya, dengue, malaria, and yellow fever. A decision on how to obtain marketing approval for the multiplex test that incorporates all analytes would be left to the manufacturer to suggest during a pre-submission meeting. One approach would require up to 5 different filings for each analyte, plus one for the platform; the individual studies and data analysis would likely be greatly simplified. A second approach would require a single study capable of validating a statistically significant number of each target pathogen across multiple sites, using NAT as a reference standard, stratified by Ct value, across age and gender, and powered to detect a sensitivity point estimate >95%,with a lower bond of the confidence interval >90%; such a study would require between 5,000-10,000 febrile patients and require approximately two years or more. 10

11 Inflection Point 3. The volume price curve in manufacturing. Part Name Comparable Cost for CD4 Cartridge Projection for HCV Cartridge (N5 line) Projection for HCV Cartridge (1 MM line) Backbone + Lid (individual components) $1.00 $2.00 $1.00 Assumes $.80 for molded part, $.20 for electrode printed lid (we had no breakdown from thinxxs). Lid Foil Bonding Chemistry $0.00 $0.20 $0.10 Move In low away volumes, from with expensive prototype hotmelt tool, higher - $0.10 cost is guess for molded [can we part? get quote for UV Vis?] [switch to Valve, die cut $0.14 $0.14 $0.05 pumped Strauss cut hotmelt electrodes instead for of $0.02 solid-phase][re to get a not-to-exceed number at volume for various Valve bonding adhesive + reservoir $0.28 $0.10 $0.05 Rob looking for UV Vis example quote perivia Housing $0.40 $0.00 $0.00 Housing now part of reservoir system Cap $0.57 $0.57 $0.25 Low-precision part, farm to cheaper mfg; can get quotes on current cap design or X1 proto-design Reservoir $0.50 $0.40 $0.40 for See ballpark Rob's spreadsheet [KD, DB find 'cartridge ballpark?] costing.xlsx' [may be able to elimiate (fully loaded with capex over 10 yrs Reagent $0.05 $0.05 $0.05 number Reagents is similar $.65); can start work immediately Electrode $0.01 $0.01 $0.01 If we can't print on the lid, may add another penny in PMMA stock; Can start this work immediately Functionalization Reagents $1.42 $2.99 $2.99 Includes A/C, SCN, apoh, anti-apoe, Ag, MBx2, assorted - can't nail down until we know more about Functonaliztion Process Components $0.00 $0.40 $0.20 chemistry [RE getting quote from Web Industries] - can't do process development until we know more about Lancets (e.g. Nonwoven + Capillaries for loading, beads, etc.) $1.71 $0.00 $0.00 chemistry. Courier Fee $0.08 $0.00 $0.00 Packaging $0.27 $0.27 $0.15 Likely less at 1MM -.15 is guess Cartridge Pouch $0.17 $0.17 $0.16 Quote of 100K & 1MM Desiccant $0.22 $0.22 $0.08 Quote of 1MM/yr from Multisorb Manufacturing Consumables $0.23 $0.23 $0.02 Assume similar, but should get much smaller at higher volumes/lot sizes - assume 1/10 burden of Label $0.01 $0.01 $0.01 1MM over 100k Materials Base Cost $7.06 $7.76 $5.52 Material Markup (8%) $0.56 $0.62 $0.44 Yield $0.40 $0.44 $ % yield, so every card is burdened with 5/95 * (materials cost + markup) Line Priming $0.57 $0.42 $0.03 assume 5% for 100K line,.05% for 1MM, which still seems high; is this included in OPE? Materials Total $8.02 $8.82 $6.28 Backbone + Lid Labor $7.19 $1.33 $0.00 Using $1.33/operator, derived from INJ number $8 for 6 operators on VLV Reservoir Labor $2.15 $1.33 $0.00 Functionalization Labor $5.34 $1.33 $0.00 Reagent production & management Other CM $2.66 $2.66 $0.26 Roughly 2 $80k / parts Reagent production labor $0.00 $1.33 $0.13 VLV was assumed to be basically free; assume one full-time body for HCV Labor Base Cost $17.34 $7.98 $0.39 Availability & Performance $2.57 $2.00 $0.10 Assume 90% avail and 90% efficiency = 80% total; equivalent to 75% OPE. Labor Total $19.91 $9.98 $0.49 Materials + Labor Total $27.93 $18.80 $6.77 SG&A (5%) $1.40 $0.94 $0.34 CM Profit (12%) $3.35 $2.26 $0.81 Total Cost $32.68 $21.99 $7.92 Amortized Capital $6.67 $10.00 $1.00 CapEx and lifttime use estimates Royalties / Licensing $0.00 $1.50 $1.50 ApoH & AgPlus royalties estimates Distribution $0.00 $4.00 $4.00 Grand Total COGS $39.35 $37.49 $14.42 Notes/Justification

12 Inflection Point 3. The volume price curve in manufacturing. Units/Yr 10,000,000 1,000,000 Cartridge Production Capacity (Cartridges/Year) July 2014 (Clinton, MA) Q (Clinton, MA) 100,000 10,000 Jun 2012 (Cambridge, MA) Cartridge Production Capacity 1, Per test price: $35 $12 $5

13 Inflection Point 4. Market dynamics Novartis and the development of Coartem Chinese (CAMMS) develop artemisia derivatives Ciba-Geigy partnership with CAMMS, with Chinese R&D companies, KPC and ZMC Malaria resurgence in the developing world Novartis forms Anti-malarial program retained Clinical research Phase III trials Regulatory approval Global Fund established, $3-6 billion/year for AIDS, TB and malaria Novartis and WHO sign MOU. Riamet introduced for travelers at $60 per dose First shipment of ACT at cost Government of Zambia interest in 2.1 million doses Lancet critical of WHO and Novartis; media, Wall Street Journal agree Novartis production capacity reaches 30 million doses 1990s

14 Millions of doses 14 Year

15 Artemisinin production

16 Millions of doses 16 Year

17 Millions of doses 17 Year

18 Millions of doses 18 Year

19 Inflection Point 4. Market dynamics

20 Inflection Point 4. Market dynamics Tests (MM) Global CD4 Need Global VL Need 46,4 43,8 43,6 38,9 40,5 37,1 33,7 33,4 29,5 25,8 25,2 26,0 25,9 25,5 24,9 24,9 25,7 21,3 18,6 15, Source: Ripin, AIS Presentation 2013 New WHO Guidelines go into effect: Routine VL for ART monitoring and CD4<500 for ART initiation

21 Inflection Point 5. The hidden costs of product support

22 Five inflection Points in Diagnostic Product Development for Impact 1 The perfect and the good. 2 The difficulty of clinical validation. 3 The volume price curve in manufacturing. 4 Market dynamics. 5 The hidden costs of product support. 22

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24 Hope 1 Technological progress

25 Hope 1 Technological progress 2 Salience

26 Hope 1 Technological progress 2 Salience 3 Champions aligned on goals

27 FIND/Monnerat Hope Thank You!! Children in the Thai-Burmese border region