Appendix E
Examples of ECRI Institute and Hayes, Inc., Quick Turnaround Reports

Efficacy of Human Papillomavirus (HPV) Vaccines for Prevention of Cervical Cancer1

Thank you for using ECRI’s Health Technology Assessment Information Service (HTAIS). This Hotline Response provides information about Efficacy of Human Papillomavirus (HPV) Vaccines for Prevention of Cervical Cancer. To prepare this Hotline Response we consulted a number of information resources. We provide a description of these resources, including a complete outline of the databases we searched, our search strategies, and the search results at the end of this Response. ECRI has published a related Hotline (1); to access this and other materials on HPV, search the HTAIS Web site using the search term: HPV.

General Comments:

About Human Papillomavirus

The human papillomavirus (HPV) is a sexually transmitted virus carried by over half of the sexually active population in the United States. Prevalence estimates of HPV in the United States range from 6.2 million to 20

NOTE: These reports are provided as examples and are not intended to represent an endorsement by the committee.

1

Reprinted, with permission, from ECRI 2006. Copyright 2007 by ECRI Institute.



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Appendix E Examples of ECRI Institute and Hayes, Inc., Quick Turnaround Reports Efficacy of Human Papillomavirus (HPV) Vaccines for Prevention of Cervical Cancer1 Thank you for using ECRI’s Health Technology Assessment Information Service (HTAIS). This Hotline Response provides information about Effi- cacy of Human Papillomavirus (HPV) Vaccines for Prevention of Cervical Cancer. To prepare this Hotline Response we consulted a number of infor- mation resources. We provide a description of these resources, including a complete outline of the databases we searched, our search strategies, and the search results at the end of this Response. ECRI has published a related Hotline (1); to access this and other materials on HPV, search the HTAIS Web site using the search term: HPV. General Comments: About Human Papillomavirus The human papillomavirus (HPV) is a sexually transmitted virus carried by over half of the sexually active population in the United States. Preva- lence estimates of HPV in the United States range from 6.2 million to 20 NOTE: These reports are provided as examples and are not intended to represent an en- dorsement by the committee. 1 Reprinted, with permission, from ECRI 2006. Copyright 2007 by ECRI Institute. 0

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06 KNOWING WHAT WORKS IN HEALTH CARE million people. In most people, the infection is entirely asymptomatic and causes no disease. However, in some people, HPV can cause genital or anal warts, recurrent respiratory papillomatosis (RRP) lesions, and/or cancer, most notably of the cervix. Cervical cancer is the 11th most common can- cer among US women, and the second most common cause of cancer in women worldwide. An estimated 9,710 new cases of cervical cancer will occur in the United States alone in 2006, and 3,700 women will die from it. Although the conditions it causes may be treatable, HPV infection has no treatment, and use of condoms may not prevent HPV transmission. (See Centers for Disease Control and Prevention (CDC) links in section 8 of the Search Summary) Other cancers thought to be caused by HPV include vaginal, vulvar, and head and neck cancer. Additional information on HPV and HPV-related diseases can be found through the Web sites listed in sec- tion 8 of the Search Summary. About HPV Vaccines Two major pharmaceutical companies have developed vaccines for HPV. These vaccines are administered in three injections: at day 1, month 2, and month 6. There are over 100 known strains of HPV, but only a few have been causally associated with cancer. Vaccines are intended to protect against the most dangerous strains of HPV. The following paragraphs include details from an Advisory Committee on Immunization Practices meeting held at the CDC in February 2006 regarding these vaccines. (See link in section 8 of the Search Summary) GlaxoSmithKline has produced a recombinant vaccine (Cervarix) against HPV strains 16 and 18, which are the strains responsible for 70% of cases of cervical cancer. This vaccine has been tested in 1,113 women for over two years. It was found to be well tolerated, with minimal, minor adverse events. It was also found to be highly efficacious, with 100% protection against persistent HPV (meaning the infection has not resolved within six months and is therefore more likely to lead to pathological changes) caused by the target strains. Through the follow-up period, 93% of patients had normal pap smears. 53 months after vaccination, 98% of patients still had HPV antigens thought to be protective. Phase III studies enrolling more than 30,000 patients internationally are currently underway. Merck & Co. has developed a vaccine (Gardasil) against HPV strains 16 and 18, as well as strains 6 and 11. Together, these strains account for more than 90% of cases of genital warts and RRP, in addition to protect- ing against cervical cancer. This vaccine has also been studied in men, who can develop cancer, RRP, and genital warts from HPV. In addition, men can transmit the virus to women, potentially causing cervical cancer in

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07 APPENDIX E their partners. The clinical trial for this vaccine enrolled 27,000 women and children in four continents. Thus far, results have been analyzed for 20,541 recipients, and 100% prophylactic efficacy has been found for cer- vical, vaginal, and vulvar cancers caused by HPT strains 16 and 18. It was also found to be efficacious in preventing re-infection in women who had previously been infected with HPV. Reported serious (unspecified) adverse events were low, affecting 0.4% of 27,000 women. The US Food and Drug Administration advisory panel on Vaccines and Related Biological Products has recommended approval of Merck & Co.’s application to market Gardasil. Formal approval by the FDA was received on June 8, 2006. Documents presented to the committee and final approval documents can be viewed through the Web sites listed in section 6 of the Search Summary. Recent Clinical Literature Our searches identified 14 randomized, controlled trials (RCTs), 37 tradi- tional reviews, and 3 cost analyses. These publications are categorized in Table 1. We subdivided the RCTs by clinical outcomes (e.g. persistent infec- tion and other treatment-requiring conditions) and intermediate outcomes (e.g. antibody titers). Since clinical outcomes are of more importance in healthcare, we summarized findings for these RCTs in Table 2. Although no evidence-based conclusions can be drawn from abstracts, the results appear promising. The three cost analyses found that vaccinating for HPV should be less costly than frequently screening for its effects (i.e. administer- ing pap smears annually rather than tri-annually) and treating its sequelae (i.e. repeated pap smears, colposcopy, LEEP (loop electrosurgical excision procedure) for dysplasia, and cancer treatments). Table 1. Recent Clinical Literature Number of Publication Type Identified References Publications Clinical 4 2-5 Randomized, Outcomes Controlled Trials (RCTs) Intermediate 10 6-15 Outcomes Reviews 37 16-52 Cost Analyses 3 53-55

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0 KNOWING WHAT WORKS IN HEALTH CARE Table 2. Randomized, Controlled Trials on Vaccine Efficacy in Clinical Outcomes Vaccine Follow-Up Citation Population Findings Studied Time Harper et al. 2006 (2) Strains 16 and Adult 4.5 years Efficacy of vaccine 18 (n=393) and women against: placebo (n=383) • incident infection was 96.9% (95% CI 81.3-99.0%) • persistent infection at 1yr was 100% (95% CI 33.6-100%) • cervical intraepithelial neoplasia was 100% (95% CI 42.4-100%) Mao et al. 2006 (3) Strain 16 Women 2 years Efficacy against (n=755) or aged 16-23 infection: 100% (95% placebo (n=750) years CI 65-100%) Villa et al. 2005 (4) Strains 16, Young 36 months Combined incidence 18, 6, and 11 women of infection with (n=277) or inoculated strains placebo (n=275) fell by 90% (95% CI 71-97%;P<0.001) Harper et al. 2004 (5) Strains 16 and Women 27 months Efficacy of vaccine 18 (n=1113) aged 15-25 against: years • incident infection was 91.6% (95% CI 64.5 to 98.0%) • persistent infection was 100% (95% CI 47 to 100%) • persistent cervical HPV infection was 95.1% • related cytological abnormalities was 92.9% Please be aware that the above opinions are based upon review of abstracts of published articles and, therefore, no firm conclusions are offered. Be- cause abstracts do not always accurately reflect the methods and findings of the full-length article or the limits on interpreting the published data, the reader is strongly encouraged to obtain the relevant articles before reaching conclusions about this technology. As such, ECRI has not evalu- ated the quality of these study designs, nor have we determined whether the authors used appropriate statistical methods to analyze their data. We are reluctant to comment on the reliability of these results in the absence of such evaluations. The purpose of this Hotline Response is to provide

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09 APPENDIX E you with a summary of the literature based on our searches, and to give you information about what this technology is purported to accomplish. This Response is not intended to provide specific guidance for the care of individual patients. Selected References Note: In preparing the Hotline Response, information specialists research the topic and compile a Bibliography. We exclude individual case reports because they may not represent routine use. Technical articles are also excluded unless they include clinical trial results. In writing the Hotline Response analysts screen the Bibliography for references relevant to the topic, and these are provided below in the narrower list of Selected References. References also include relevant ECRI content on your topic including ECRI documents that are not part of your HTAIS membership benefits. For an electronic copy of any non-HTAIS ECRI documents that are ref- erenced in your Hotline Response, please contact the Hotline Service. For routine access to ECRI documents that are provided through other ECRI Membership Services, please contact Don Cummins. 1. ECRI. Concerns about human papillomavirus (HPV) vaccination [Ho- tline]. ECRI 2. Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, Jenkins D, Schuind A, Costa Clemens SA, Dubin G. Sustained efficacy up to 4.5 years of a bivalent Ll virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367(95 18): 1247-55. PubMed 16631880 [PMID] 3. Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ, Alvarez FB, Bautista OM, Jansen KU, Barr E. Efficacy of human pap- illomavirus—16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;l07(l):l8-27. PubMed 16394035 [PMID] 4. Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Roimett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadriva- lent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled

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0 KNOWING WHAT WORKS IN HEALTH CARE multicentre phase II efficacy trial. Lancet Oncol. 2005;6(5):271-8. PubMed 15863374 [PMID] 5. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G. Efficacy of a bivalent L1 virus- like particle vaccine in prevention of infection with human papillomavims types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364(9447):1757-65. PubMed 15541448 [PMID] 6. Pinto LA, Castle PE, Roden RB, Harro CD, Lowy DR, Schiller JT, Wallace D, Williams M, Kopp W, Frazer IH, Berzofsky JA, Hildesheim A. HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood. Vaccine. 2005;23(27):3555-64. PubMed 15855014 [PMID] 7. Poland GA, Jacobson RM, Koutsky LA, Tamms GM, Railkar R, Smith JF, Bryan JT, Cavanaugh PF Jr, Jansen KU, Barr E. Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2-year randomized controlled clinical trial. Mayo Clin Proc. 2005;80(5):601-10. PubMed 15887427 [PMID] 8. Smith KL, Tristram A, Gallagher KM, Fiander AN, Man S. Epitope specificity and longevity of a vaccine-induced human T-cell response against HPV18. Int Immunol. 2005;17(2):167-76. PubMed 15623547 [PMID] 9. Ault KA, Giuliano AR, Edwards RP, Tamms G, Kim LL, Smith JF, Jansen KU, Allende M, Taddeo FJ, Skulsky D, Barr E. A phase I study to evaluate a human papillomavirus (HPV) type 18 Ll VLP vaccine. Vaccine. 2004;22(23-24):3004-7. PubMed 15297048 [PMID] 10. Fife KR, Wheeler CM, Koutsky LA, Barr E, Brown DR, Schiff MA, Kiviat NB, Jansen KU, Barber H, Smith JF, Tadesse A, Giacoletti K, Smith PR, Suhr G, Johnson DA. Dose-ranging studies of the safety and immuno- genicity of human papillomavirus Type 11 and Type 16 virus-like particle candidate vaccines in young healthy women. Vaccine. 2004;22(2l-22):2943- 52. PubMed 15246631 11. Pinto LA, Edwards J, Castle PE, Hano CD, Lowy DR, Schiller JT, Wallace D, Kopp W, Adelsberger JW, Baseler MW, Berzofsky JA, Hildesheim A. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like par- ticles. J Infect Dis. 2003;188(2):327-38. PubMed 12854090 [PMID] 12. de Jong A, O’Neill T, Khan AY, Kwappenberg KM, Chisholm SE, Whittle NR, Dobson JA, Jack LC, St Clair Roberts JA, Offringa R, van der Burg SH, Hickling JK. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vac-

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 APPENDIX E cination with TA-CIIN, an HPV16 L2E7E6 fusion protein vaccine. Vaccine. 2002;20(29-30):3456-64. PubMed 12297390 [PMID] 13. Emeny RT, Wheeler CM, Jansen KU, Hunt WC, Fu TM, Smith JF, MacMullen S, Esser MT, Paliard X. Priming of human papillomavirus type l1-specific humoral and cellular immune responses in college-aged women with a virus-like particle vaccine. J Virol. 2002;76(15):7832-42. PubMed 12097595 [PMID] Full text 14. Evans TG, Bonnez W, Rose RC, Koenig S, Demeter L, Suzich JA, O’Brien D, Campbell M, White WI, Baisley J, Reichman RC. A Phase 1 study of a recombinant virus like particle vaccine against human papillo- mavirus type 11 in healthy adult volunteers. J Infect Dis. 2001; 183(10): 1485-93. PubMed 11319684 [PMID] 15. Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, Reynolds MJ, Mast TC, Robinson R, Murphy BR, Karron RA, Dillner J, Schiller JT, Lowy DR. Safety and immunogenicity trial in adult volunteers of a hu- man papillomavirus 16 Ll virus-like particle vaccine. J Natl Cancer Inst. 2001;93(4):284-92. PubMed 11181775 [PMID] Full text 16. Giles M, Garland S. Human papillomavirus infection: An old disease, a new vaccine. Aust N Z J Obstet Gynaecol. 2006;46(3):180-5. PubMed 16704468 [PMID] 17. Stanley MA. Human papillomavirus vaccines. Rev Med Virol. 2006; 16(3):139-49. PubMed 16710836 [PMID] 18. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest. 2006; 116(5): 1167-73. PubMed 16670757 [PMID] Full text 19. Crosbie EJ, Kitchener HC. Human papillomavirus in cervical screening and vaccination. Clin Sci (Lond). 2006; 11 0(5):543-52. PubMed 16597323 [PMID] 20. Monsonego J. [Cervical cancer prevention: the impact of HPV vacci- nation]. Gynecol Obstet Fertil. 2006;34(3): 189-201. PubMed 16529969 [PMIDJ 21. Feeley C. Advances in cervical cancer screening and human papilloma- virus vaccines. J Br Menpause Soc. 2006;12(l):19-23. PubMed 16513018 [PMID] 22. Kahn JA. Vaccination as a prevention strategy for human papilloma- vims-related diseases. J Adolesc Health. 2005;37 (6 Suppl):S10-6. PubMed 16310136 [PMID] 23. Foerster V, Murtagh J. Vaccines for prevention of human papillo-

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 KNOWING WHAT WORKS IN HEALTH CARE mavirus infection. Issues Emerg Health Technol. 2005;75:1-4. Pubmed 16544439 [PMID] 24. Campbell K. Preventing cervical cancer by vaccinating against HPV. Nurs Times. 2005;10l(46):21-2. PubMed 16315796 [PMID] 25. Govan VA. Strategies for human papillomavims therapeutic vaccines and other therapies based on the e6 and e7 oncogenes. Ann NY Acad Sci. 2005;1056:328-43. PubMed 16387699 [PMID] 26. Kahn JA, Bernstein DI. Human papillomavirus vaccines and adoles- cents. Curr Opin Obstet Gynecol. 2005; 1 7(5):476-82. PubMed 16141761 [PMID] 27. Villa LL. Prophylactic HPV vaccines: Reducing the burden of HPV- related diseases. Vaccine. 2005. PubMed 16194583 [PMID] 28. Simon P, Monnier S, Buxant F, Noel JC. [Anti-HPV vaccination against cervical cancer]. Rev Med Brux. 2005;26(5):433-8. PubMed 16318096 [PMID] 29. Scheurer ME, Tortolero-Luna G, Adler-Storthz K. Human papillomavi- rus infection: biology, epidemiology, and prevention. Int J Gynecol Cancer. 2005;15(5):727-46. PubMed 16174218 [PMID] 30. Sundar SS, Gornall RJ, Kehoe ST. Advances in the management of cervical cancer. J Br Menopause Soc. 2005;11(3):91-5. PubMed 16156999 [PMID] 31. Kadish AS, Einstein MH. Vaccine strategies for human papillomavirus- associated cancers. Cur Opin Oncol. 2005;17 (5):456-61. PubMed 16093795 [PMID] 32. Elbasha EH, Galvani AP. Vaccination against multiple HPV types. Math Biosci. 2005;197(1):88-117. PubMed 16095627 [PMID] 33. Denny L. The prevention of cervical cancer in developing countries. BJOG. 2005; 112(9): 1204-12. PubMed 16101597 [PMID] 34. Williamson AL, Passmore JA, Rybicki EP. Strategies for the prevention of cervical cancer by human papillomavirus vaccination. Best Pract Res Clin Obstet Gynaecol. 2005;19(4):531-44. PubMed 16150392 [PMID] 35. Mahdavi A, Monk BJ. Vaccines against human papillomavirus and cervical cancer: promises and challenges. Oncologist. 2005;10(7):528-38. PubMed 16079320 [PMID] Full text 36. Shew ML, Fortenberry JD. HPV infection in adolescents: natural his- tory, complications, and indicators for viral typing. Semin Pediatr Infect Dis. 2005;16(3):168-74. PubMed 16044390 [PMID]

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 APPENDIX E 37. Hantz S, Alain S, Denis F. [Anti-papillomavirus vaccines and prevention of cervical cancer: progress and prospects]. Presse Med. 2005;34(10):745- 53. PubMed 16026130 [PMID] 38. Leung AK, Kellner JD, Davies HD. Genital infection with human papil- lomavirus in adolescents. Adv Ther. 2005;22(3):187-97. PubMed 16236680 [PMID] 39. Bourgault-Villada I. [Vaccination against human papillomaviruses]. Therapie. 2005;60(3):27 1-4. PubMed 16128270 [PMID] 40. Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine. 2005;23(17- 18):2388-94. PubMed 15755633 [PMID] 41. Stem PL. Immune control of human papillomavims (HPV) associ- ated anogenital disease and potential for vaccination. J Clin Virol. 2005; 32(Suppl l):S72-81. PubMed 15753015 [PMID] 42. Gravitt PE, Shah KV. A Virus-based Vaccine May Prevent Cervical Can- cer. Curr Infect Dis Rep. 2005;7(2):l25-l3l. PubMed 15727740 [PMID] 43. Simon P. Progress towards a vaccine for cervical cancer. Curr Opin Obstet Gynecol. 2005;17(1):65-70 PubMed 15711414 [PMID] 44. Maclean J, Rybicki EP, Williamson AL. Vaccination strategies for the prevention of cervical cancer. Expert Rev Anticancer Ther. 2005;5(1):97- 107. PubMed 15757442 [PMID] 45. Christensen ND. Emerging human papillomavirns vaccines. Expert Opin Emerg Drugs. 2005;10(1):5-19. PubMed 15757400 [PMID] 46. Valdespino-Gomez VM. [Preventive vaccines and immunotherapy clini- cal trials against cervical cancer]. Cir Cir. 2005;73(1): 57-69. PubMed 15888272 [PMID] 47. Santin AD, Bellone S, Roman JJ, Burnett A, Cannon MJ, Pecorelli S. Therapeutic vaccines for cervical cancer: dendritic cell-based immunother- apy. CurrPharm Des. 2005;11(27):3485-500. PubMed 16248803 [PMID] 48. Brinkman JA, Caffrey AS, Muderspach LI, Roman LD, Kast WM. The impact of anti HPV vaccination cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management. Eur J Gynaecol Oncol. 2005;26(2):129-42. PubMed 15857016 [PMID] 49. Kang M, Lagakos SW. Evaluation of log-rank tests for infrequent observations from a multi-state process, with application to HPV vaccine efficacy. Stat Med. 2004;23(23):3681-96. PubMed 15534891 [PMID]

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 KNOWING WHAT WORKS IN HEALTH CARE 50. Joura EA. [Human papillomavirus and cervical cancer: presence and future of vaccination]. Gynalcol Geburtshilfliche Rundsch. 2004;44(3):142- 5. PubMed 15211060 [PMID] 51. Franceschi S. [Human papillomavirus: a vaccine against cervical car- cinoma uterine]. Epidemiol Prey. 2002;26(3): 140-4. PubMed 12197051 [PMID] 52. Gissmann L. [Possibilities of vaccination against HPV infections in cervix carcinoma]. Zentralbl Gynakol. 2001; 123(5):299-301. PubMed 11449623 [PMID] 53. Goldie SJ, Kohli M, Grima D, Weinstein MC, Wright TC, Bosch FX, Franco E. Projected clinical benefits and cost-effectiveness of a human pap- illomavirus 16/18 vaccine. J Natl Cancer Inst. 2004;96 (8):604-15. PubMed 15100338 [PMID] Full text 54. Kulasingam SL, Myers ER. Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA. 2003;290(6):781-9. PubMed 12915431 [PMID] 55. Sanders GD, Taira AV. Cost-effectiveness of a potential vaccine for hu- man papillomavirus. Emerg Infect Dis. 2003;90):37-48. PubMed 12533280 [PMID] Search Summary: The following databases were used to identify the literature and related ma- terials. Please note that underlined titles are hyperlinked to the actual docu- ments. For all search results, click on the title to access the document. 1. PubMed (National Library of Medicine) (www.pubmed.gov) (2001 through May 25, 2006) Search Strategy: S1 papillomavirus, human[mh] OR papillomavirus infections[mh] S2 immunization[mh] OR vaccines[mh] S3 “papilloma virus”[ti] OR “papilloma viruses”[ti] OR papillomavirus*[ti] OR hpv[ti] OR cervical[ti] OR cervix[ti] S4 vaccin*[ti] S5 (S1 AND S2) OR (S3 AND S4) Results: There were 106 records identified. These records are included in the Bibliography.

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 APPENDIX E 2. The Cochrane Library (Published by John Wiley & Sons, Ltd.) (http://www.mrw.interscience.wiley.com/cochrane/) (2006, Issue 2) (2001 through May 25, 2006) Search Strategy: S1 “papilloma virus’ OR “papilloma viruses” OR papillomavirus* OR hpv OR cervical OR cervix [in Record Title] S2 vaccin* [in Record Title] S3 S1 AND S2 Results: There were no unique bibliographic records; however the following full text document was identified. (This document is also included in the Selected References list). • Canadian Coordinating Office for Health Technology Assessment (now Canadian Agency for Drugs and Technologies in Health CADTH). Foerster V, Murtagh J. Vaccines for prevention of human papillomavirus infection. [Issues in Emerging Health Technologies Issue 7:00]. 3. International Health Technology Assessment (1HTA) database (ECRI) (http://www.ta.ecri.org/IHTA/) (2001 through May 25, 2006) Search Strategy: (HPV OR “papilloma*”) AND “vaccin*”; HPV AND (cervical OR cervix) Results: There were no relevant records identified. 4. National Guideline Clearinghouse (NGC) Web site (www.guideline.gov) (2001 through May 25, 2006) Search Strategy: (HPV AND “papilloma*”) AND vaccin*”; HPV The following databases were used to identify the literature and related ma- terials. Please note that underlined titles are hyperlinked to the actual docu- ments. For all search results, click on the title to access the document. Results: There were no documents mentioning HPV vaccines; however, there were numerous documents on other issues concerning HPV and cer- vical cancer. To access, search the NGC Web site using the search terms: HPV.

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0 KNOWING WHAT WORKS IN HEALTH CARE DePuy Spine (a Johnson & Johnson company): http://www.depuyspine. com/home.asp Symphony II Platelet Concentrate System info: http://www.depuyspine. com/products/biologicssolutions/ii.asp Symphony II Platelet Concentrate System product insert: http://www. depuyspine.com/ds_products_syndication/packageinserts/0902_90_ 022.pdf Harvest Technologies LLC: http://www.harvesttech.com/index.htm SmartPReP Platelet Concentrate System: http://www.harvesttech.com/ lntlPRP_OLD.htm Medtronic Inc.: http://www.medtronic.com/ Magellan Autologous Platelet Separator: http://www.medtronic.com/ cardsurgery/bloodmgmt/magellan_ovrw.html Payer Coverage Policies: Three payer coverage policies were located that refer to the use of PRP in bone healing. All policies consider its use experimental and investigational or unproven for bone healing and other orthopedic indications. Aetna: http://www.aetna.com/cpb/medical/dataI400_ 499/0411.html CIGNA HealthCare: http://www.cigna.com/health/provider/ medical/procedural/coverage_positions/medical/mm_ 0068_ coveragepositioncriteria_woundhealing.pdf Regence Group: http://www.regence.com/trgmedpol/medicine/med77.html Online Articles: Percutaneous injection of autogenous growth factors in patient with nonunion of the humerus. A case report (Bielecki and Gazdzik, 2006), Journal of Orthopaedics: http:Ilwww.jortho.org1200613131e15/index.htm Treatment of recalcitrant enthesopathy of the hip with platelet rich plasma — a report of three cases (Scioli M, 2006), Clinical Orthopaedic Society News (NOTE: Article is on pages 6-7): http://www.bmetbiologics.corn/ international/print/Scioli_newsletter_submission.pdf Overview of bone grafting (2002), Medscape Today: http://www.medscape. com/viewarticle/4439021 A comprehensive search of the Internet did not return any information regard- ing evidence-based practice guidelines or ongoing clinical trials for PRP for bone healing and fusion. Search Results with Abstracts January 15, 2007 MEDLINE, EMBASE Search terms: platelet concentrate, platelet-rich plasma combined with spinal, fusion, bone AND fusion, bone healing, orthopedic surgery, platelet concentrate, platelet gel combined with orthopedic sur- gery, bone healing, spinal fusion Search limits: English-language human clinical trials and review articles pub- lished in the last 5 years

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 APPENDIX E Search yield: 14 citations Retrieved: 12 abstracts 1: Foot & Ankle International. 27(12):1079-85, 2006 Dec. Arthroscopic ankle arthrodesis: factors influencing union in 39 consecutive patients. Collman DR. Kaas MH. Schuberth JM. Department of Orthopaedic Surgery, Kaiser Permanente Medical Group, Modesto, CA, USA. BACKGROUND: Arthroscopic ankle arthrodesis is an effective alternative to open techniques with established advantages in select patient populations. The purpose of this study was to evaluate patients who had arthroscopic an- kle arthrodesis for end-stage arthritis with minimal to no deformity of the ankle and to report factors influencing union. METHODS: Thirty-nine consecutive patients had arthroscopic ankle arthrodesis between 1994 and 2003. Clinical records and radiographs were retrospectively reviewed to evaluate variable that could predispose patients to nonunion. Union outcomes were correlated with etiology of arthritis, ankle deformity, medical co-morbidities, and the use of demineralized bone matrix or platelet-rich plasma. Arthroscopic ankle arthrodesis was accomplished with a consistent technique using crossed transmalleolar cannulated screw fixation. RESULTS: Thirty-four of 39 patients (87.2%) achieved radiographic and clinical union. The average time to fusion was 47 (range 37 to 70) days. Poor bone quality and inherent positional ankle deformity were identified as risk factors for nonunion. Patients who smoked, had diabetes rnellitus, peripheral neuropathy, or other medical co-morbidi- ties attained ankle union in nearly all cases, In obese patients, there was an observed trend towards ankle nonunion (relative risk 5.81, p = 0.049, Fishers Exact test). The addition of demineralized bone matrix or platelet-rich plasma did not improve the rate of ankle union. Aside from nonunion, 10 patients de- veloped minor complications. CONCLUSION: Arthroscopic ankle arthrodesis achieves high union rates, facilitates short time to union, and permits rapid patient mobility. Careful patient selection is important for the procedure. Syn- thetic allograft or platelet-rich plasma did not enhance the fusion rate. Obese patients showed a trend towards nonunion in this series. UI: 17207436 2: Journal of Extra-Corporeal Technology. 38(2):174-87. 2005 Jun. Platelet-rich plasma and platelet gel: a review. Everts PA. Knape JT. Weibrich C. Schonberger JR. Hoffmann J. Overdevest EP. Box HA. van Zundert A. Department of Extra Corporeal Blood Management, Catharina Hospital, Eind- hoven, The Netherlands. everts@elive.nl Strategies to reduce blood loss and transfusion of allogeneic blood products

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 KNOWING WHAT WORKS IN HEALTH CARE during surgical procedures are important in modern times. The most important and well-known autologous techniques are preoperative autologous predona- tion, hemodilution, perioperative red cell salvage, postoperative wound blood autotransfusion, and pharmacologic modulation of the hemostatic process. At present, new developments in the preparation of preoperative autologous blood component therapy by whole blood platelet-rich plasma (PRP) and platelet-poor plasma (PPP) sequestration have evolved, This technique has been proven to reduce the number of allogeneic blood transfusions during open heart surgery and orthopedic operations. Moreover, platelet gel and fi- brin sealant derived from PRP and PPP mixed with thrombin, respectively, can be exogenously applied to tissues to promote wound healing, bone growth, and tissue sealing. However, to our disappointment, not many well-designed scientific studies are available, and many anecdotic stories exist, whereas questions remain to be answered. We therefore decided to study periopera- tive blood management in more detail with emphasis on the application and production of autologous platelet gel and the use of fibrin sealant. This review addresses a large variety of aspects relevant to platelets, platelet-rich plasma, and the application of platelet gel. In addition, an overview of recent animal and human studies is presented. Publication Types: Review UI: 16921694 3: Advances in Therapy. 23(2):218-37, 2006 Mar-Apr. Autologous platelet-rich plasma for wound and osseous healing: a review of the literature and commercially available products. Roukis TS. Zgonis T. Tiernan B. Limb Preservation Service, Department of Vascular Surgery MCHJ-SV, Ma- digan Army Medical Center, Tacoma, Washington 98431, USA. The application of autologous platelets that have been sequestered, con- centrated, and mixed with thrombin to create growth factor-concentrated, autologous platelet-rich plasma for application to soft tissue wounds and for osseous healing has been a subject of great interest for much of the past 2 decades. Autologous platelet-rich plasma, which consists of both quantitative and qualitative components, has the greatest potency or ability to produce the desired effect. Manufacturers prepare autologous platelet-rich plasma with the ultimate goal of maximizing its benefits while minimizing potential risks, Unfortunately, the manufacturing processes for autologous platelet-rich plasma are highly variable, and the types of proprietary systems available on the market for soft tissue and osseous applications are numerous. The authors provide here an in-depth review of commercially available systems for delivery of autologous platelet-rich plasma that emphasizes the subtle yet important differences among systems. In addition, a detailed review of the literature regarding the use of autologous platelet-rich plasma in soft tissue

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 APPENDIX E and osseous healing is provided. Although findings are not yet conclusive, autologous platelet-rich plasma has been shown to be safe, reproducible, and effective in mimicking the natural processes of soft tissue wound and osseous healing. Publication Types: Research Support, Non-U.S. Gov’t Review UI: 16751155 4: Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 76(2):364-72, 2006 Feb. Evaluation of bone healing enhancement by lyophilized bone grafts supple- mented with platelet gel: a standardized methodology in patients with tibial osteotomy for genu varus. Savarino L. Cenni F. Tarabusi C. Dallari D. Stagni C. Cenacchi A. Fornasari PM. Giunti A. Baldini N. Laboratory for Pathophysiology of Orthopaedic Implants, Istituti Ortopedioi Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy. lucia.savarino@ior.it Orthopedic practice may be adversely affected by an inadequate bone re- pair that might compromise the success of surgery. In recent years, new approaches have been sought to improve bone healing by accelerating the rate of new bone formation and the maturation of the matrix. There is cur- rently great interest in procedures involving the use of platelet gel (PG) to improve tissue healing, with satisfactory results both in vitro and in maxillo- facial surgery. Otherwise, to our knowledge, only a preliminary clinical study was undertaken in the orthopedic field [Kitoh et al., Bone 2004;35:892-898] and the efficacy of PG is still controversial. Our paper focuses on the effect on bone regeneration by adding PG to lyophilized bone chips used for ortho- pedic applications. The clinical model and the laboratory methodology were standardized. As a clinical model, we employed the first series of patients of a randomized case-control study undergoing high tibial osteotomy (HTO) for genu varus. Ten subjects were enrolled: in 5 patients lyophilized bone chips supplemented with PG were inserted during tibial osteotomy (group A); 5 patients were used as a control (group B) and lyophilized bone chips without gel were applied. Forty-five days after surgery, computed tomography scan guided biopsies of grafted areas were obtained and the bone maturation was evaluated by a standardized methodology: the Osteogenic and angiogenio processes were semi-quantitatively characterized by using histomorphometry, and the mineral component of the lyophilized and host bone was analyzed by using X-ray diffraction technique with sample microfocusing and miororadiog- raphy. Lyophilized bone with PG seems to accelerate the healing process, as shown by new vessel formation and deposition of newly formed bone, with no evidence of inflammatory cell infiltrate, when compared with lyophilized bone without gel. On the contrary, lyophilized bone undergo a resorption

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 KNOWING WHAT WORKS IN HEALTH CARE process, and a fibrous tissue often fills the spaces between chips. A histio- cytic/giant-cell reaction is sometimes present. Otherwise, no differences have been found concerning microstructure. Our findings show the reliability of the methodology used to monitor early bone repair. The completion of the study and the evaluation of the ultimate clinical outcome are necessary in order to verify PG in vivo effects in orthopedic surgery. Publication Types: Randomized Controlled Trial UI: 16161123 5: Journal of Surgical Orthopaedic Advances, 14(1):l7-22, 2005. Union rates using autologous platelet concentrate alone and with bone graft in high-risk foot and ankle surgery patients. Bibbo C. Bono CM. Lin SS. Department of Orthopaedic Surgery, Marshiceld Clinic, 1000 North Oak Av- enue, Marshfield, WI 54449, USA. bibbo.christopher@marshfieldclinic.org Adjuvant use of autologous platelet concentrate (APC) to assist bone healing in foot and ankle surgery has not been reported. This study examined the clinical results and complications after the adjuvant use of APC in high-risk patients undergoing elective foot and ankle surgery. Patients at risk for bone- healing complications were prospectively enrolled over a 6-month period for the intraoperative application of APC. Patients were followed every 2 weeks for radiographic union and complications. Sixty-two high-risk patients were enrolled, totaling 123 procedures. Mean patient age was 51 years (range, 16-76), there were 36 females and 26 males, and 24 patients were smokers. Overall, a 94% union rate was achieved at a mean of 41 days. For APC alone, the mean time to union was 40 days; when APC was used with autograft, the mean time to union was 45 days (p = .173, two-tailed t-test). These data sug- gest that adjuvant APC results in an acceptable time to union and may be a useful adjunct to promote osseous healing in high-risk patients undergoing elective foot and ankle surgery. UI: 15766437 6: Foot Ankle Int. 2005 Oct;26(l0):640-6. The use of autologous concentrated growth factors to promote syndesmosis fusion in the Agility total ankle replacement. A preliminary study. Coetzee JC, Pomeroy GC, Watts JD, Barrow C. Department of Orthopaedic Surgery, University of Minnesota R200, 2450 Riverside Avenue South, Minneapolis, MN 55454, USA. Coetz001@tc.umn. edu BACKGROUND: The Agility (DePuy, Warsaw, Indiana) total ankle replace- ment has been in use since 1984. One of the most common complications

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 APPENDIX E continues to be delayed union or nonunions of the distal tibiofibular syndes- mosis. In the 1999, 114 Agility total ankle replacements were done at two centers in the United States without the use of autologous reported studies on the Agility ankle the delayed union and nonunion rate can be as high as 38%. METHODS: Since concentrated growth factors. Since July of 2001, 66 Agility ankles were implanted with Symphony (DePuy, Warsaw, Indiana) augmented bone grafting. The standard operative technique was followed in all the patients. Prospective data was collected on all patients. The standard ankle radiographs were taken preoperatively and postoperative at 8 weeks, 12 weeks, 16 weeks, 6 months, and yearly. CT scans were obtained at 6 months if fusion at the syndesmosis was questionable, The Graphpad Instat software (Graphpad Software Inc., San Diego, CA) was used for statistical analysis. The two-tailed unpaired t-test was used, and the value <0.05 was considered significant. RESULTS: There was no statistical difference in the demographic data for the two groups. In 114 ankle replacements without autologous concentrated growth factors 70 fused at 8 weeks (61%), 14 fused at 12 weeks (12%), 13 fused at 6 months (12%). There were 17 nonunions (15%); delayed unions (3 to 6 months) and nonunions, therefore, equaled 27%. The syndesmosis fused in 50 of the 66 ankle replacements (76%) that had autologous concentrated growth fractures at 8 weeks (76%); 12 fused at 3 months (18%). 2 fused at 6 months (3%), 2 had nonunions (3%). Delayed unions (3 to 6 months) and nonunions equaled 6%. There was a statistically significant improvement in the 8- and 12-week fusion rates, and a statisti- cally significant reduction in delayed unions and nonunions. CONCLUSION: Autologous concentrated growth factors appear to make a significant positive difference in the syndesmosis union rate in total ankle replacements. Publication Types: Comparative Study PMID: 16221457 [PubMed - indexed for MEDLINE] 7: Foot & Ankle International. 26(6):458-61, 2005 Jun. Enhancement of syndesmotic fusion rates in total ankle arthroplasty with the use of autologous platelet concentrate, Barrow CR. Pomeroy GC. Orthopaedic Specialty of Spokane, 785 East Holland Avenue, Spokane, WA 99218, USA. cbarrow@orthospecialtyclinic.com BACKGROUND: One of the challenges of total ankle arthroplasty continues to be achieving a solid distal fusion of the tibiotibular joint. Delayed union rates of 29% to 38% and the nonunion rates of 9% to 18% for syndesmotic fusion have been documented. The risk of tibial component migration has been re- ported to increase 8.5 times if a solid syndesmotic fusion is absent. Growth factors have been shown to accelerate bone healing and may enhance the

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6 KNOWING WHAT WORKS IN HEALTH CARE fusion of the syndesmosis and, thereby, decrease the frequency of nonunion and subsequent tibial component migration. METHODS: An autologous plate- let concentrate was used to increase the amount of growth factors at the site of the distal tibiofibular joint fusion in 20 total ankle arthroplasties. RESULTS: Our 6-month fusion rate was 100%. When compared to historical controls (6-month fusion rate of 62%) the difference was statistically significant (p CONCLUSION: The improved rate of distal tibiofibular fusion may be attribut- able to the increased presence of growth factors provided by an autologous platelet concentrate. UI: 15960912 8: Spine. 30(9):E243-6; discussion E247. 2005 May 1. Platelet gel (AGF) fails to increase fusion rates in instrumented posterolateral fusions. Carreon LY. Glassman SD. Anekstein Y. Puno RM. Leatherman Spine Center, Louisville, Kentucky 40202, USA. lcarreon@spinemds.com STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the effect on fusion of adding platelet gel to autologous iliac crest graft. SUM- MARY OF BACKGROUND DATA: Platelet gel is an osteoinductive material prepared by ultra-concentration of platelets and contains multiple growth fac- tors. Proprietary commercial methods are available for harvesting autologous platelet gel concentrates for use as graft supplement in spine fusions. METH- ODS: We reviewed 76 consecutive patients who underwent instrumented posterolateral lumbar fusion with autologous iliac crest bone graft mixed with autologous growth factor (AGF). A control group was randomly selected from patients who underwent instrumented posterolateral lumbar fusion with autologous bone graft alone. The groups were matched for age, sex, smok- ing history, and number of levels fused, Demographic, surgical, and clinical data were collected from medical records. Diagnosis of nonunion was based on exploration during revision surgery or evidence of nonunion on computer- ized tomography. The Fisher exact test was used to compare fusion rates. RESULTS: In both groups, mean age was 50 years, and 24% were smokers. The nonunion rate was 25% in the AGF group and 17% in the control group. This difference was not statistically significant (P= 0.18). CONCLUSIONS: Platelet gel preparation requires blood draws from the patient. This procedure adds to the risk and cost of surgery. The technique for AGF harvest evalu- ated in this study provides the highest concentration of platelets among the commercially available methods. Despite this, we showed that platelet gel failed to enhance fusion rate when added to autograft in patients undergoing instrumented posterolateral spinal fusion. The authors do not recommend the use of platelet gel to supplement autologous bone graft during instrumented posterolateral spinal fusion.

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7 APPENDIX E Publication Types: Research Support. Non-U.S. Gov’t UI: 15864142 9: Clinics in Podiatric Medicine & Surgery. 22(4):561-84, vi, 2005 Oct. The utilization of autologous growth factors for the facilitation of fusion in complex neuropathic fractures in the diabetic population. Grant WP. Jerlin EA. Pietrzak WS. Tam HS. Tidewater Foot and Ankle Center, 762 Independence Blvd., Suite 771, Vir- ginia Beach, VA 23455, USA. charcotking@yahoo.com A review of current knowledge of autologous growth factors as used in foot and ankle surgery is presented. This knowledge is clinically correlated with 50 Charcot’s foot reconstruction patients who had diabetes and who were randomized to a platelet-rich plasma (PRP) concentration system (Sym- phony, DePuy, Warsaw, Indiana) or a hollow-fiber hemoconcentration system (Interpore Cross AGF, Interpore Cross, Irvine, California) trial. Although the literature supports the notion that Symphony produces a higher yield of intact platelets mole consistently, clinically, a statistically significantly higher num- ber of patients treated with Interpore Cross AGF went onto solid fusion. The findings may indicate that one type of PRP may be indicated for a particular clinical circumstance based on the patient’s medical history and resultant lo- cal wound environment. Publication Types: Case Reports Comparative Study Review UI: 16213380 10: Bone. 35(4):892-8, 2004 Oct. Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis—a preliminary result of three cases. Kitoh H. Kitakoji T. Tsuchiya H. Mitsuyama H. Nakamura H. Katoh M. Ishiguro N. Department of Orthopaedic Surgery, Nagoya University School of Medicine, Showa-ku, Nagoya, Aichi 466-8550, Japan. hkitoh@med.nagoya-u.ac.jp Clinical results of distraction osteogenesis with transplantation of marrow- derived mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) were reviewed in three femora and two tibiae of the two patients with achon- droplasia and one patient with congenital pseudarthrosis of the tibia. MSCs derived from the iliac crest were cultured with osteogenic supplements and differentiated into osteoblast-like cells. PRP, which is known to contain several

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 KNOWING WHAT WORKS IN HEALTH CARE growth factors and coagulate immediately by a minute introduction of throm- bin and calcium, was prepared just before transplantation. Culture-expanded osteoblast-like coils and autologous PRP were injected into the distracted callus with the thrombin-calcium mixture so that the PRP gel might develop within the injected site. Transplantation of MSCs and PRP was done at the lengthening and consolidation period in each patient. The target lengths were obtained in every leg without major complications and the average healing index was 23.0 days/cm (18.8-26.9 days/cm). Although these results are still preliminary, transplantation of osteoblast-like cells and PRP, which seemed to be a safe and minimally invasive cell therapy, could shorten the treatment period by acceleration of bone regeneration during distraction osteogenesis. Publication Types: Case Reports Research Support, Non-U.S. Gov’t UI: 15454096 11: Journal of Spinal Disorders & Techniques. 1 7(5):380-4, 2004 Oct. Role of activated growth factors in lumbar spinal fusions. Castro EP Jr. Tulane Health Sciences, New Orleans, Louisiana. fcastro@seortho.com BACKGROUND: The concentration of platelets into an activated growth factor (AGF) gel may stimulate graft consolidation into a fusion mass. Preoperative hemodilution and intraoperative clot activation may also reduce the overall blood loss. Consequently, the need for postoperative transfusions may also be reduced. OBJECTIVE: The objective of this work was to report our experi- ence with AGF platelet gels in transforaminal lumbar interbody fusion (TLIF) procedures. METHODS: A consecutive series of patients between 1996 and 1999 undergoing one- and two-level TLIFs with AGF were compared with a consecutive series of TLIF patients who did not receive AGF. Sixty-two con- trol subjects who did not receive AGF and 22 patients who received an AGF platelet gel were compared after 41 and 34 months of follow-up, respectively. RESULTS: On average, the AGF group required 18 minutes of additional preincision anesthesia (P = 0.0001). No statistical differences in the operative times, estimated blood loss, postoperative drainage, percentage of patients requiring a transfusion, or length of hospitalization were appreciated between the two groups. The 19% decrease in the arthrodesis rate of the AGF group, as compared with the control group, did not reach statistical significance. Platelet counts from the AGF platelet concentrates demonstrated an average 3.5-fold increase compared with preoperative serum levels. CONCLUSIONS: The theoretical benefits of AGF platelet gel technology were not clinically ap- preciated. The cost of implementing this technology may therefore outweigh its theoretical benefits.

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9 APPENDIX E Publication Types: Clinical Trial Comparative Study Controlled Clinical Trial UI: 15385877 12: Journal of Extra-Corporeal Technology. 36(l):28-35, 2004 Mar Comparison of methods for point of care preparation of autologous platelet gel. Kevy SV. Jacobson MS. Harvard Medical School, Director Emeritus, Transfusion Service, Children’s Hospital and CBR Laboratories, Boston, Massachusetts 02115, USA. A platelet gel (PG) is produced by the addition of calcium chloride and throm- bin to a platelet concentrate (PC). PG releases multiple growth factors, which have the ability to initiate and stimulate one growth factor’s function in the presence of others. This finding has resulted in the use of PG in orthopedic, plastic, and reconstructive surgery. The study compared the commercial systems available for the preparation of PG. All procedures were performed according to the manufacturers directions. The devices were evaluated with respect to ease of use, collection efficiency, platelet quality, and growth factor release. The SmartPReP requires only four processing steps compared to 12 to 24 required by other devices. The SmartPReP and the CATS were the most reproducible, as evidenced by their low coefficient of variation of 13% and 16%. The mean platelet yield was 72% for the SmartPReP, 58% for the 3iPCCS, 54% for the Sequestra, 31% for the Secquire, 31% for the CATS, 27% for the lnterpore Cross, and 42.6% for the Biomet OPS. The mean total amount of PDGF-AB and TGF-B1 obtained from the SmartPReP is greater than other systems evaluated. The SmartPReP produced a consistent PC with a yield that was four times baseline range with the lowest coefficient of variation. Publication Types: Comparative Study Research Support, Non-U.S. Gov’t UI: 15095838

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