TFOS DEWS II - Design klinischer Studien
Gary D. Novack, PhD1,'Correspondence information about the author PhD Gary D. NovackEmail the author PhD Gary D. Novack, Penny Asbell, MD, Stefano Barabino, MD, PhD, Michael V.W. Bergamini, PhD, Joseph B. Ciolino, MD, Gary N. Foulks, MD, Michael Goldstein, MD, Michael A. Lemp, MD, Stefan Schrader, MD, PhD, Craig Woods, PhD, MCOptom, Fiona Stapleton, PhD, MCOptom
German translation sponsored by Allergan
Um die Qualität von klinischen Studien zu verbessern, um die Ressourcen zu optimieren und um die Chance zu erhöhen, dass neue Therapeutika Patienten mit Trockenem Auge erreichen, hat der TFOS DEWS II-Unterausschuss für klinische Studien die folgenden Empfehlungen abgegeben.
Zuerst sollen Studien nach den Grundsätzen der Good Clinical Practice (GCP) durchgeführt werden. Dies kann eine entmutigende Aufgabe sein. Klinische Studienleiter sollten jedoch Kollegen und Experten aus der Medikamentenentwicklung konsultieren, die mit diesem Kontrollsystem vertraut sind. Dazu gehören geeignete Schutzmaßnahmen für die Studienteilnehmer. Die GCP erfordert außerdem die Einhaltung der entsprechenden regulatorischen Anforderungen der Gesetzgebung im Hinblick auf die Durchführung von Studien und kann zusätzliche regulatorische Einreichungen erfordern, wenn Studienmaterial in einem anderen Staat oder Land erstellt und von dort aus versendet wird.
Es ist nützlich, das Consolidated Standards of Reporting Trials (ConSORT)-Statement vor der Planung und dem Beginn einer Studie durchzugehen. Als nächstes hat der Unterausschuss empfohlen, dass Design, Behandlungen und Stichprobengröße mit der Prüfbehandlung, den Zielen der Studie und der Entwicklungsphase konsistent sind. So kann z. B. ein Crossover-Design oder ein Paarvergleich für eine Komfort-Studie mit normalen Freiwilligen geeignet sein, nicht aber für eine lang andauernde Behandlung mit Potenzial für systemische oder kontralaterale Wirkungen. Außerdem sollte die Dosis eines Medikaments oder Biologikums nicht nur geringer sein als die Dosis, die in nichtklinischen oder vorherigen klinischen Studien toxisch oder nicht verträglich war, sondern sie muss auch hinsichtlich der Dosis und Dosierungsfrequenz ausreichen, um therapeutische Konzentrationen an den vorgesehenen Wirkungsstellen abzugeben. Die Dauer der Behandlung muss zumindest für eine pivotale Studie auch mit dem Wirkmechanismus und dem zeitlichen Verlauf der Wirkung konsistent sein. Für pivotale Studien ist die Stichprobengröße der Schlüssel zur potentiellen Validität der Studie.
Ergebnismessungen sind wichtig, um die Wirksamkeit der Behandlung festzustellen, und sollten wenn möglich minimalinvasive objektive Metriken umfassen, die sich am erwarteten Wirkmechanismus der Behandlung orientieren. Die Erforschung neuer Möglichkeiten zur Evaluierung des Trockenen Auges, wie z. B. von Biomarkern, kann zu einer Verbesserung des Designs klinischer Studien zum Trockenen Auge führen und im Hinblick auf die Wirksamkeit neuer Behandlungen größere Klarheit schaffen.
[1] Design and conduct of clinical trials: Report of the Clinical Trials Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:153–162.
[2] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II Definition and Classification report. Ocul Surf 2017;15:276–283.
[3] Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38(6):727–735.
[4] Felson David T, Anderson Jennifer J, Boers Maarten, Bombardier Claire, Chernoff Miriam, Fried Bruce, et al. The American college of rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993;36(6):729–740.
[5] Sullivan BD, Crews LA, Sönmez B, de la Paz MF, Comert E, Charoenrook V, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea 2012;31(9):1000–1008.
[6] Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51(12):6125–6130.
[7] Sullivan DA, Hammitt KM, Schaumberg DA, Sullivan BD, Begley CG, Gjorstrup P, et al. Report of the TFOS/ARVO Symposium on global treatments for dry eye disease: an unmet need. Ocul Surf 2012;10(2):108–116.
[8] Pocock Stuart J, Gersh Bernard J. Do current clinical trials meet Society's needs? J Am Coll Cardiol 2014;64(15):1615–1628.
[9] van Herwaarden N, van der Maas A, Minten MJ, van den Hoogen FH, Kievit W, van Vollenhoven RF, et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 2015;350:h1389.
[10] Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015;72(7):714–726.
[11] Bajard A, Chaubaud S, Cornu C, Castellan AC, Malik S, Kurbatova P, et al. An in silico approach helped to identify the best experimental design, population, and outcome for future randomized clinical trials. J Clin Epidemiol 2016;69:125–136.
[12] Hertel J, Locatelli F, Spasovski G, Dimkovic N, Wanner C. Randomized, double-blind, placebo-controlled, withdrawal study of colestilan after dose titration in chronic kidney disease dialysis patients with hyperphosphatemia. Nephron 2015;130(4):229–238.
[13] Anonymous. International conference on harmonisation; good clinical practice: consolidated guideline; notice of availability. Fed Reg 1997;62:25694.
[14] Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, Dana R, Deng SX, et al. TFOS DEWS II Management and Therapy report. Ocul Surf 2017;15:575–628.
[15] Anonymous. Guidance for industry CGMP for phase 1 investigational drugs. 2008.
[16] Anonymous. Guidance for industry - INDs for phase 2 and phase 3 studies - chemistry, manufacturing, and controls information. 2003.
[17] ICoMJ. In: Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. 2015.
[18] Chalmers I. Proposal to outlaw the term “negative trial. BMJ 1985;290:1002.
[19] Brice A, Chalmers I. Medical journal editors and publication bias. BMJ 2013;347:f6170.
[20] DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical Trial Registration: A Statement from the International Committee of Medical Journal. JAMA 2004;292:1363–1364.
[21] Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database–update and key issues. N Engl J Med 2011;364:852–860.
[22] Zarin DA, Tse T, Ross JS. Trial-results reporting and academic medical centers. N Engl J Med 2015;372(24):2371–2372.
[23] Anonymous. Clinical trials registration and results information submission. Fed Reg 2016;81:64982–65157.
[24] Contreras JL. NIH's genomic data sharing policy: timing and tradeoffs. Trends Genet 2015;31(2):55–57.
[25] Strom BL, Buyse M, Hughes J, Knoppers BM. Data sharing, year 1-access to data from industry-sponsored clinical trials. N Engl J Med 2014;371(22):2052–2054.
[26] Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
[27] Doshi P. No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility. BMJ 2015;351:h4629.
[28] Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320.
[29] Hudson KL, Collins FS. Sharing and reporting the results of clinical trials. JAMA 2015;313:355–356.
[30] Taichman DB, Backus J, Baethge C, Bauchner H, de Leeuw PW, Drazen JM, et al. Sharing clinical trial data: a proposal from the international committee of medical journal editors. PLoS Med 2016;13:e1001950.
[31] Drazen JM. Data sharing and the journal. N Engl J Med 2016;374:e24.
[32] McNutt M. Data sharing. Science 2016;351:1007.
[33] Wald N. Sharing clinical trial data. J Med Screen 2017;24(2):57.
[34] Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276:637–639.
[35] Novack GD. The CONSORT statement for publication of controlled clinical trials. Ocul Surf 2004;2(1):45–46.
[36] Ellenberg SS, Fleming TR, DeMets DL. Data monitoring committees in clinical trials: a practical perspective. Chichester, West Sussex, England: John Wiley & Sons, Ltd; 2002.
[37] Novack GD. Data monitoring Committees. Ocul Surf 2010;8(1):40–43.
[38] Novack GD. Why aren't there more pharmacotherapies for dry eye? Ocul Surf 2014;12(3):227–230.
[39] Chao W, Belmonte C, Benitez Del Castillo JM, Bron AJ, Dua HS, Nichols KK, et al. Report of the inaugural meeting of the TFOS i(2) = initiating innovation series: targeting the unmet need for dry eye treatment. Ocul Surf 2016;14(2):264–316.
[40] Lemp MA, Bron AJ, Baudouin C, Benítez Del Castillo JM, Geffen D, Tauber J, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011;151(5):792–798. e1.
[41] Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea 1998;17(6):584–589.
[42] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II Epidemiology report. Ocul Surf 2017;15:334–365.
[43] Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II Pathophysiology report. Ocul Surf 2017;15:438–510.
[44] Fonn D, Toit R, Simpson TL, Vega JA, Situ P, Chalmers RL. Sympathetic swelling response of the control eye to soft lenses in the other eye. Invest Ophthalmol Vis Sci 1999;40:3116–3121.
[45] Mgarrech M, Rousseau A, Sauer A, Kaswin G, Barreau E, Bourcier T, et al. Lacrymal secretion in the non-affected fellow eye of patients with recurrent unilateral herpetic keratitis. Acta Ophthalmol 2012;90.
[46] Simard-Lebrun A, Boisjoly H, Al-Saadi A, Choremis J, Mabon M, Chagnon M. Association between unilateral quiescent stromal herpetic keratitis and bilateral dry eyes. Cornea 2010;29(11):1291–1295.
[47] Jabbarvand M, Hashemian H, Khodaparast M, Rafatnejad A, Beheshtnejad A, Salami A. Do unilateral herpetic stromal keratitis and neurotrophic ulcers cause bilateral dry eye? Cornea 2015;34:768–772.
[48] Cruzat A, Schrems WA, Schrems-Hoesl LM, Cavalcanti BM, Baniasadi N, Witkin D, et al. Contralateral clinically unaffected eyes of patients with unilateral infectious keratitis demonstrate a sympathetic immune response. Invest Ophthalmol Vis Sci 2015;56(11):6612–6620.
[49] Urzua CA, Vasquez DH, Huidobro A, Hernandez H, Alfaro J. Randomized double-blind clinical trial of autologous serum versus artificial tears in dry eye syndrome. Curr Eye Res 2012;37(8):684–688.
[50] Lemp MA, Sullivan BD. Bilaterality in dry eye disease: implications for clinical trials. In: S DA, editor. 8th international conference on the tear film & ocular surface: basic science and clinical relevance. Montpelier, France; 2016. Abstract #45.
[51] Sullivan BD, Crews LA, Messmer EM, Foulks GN, Nichols KK, Baenninger P, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol 2014;92(2):161–166.
[52] Bron AJ, Tomlinson A, Foulks GN, Pepose JS, Baudouin C, Geerling G, et al. Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf 2014;12(2 Suppl):S1–S31.
[53] Sullivan BD, Pepose JS, Foulks GN. Progressively increased variation in tear osmolarity mirrors dry eye severity. JAMA Ophthalmol 2015;133(12):1481–1482.
[54] Pepose Jay S, Sullivan Benjamin D, Foulks Gary N, Lemp Michael A. The value of tear osmolarity as a metric in evaluating the response to dry eye therapy in the clinic and in clinical trials. Am J Ophthalmol 2014;157(1):4–6.
[55] Ederer F. Shall we count numbers of eyes or numbers of subjects? Arch Ophthalmol 1973;89(1):1–2.
[56] Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf 2017;15:539–574.
[57] Gold H, Kwit NT. The xanthines (theobromine and aminophylline) in the treatment of cardiac pain. JAMA 1937;108:2173–2179.
[58] Reidenberg MM. Clinical pharmacology: the scientific basis of therapeutics. Clin Pharmacol Ther 1999;66(1):2–8.
[59] Foulks GN. Challenges and pitfalls in clinical trials of treatments for dry eye. Ocul Surf 2003;1(1):20–30.
[60] Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000;107(4):631–639.
[61] Kinoshita S, Oshiden K, Awamura S, Suzuki H, Nakamichi N, Yokoi N, et al. A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye. Ophthalmology 2013;120(6):1158–1165.
[62] Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, et al. Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology 2015;122(12):2423–2431.
[63] Tomlinson A, Hair M, McFadyen A. Statistical approaches to assessing single and multiple outcome measures in dry eye therapy and diagnosis. Ocul Surf 2013;11(4):267–284.
[64] Alves M, Fonseca EC, Alves MF, Malki LT, Arruda GV, Reinach PS, et al. Dry eye disease treatment: a systematic review of published trials and a critical appraisal of therapeutic strategies. Ocul Surf 2013;11(3):181–192.
[65] Novack GD, Crockett RS. Regression to the mean. Ocul Surf 2009;7(3):163–165.
[66] McDonald CJ, Mazzuca SA, McCabe Jr. GP. How much of the placebo 'effect' is really statistical regression? Stat Med 1983 Oct-Dec;2(4):417–427.
[67] Amparo F, Schaumberg DA, Dana R. Comparison of two questionnaires for dry eye symptom assessment: the ocular surface disease index and the symptom assessment in dry eye. Ophthalmology 2015;122(7):1498–1503.
[68] Barton S. Which clinical studies provide the best evidence? The best RCT still trumps the best observational study. Br Med J 2000;321(7256):255–256.
[69] Pinto-Fraga J, López-Miguel A, González-García MJ, Fernández I, López-de-la-Rosa A, Enríquez-de-Salamanca A, et al. Topical fluorometholone protects the ocular surface of dry eye patients from desiccating stress. Ophthalmology 2016;123(1):141–153.
[70] Kangari H, Eftekhari MH, Sardari S, Hashemi H, Salamzadeh J, Ghassemi-Broumand M, et al. Short-term consumption of oral omega-3 and dry eye syndrome. Ophthalmology 2013;120(11):2191–2196.
[71] Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev 2010;(1):CD003974.
[72] Foulks GN. The evolving treatment of dry eye. Ophthalmol Clin N Am 2003;16(1):29–35.
[73] Novack GD, David R, Lee PF, Freeman MI, Duzman E, Batoosingh AL. Effect of changing medication regimens in glaucoma patients. Ophthalmologica 1988;196(1):23–28.
[74] Maier NRF, Verser GC. Psychology in industrial organizations. 5 ed. Boston: Houghton Mifflin Co;; 1982.
[75] Nelson JD, Gordon JF. Topical fibronectin in the treatment of keratoconjunctivitis sicca. Am J Ophthalmol 1992;114(4):441–447.
[76] Matsumoto Y, Ohashi Y, Watanabe H, Tsubota K, ; Diquafosol Ophthalmic Solution Phase 2 Study Group.. Efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome: a Japanese phase 2 clinical trial. Ophthalmology 2012;119(10):1954–1960.
[77] Sosne G, Ousler GW. Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE™) model. Clin Ophthalmol 2015;9:877–884.
[78] Sosne G, Dunn SP, Kim C. Thymosin B4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. Cornea 2015:34.
[79] Skelly AC, Dettori JR, Brodt ED. Assessing bias: the importance of considering confounding. Evid Based Spine Care J 2012;3(1):9–12.
[80] Lemp MA. Report of the national eye institute/industry workshop on clinical trials in dry eyes. CLAO J 1995;21(4):221–232.
[81] Eisner A. Sex, eyes, and vision: male/female distinctions in ophthalmic disorders. Curr Eye Res 2015;40:96–101.
[82] Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Arch Ophthalmol 2009;127(6):763–768.
[83] McMonnies CW. Incomplete blinking: exposure keratopathy, lid wiper epitheliopathy, dry eye, refractive surgery, and dry contact lenses. Contact Lens Anter Eye 2007;30(1):37–51.
[84] Foulks GN, Borchman D, Yappert M. Modification of meibomian gland lipids by topical azithromycin. Invest Ophthalmol Vis Sci 2009;50. ARVO E-Abstract 2676.
[85] Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci 2011;52(4):1994–2005.
[86] Carracedo G, Recchioni A, Alejandre-Alba N, Martin-Gil A, Crooke A, Morote IJ, et al. Signs and symptoms of dry eye in keratoconus patients: a pilot study. Curr Eye Res 2015;40(11):1088–1094.
[87] Gallar J, Acosta MC, Moilanen JA, Holopainen JM, Belmonte C, Tervo TM. Recovery of corneal sensitivity to mechanical and chemical stimulation after laser in situ keratomileusis. J Refract Surg 2004;20(3):229–235.
[88] Kheirkhah A, Dohlman TH, Amparo F, Arnoldner MA, Jamali A, Hamrah P, et al. Effects of corneal nerve density on the response to treatment in dry eye disease. Ophthalmology 2015;122(4):662–668.
[89] Narayanan S, Redfern RL, Miller WL, Nichols KK, McDermott AM. Dry eye disease and microbial keratitis: is there a connection? Ocul Surf 2013;11(2):75–92.
[90] Quinto GG, Campos M, Behrens A. Autologous serum for ocular surface diseases. Arq Bras Oftalmol 2008 Nov-Dec;71(6 Suppl):47–54.
[91] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, et al. TFOS DEWS II Iatrogenic report. Ocul Surf 2017;15:511–538.
[92] Rohit A, Willcox MD, Brown SH, Mitchell TW, Stapleton F. Clinical and biochemical tear lipid parameters in contact lens wearers. Optom Vis Sci 2014;91(12):1384–1390.
[93] Brissette AR, Mednick ZD, Schweitzer KD, Bona MD, Baxter SA. Punctal plug retention rates for the treatment of moderate to severe dry eye: a randomized, double-masked, controlled clinical trial. Am J Ophthalmol 2015;160(2):238–242.
[94] Dumbleton K, Caffery B, Dogru M, Hickson-Curran S, Kern J, Kojima T, et al. The TFOS international workshop on contact lens discomfort: report of the subcommittee on Epidemiology. Invest Ophthalmol Vis Sci 2013;54:TFOS20–TFOS36.
[95] Blackwell B. Treatment adherence. Br J Psychiatry 1976;129:513–531.
[96] Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Ann Rev Pharm Toxicol 2011;52:275–301.
[97] Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol 2009;127(6):732–736.
[98] Novack GD. Pipeline: thoughts generated by the annual meeting of the american society of clinical pharmacology and therapeutics. Ocul Surf 2004;2:212–214.
[99] Robin AL, Novack GD, Covert DW, Crockett RS, Marcic TS. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol 2007;144(4):533–540.
[100] Karanicolas PJ, Farrokhyar F, Bhandari M. Practical tips for surgical research: blinding: who, what, when, why, how? Can J Surg 2010;53(5):345–348.
[101] Standardisation IOf. Clinical investigation of medical devices for human subjects - good clinical practice. Int Organ Stand 2011.
[102] Marinho DR, Burmann TG, Kwitko S. Labial salivary gland transplantation for severe dry eye due to chemical burns and Stevens-Johnson syndrome. Ophthalmic Plast Reconstr Surg 2010 May-Jun;26(3):182–184.
[103] Koffler BH, McDonald M, Nelinson DS, Group LACS. Improved signs, symptoms, and quality of life associated with dry eye syndrome: hydroxypropyl cellulose ophthalmic insert patient registry. Eye Contact Lens 2010;36:170–176.
[104] Pult H, Riede-Pult BH, Purslow C. A comparison of an eyelid-warming device to traditional compress therapy. Optom Vis Sci 2012;89:E1035–E1041.
[105] Purslow C. Evaluation of the ocular tolerance of a novel eyelid-warming device used for meibomian gland dysfunction. Contact Lens Anter Eye 2013;36(5):226–231.
[106] Benitez Del Castillo JM, Kaercher T, Mansour K, Wylegala E, Dua H. Evaluation of the efficacy, safety, and acceptability of an eyelid warming device for the treatment of meibomian gland dysfunction. Clin Ophthalmol 2014;8:2019–2027.
[107] Finis D, König C, Hayajneh J, Borrelli M, Schrader S, Geerling G. Six-month effects of a thermodynamic treatment for MGD and implications of meibomian gland atrophy. Cornea 2014;33(12):1265–1270.
[108] Sim HS, Petznick A, Barbier S, Tan JH, Acharya UR, Yeo S, ; Collaborative Research Initiative for Meibomian Gland Dysfunction (CORIM)., et al. A randomized, controlled treatment trial of eyelid-warming therapies in meibomian gland dysfunction. Ophthalmol Ther 2014;3(1–2):37–48.
[109] Choi W, Kim JC, Kim WS, Oh HJ, Yang JM, Lee JB, et al. Clinical effect of antioxidant glasses containing extracts of medicinal plants in patients with dry eye disease: a multi-center, prospective, randomized, double-blind, placebo-controlled trial. PloS One 2015;10(10):e0139761.
[110] Murakami DK, Blackie CA, Korb DR. All warm compresses are not equally efficacious. Optom Vis Sci 2015;92:e327–e333.
[111] Toyos R, McGill W, Briscoe D. Intense pulsed light treatment for dry eye disease due to meibomian gland dysfunction; a 3-year retrospective study. Photomed Laser Surg 2015;33(1):41–46.
[112] Villani Edoardo, Garoli Elena, Canton Veronica, Pichi Francesco, Nucci Paolo, Ratiglia Roberto. Evaluation of a novel eyelid-warming device in meibomian gland dysfunction unresponsive to traditional warm compress treatment: an in vivo confocal study. Int Ophthalmol 2015;35(3):319–323.
[113] Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of self-applied heat therapy for meibomian gland dysfunction. Optom Vis Sci 2015;92(9):e321–e326.
[114] Wang MT, Gokul A, Craig JP. Temperature profiles of patient-applied eyelid warming therapies. Contact Lens Anter Eye 2015;38(6):430–434.
[115] Greiner JV. Long-term (3 Year) effects of a single thermal pulsation system treatment on meibomian gland function and dry eye symptoms. Eye Contact Lens 2016;42(2):99–107.
[116] Zhao Y, Veerappan A, Yeo S, Rooney DM, Acharya RU, Tan JH, et al. Clinical trial of thermal pulsation (LipiFlow) in meibomian gland dysfunction with preteatment meibography. Eye Contact Lens 2016;42(6):339–346.
[117] Friedman NJ, Butron K, Robledo N, Loudin J, Baba SN, Chayet A. A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease. Clin Ophthalmol 2016;10:795–804.
[118] Novack GD. The development of drugs vs devices. Ocul Surf 2011;9(1):56–57.
[119] Copay AG, Subach BR, Glassman SD, Polly Jr. DW, Schuler TC. Understanding the minimum clinically important difference: a review of concepts and methods. Spine J 2007 Sep-Oct;7(5):541–546.
[120] Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989;10(4):407–415.
[121] Stratford PW, Binkley JM, Riddle DL, Guyatt GH. Sensitivity to change of the Roland-morris back pain questionnaire: part 1. Phys Ther 1998;78(11):1186–1196.
[122] Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23(8):762–770.
[123] Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006;25(8):900–907.
[124] The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye WorkShop. Ocul Surf 2007;2007(5):75–92.
[125] Sullivan B. Challenges in using signs and symptoms to evaluate new biomarkers of dry eye disease. Ocul Surf 2014;12(1):2–9.
[126] Suzuki M, Massingale ML, Ye F, Godbold J, Elfassy T, Vallabhajosyula M, et al. Tear osmolarity as a biomarker for dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51(9):4557–4561.
[127] Huang JF, Yafawi R, Zhang M, McDowell M, Rittenhouse KD, Sace F, et al. Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology 2012;119(7):e43–e50.
[128] See C, Bilonick RA, Feuer W, Galor A. Comparison of two methods for composite score generation in dry eye syndrome. Invest Ophthalmol Vis Sci 2013;54(9):6280–6286.
[129] Sullivan BD, Eldridge DC, Berg M, Kosheleff V, Porreco A, Truitt J, et al. Diagnostic performance of osmolarity combined with subset markers of dry eye disease in an unstratified patient population. Invest Ophthalmol Vis Sci 2010;51. ARVO E-Abstract 3380.
[130] Leonardi A, Van Setten G, Amrane M, Ismail D, Garrigue JS, Figueiredo FC, et al. Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial. Eur J Ophthalmol 2016;26(4):287–296.
[131] Willcox MDP, Argüeso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, et al. TFOS DEWS II Tear Film report. Ocul Surf 2017;15:366–403.
[132] Jackson DC, Zeng W, Wong CY, Mifsud EJ, Williamson NA, Ang CS, et al. Tear interferon-gamma as a biomarker for evaporative dry eye disease. Invest Ophthalmol Vis Sci 2016;57(11):4824–4830.
[133] Baudouin C, Aragona P, Van Setten G, Rolando M, Irkeç M, Benítez del Castillo J, et al. Diagnosing the severity of dry eye: a clear and practical algorithm. Br J Ophthalmol 2014;98(9):1168–1176.
[134] Cardona G, Marcellán C, Fornieles A, Vilaseca M, Quevedo L. Temporal stability in the perception of dry eye ocular discomfort symptoms. Optom Vis Sci 2010;87(12):1023–1029.
[135] Tran N, Graham AD, Lin MC. Ethnic differences in dry eye symptoms: effects of corneal staining and length of contact lens wear. Contact Lens Anter Eye 2013;36(6):281–288.
[136] Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136(2):318–326.
[137] O'Brien PD, Collum LM. Dry eye: diagnosis and current treatment strategies. Curr Allergy Asthma Rep 2004;4(4):314–319.
[138] Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, et al. Minimal clinically important difference for the ocular surface disease index. Arch Ophthalmol 2010;128:94–101.
[139] Vitale S, Goodman LA, Reed GF, Smith JA. Comparison of the NEI-VFQ and OSDI questionnaires in patients with Sjögren's syndrome-related dry eye. Health Qual Life Outcomes 2004;2:44.
[140] Begley CG, Caffery B, Chalmers RL, Mitchell GL, Dry Eye Investigation (DREI) Study Group. Use of the dry eye questionnaire to measure symptoms of ocular irritation in patients with aqueous tear deficient dry eye. Cornea 2002;21(7):664–670.
[141] Grubbs Jr. JR, Tolleson-Rinehart S, Huynh K, Davis RM. A review of quality of life measures in dry eye questionnaires. Cornea 2014;33(2):215–218.
[142] Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol 2000;118(5):615–621.
[143] Schaumberg DA, Gulati A, Mathers WD, Clinch T, Lemp MA, Nelson JD, et al. Development and validation of a short global dry eye symptom index. Ocul Surf 2007;5(1):50–57.
[144] Ridder 3rd WH, Tomlinson A, Huang JF, Li J. Impaired visual performance in patients with dry eye. Ocul Surf 2011;9(1):42–55.
[145] Rajagopalan K, Abetz L, Mertzanis P, Espindle D, Begley C, Chalmers R, et al. Comparing the discriminative validity of two generic and one disease-specific health-related quality of life measures in a sample of patients with dry eye. Value Health 2005 Mar-Apr;8(2):168–174.
[146] Rolando M, Iester M, Macrí A, Calabria G. Low spatial-contrast sensitivity in dry eyes. Cornea 1998;17(4):376–379.
[147] Puell MC, Benítez-del-Castillo JM, Martínez-de-la-Casa J, Sánchez-Ramos C, Vico E, Pérez-Carrasco MJ, et al. Contrast sensitivity and disability glare in patients with dry eye. Acta Ophthalmol Scand 2006;84(4):527–531.
[148] Huang FC, Tseng SH, Shih MH, Chen FK. Effect of artificial tears on corneal surface regularity, contrast sensitivity, and glare disability in dry eyes. Ophthalmology 2002;109(10):1934–1940.
[149] Ridder 3rd WH, Zhang Y, Huang JF. Evaluation of reading speed and contrast sensitivity in dry eye disease. Optom Vis Sci 2013;90(1):37–44.
[150] Goto E, Yagi Y, Matsumoto Y, Tsubota K. Impaired functional visual acuity of dry eye patients. Am J Ophthalmol 2002;133(2):181–186.
[151] Ishida R, Kojima T, Dogru M, Kaido M, Matsumoto Y, Tanaka M, et al. The application of a new continuous functional visual acuity measurement system in dry eye syndromes. Am J Ophthalmol 2005;139(2):253–258.
[152] Denoyer A, Rabut G, Baudouin C. Tear film aberration dynamics and vision-related quality of life in patients with dry eye disease. Ophthalmology 2012;119(9):1811–1818.
[153] Biomarkers Definitions Working G.. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95.
[154] Hagan S, Martin E, Enríquez-de-Salamanca A. Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine. EPMA J 2016;7:15.
[155] Lemp MA, Sullivan BD, Crews LA. Biomarkers in dry eye disease. Eur Ophthalmic Rev 2012;6:157–163.
[156] Zhou L, Beuerman RW, Chan CM, Zhao SZ, Li XR, Yang H, et al. Identification of tear fluid biomarkers in dry eye syndrome using iTRAQ quantitative proteomics. J Proteom Res 2009;8(11):4889–4905.
[157] Massingale ML, Li X, Vallabhajosyula M, Chen D, Wei Y, Asbell PA. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea 2009;28(9):1023–1027.
[158] Epstein SP, Gadaria-Rathod N, Wei Y, Maguire MG, Asbell PA. HLA-DR expression as a biomarker of inflammation for multicenter clinical trials of ocular surface disease. Exp Eye Res 2013;111:95–104.
[159] Wei Y, Gadaria-Rathod N, Epstein S, Asbell P. Tear cytokine profile as a noninvasive biomarker of inflammation for ocular surface diseases: standard operating procedures. Invest Ophthalmol Vis Sci 2013;54(13):8327–8336.
[160] Paletta Guedes RA, Paletta Guedes VM, Freitas SM, Chaoubah A. Does the type of treatment have an influence on utility values in a glaucoma population? Clin Ophthalmol 2015;9:1645–1650.
[161] Bourcier T, Acosta MC, Borderie V, Borrás F, Gallar J, Bury T, et al. Decreased corneal sensitivity in patients with dry eye. Invest Ophthalmol Vis Sci 2005;46(7):2341–2345.
[162] Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, et al. TFOS DEWS II Pain and Sensation report. Ocul Surf 2017;15:404–437.
[163] Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol 2016;100(1):128–134.
[164] Goto T, Zheng X, Okamoto S, Ohashi Y. Tear film stability analysis system: introducing a new application for videokeratography. Cornea 2004;23(8 Suppl):S65–S70.
[165] Potvin R, Makari S, Rapuano CJ. Tear film osmolarity and dry eye disease: a review of the literature. Clin Ophthalmol 2015;9:2039–2047.
[166] Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990;108(1):84–88.
[167] Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf 2005;3(3):143–154.
[168] Kojima T, Matsumoto Y, Ibrahim OM, Wakamatsu TH, Uchino M, Fukagawa K, et al. Effect of controlled adverse chamber environment exposure on tear functions in silicon hydrogel and hydrogel soft contact lens wearers. Invest Ophthalmol Vis Sci 2011;52(12):8811–8817.
[169] Meerovitch K, Torkildsen G, Lonsdale J, Goldfarb H, Lama T, Cumberlidge G, et al. Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol 2013;7:1275–1285.
[170] Patane MA, Cohen A, From S, Torkildsen G, Welch D, Ousler 3rd GW. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial. Clin Ophthalmol 2011;5:633–643.
[171] Semba CP, Torkildsen GL, Lonsdale JD, McLaurin EB, Geffin JA, Mundorf TK, et al. A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye. Am J Ophthalmol 2012;153(6):1050–1060. e1.
[172] Novack GD. Translating drugs from animals to humans: do we need to prove efficacy? Transl Vis Sci Technol 2013;2:1–4.
[173] Tang-Liu DD, Liu SS, Weinkam RJ. Ocular and systemic bioavailability of ophthalmic flurbiprofen. J Pharmacokinet Biopharm 1984;12(6):611–626.
[174] Novack GD, Moyer ED. How much nonclinical safety data are required for a clinical study in ophthalmology? J Ocul Pharmacol Ther 2016 Jan-Feb;32(1):5–10.
[175] Edeki TI, He H, Wood AJJ. Pharmacogenetic explanation for excessive b-blockade following timolol eye drops: potential for oral-ophthalmic drug interaction. JAMA 1995;274:1611–1613.
[176] Novack GD, Stamer WD. The “T” in JOPT. J Ocul Pharmacol Ther 2015;31:129.
[177] Haidar SH, Davit B, Chen ML, Conner D, Lee L, Li QH, et al. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res 2008;25(1):237–241.
[178] Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 2009;43(10):1583–1597.
[179] Woodcock J. Evidence vs. access: can twenty-first-century drug regulation refine the tradeoffs? Clin Pharmacol Ther 2012;91(3):378–380.
[180] Levitan B. A concise display of multiple end points for benefit-risk assessment. Clin Pharmacol Ther 2011;89(1):56–59.
[181] Poland B, Hodge FL, Khan A, Clemen RT, Wagner JA, Dykstra K, et al. The clinical utility index as a practical multiattribute approach to drug development decisions. Clin Pharmacol Ther 2009;86(1):105–108.
[182] Korsan B, Dykstra K, Pullman W. Transparent trade-offs. Pharm Exec 2005.
[183] Goyal N, Gomeni R. A novel metric to assess the clinical utility of a drug in the presence of efficacy and dropout information. Clin Pharmacol Ther 2012;91(2):215–219.
[184] Novack GD. The benefit/risk of good therapeutics. Ocul Surf 2012;10(4):264–266.
[185] Novack GD. Decoding the packaging insert: indications. Ocul Surf 2003;1(3):150–151.
[186] Gadek TR, Burdick DJ, McDowell RS, Stanley MS, Marsters Jr. JC, Paris KJ, et al. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 2002;295(5557):1086–1089.
[187] Anonymous. Assessment report: Ikervis. 2016.
[188] Kinoshita S, Awamura S, Oshiden K, Nakamichi N, Suzuki H, Yokoi N, et al. Rebamipide (OPC-12759) in the treatment of dry eye: a randomized, double-masked, multicenter, placebo-controlled phase II study. Ophthalmology 2012;119(12):2471–2478.
[189] Kinoshita S, Oshiden K, Awamura S, Suzuki H, Nakamichi N, Yokoi N, ; Rebamipide Ophthalmic Suspension Phase 3 Study Group.. A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye. Ophthalmology 2013;120(6):1158–1165.
[190] Greiner JV. A single LipiFlow® Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 months. Curr Eye Res 2012;37(4):272–278.
[191] Finis D, Hayajneh J, König C, Borrelli M, Schrader S, Geerling G. Evaluation of an automated thermodynamic treatment (LipiFlow®) system for meibomian gland dysfunction: a prospective, randomized, observer-masked trial. Ocul Surf 2014;12(2):146–154.
[192] Anonymous. De novo classification request for TearScience, Inc. Lipiflox(R) thermal pulsation system. Device Classification under Section 513(a)(1)(de novo). 2010.
[193] Gumus K, Schuetzle KL, Pflugfelder SC. Randomized controlled crossover trial comparing the impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation. Am J Ophthalmol 2017;177:159–168.
[194] 513(f)(2) - Evaluation of automatic class III designation, guidance for industry and CDRH staff. In: Evaluation OoD, editor. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FDA, Center for Devices and Radiological Health, Rockville, MD 208501998.
[195] Geerling G, Raus P, Murube J. Minor salivary gland transplantation. Dev Ophthalmol 2008;41:243–254.
[196] Geerling G, Sieg P. Transplantation of the major salivary glands. Dev Ophthalmol 2008;41:255–268.
[197] International Conference on Harmonisation. Statistical principles for clinical trials (E9). 1998.
[198] Novack GD. The Importance of A Priori statistical planning in controlled clinical trials. Am J Ophthalmol 2015;160(1):4–5. e1.
[199] Huque M, Rohmel J. Multiplicity problems in clinical trials: a regulatory perspective. In: Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical statistics. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. p. 1–33.
[200] Musch DC, Gillespie BW. The state of being noninferior. Ophthalmology 2006;113(1):1–2.
[201] Novack GD. Some are more equal than others. Ocul Surf 2014;12(2):155–158.
[202] Novack GD. Ophthalmic beta-blockers since timolol. Surv Ophthalmol 1987 Mar-Apr;31(5):307–327.
[203] Avni I, Garzozi HJ, Barequet IS, Segev F, Varssano D, Sartani G, et al. Treatment of dry eye syndrome with orally administered CF101: data from a phase 2 clinical trial. Ophthalmology 2010;117(7):1287–1293.
[204] Capita L, Chalita MR, dos Santos-Neto LL. Prospective evaluation of hypromellose 2% for punctal occlusion in patients with dry eye. Cornea 2015;34(2):188–192.
[205] Simmons PA, Carlisle-Wilcox C, Chen R, Liu H, Vehige JG. Efficacy, safety, and acceptability of a lipid-based artificial tear formulation: a randomized, controlled, multicenter clinical trial. Clin Ther 2015;37(4):858–868.
[206] Steven P, Scherer D, Krösser S, Beckert M, Cursiefen C, Kaercher T. Semifluorinated alkane eye drops for treatment of dry eye disease-a prospective, multicenter noninterventional study. J Ocul Pharmacol Ther 2015;31(8):498–503.
[207] Sheppard JD, Torkildsen GL, Lonsdale JD, D'Ambrosio Jr. FA, McLaurin EB, Eiferman RA, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology 2014;121(2):475–483.
[208] Shimmura S, Ono M, Shinozaki K, Toda I, Takamura E, Mashima Y, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995;79(11):1007–1011.