Advertisement

Pharmaceutical Research

, 36:54 | Cite as

Ophthalmic Drug Discovery and Development: Regulatory Aspects of Patient Focused Drug Development in Ophthalmology

  • Cheryl L. Rowe-RendlemanEmail author
Expert Review
  • 300 Downloads
Part of the following topical collections:
  1. Ophthalmic Drug Discovery and Development

Abstract

In 2009, members of the ophthalmic research community held a joint meeting with members of the Food and Drug Administration (FDA) and the National Eye Institute (NEI) to define and describe the types of patient-focused drug development (PFDD) tools used in ophthalmology. Since then numerous reports have been published which indicate that many of the questionnaires used for patient-reported outcomes (PROs) in ophthalmic clinical development lack rigor and reliability according to modern methods. In 2017, the FDA began development of a series of four methodological guidances for sponsors of clinical trials on the significance of PFDD. The new guidances delineate the FDA’s thinking and commitments under the Prescription Drug User Fee Act to implement a more structured approach to the assessment of risks and benefits in clinical trials. In these guidances, the FDA provides steps that drug and device manufacturers should follow, not only to obtain, but also to develop reliable and validated tools that measure patients’ experience in clinical trials. Subsequent efforts have resulted in the development and validation of PROs specifically for ophthalmology. The purpose of this paper is to assesses the PROs currently used in ophthalmology and to provide practical strategies for incorporating them into clinical trials.

Key Words

clinical trials FDA patient-reported outcomes PROMs PROs 

Notes

References

  1. 1.
    H.R.6 - 21st Century Cures Act 2015. Available from: https://www.congress.gov/bill/114th-congress/house-bill/6%20on%201. Accessed on: 10/31/2018.
  2. 2.
    US Food and Drug Administration. Patient-focused drug development: Disease area meetings held in fiscal years 2013–2017. Available from: https://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm347317.htm. Accessed on: 1/7/2019.
  3. 3.
    US Food and Drug Administration. Patient-focused drug development: Collecting comprehensive and representative input: Guidance for industry, Food and Drug Administration Staff, and other stakeholders. 2018. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM610442.pdf. Accessed on: 10/31/2018.
  4. 4.
    Methods to identify what is important to patients and select, develop, or modify fit-for-purpose clinical outcomes assessments. FDA, Department of Health and Human Services. Workshop October 15–16, 2018. Available from: https://www.fda.gov/downloads/Drugs/NewsEvents/UCM620707.pdf. Accessed on: 10/31/2018.
  5. 5.
    Revicki DA, Osoba D, Fairclough D, Barofsky I, Berzon R, Leidy NK, et al. Recommendations on health-related quality of life research to support labeling and promotional claims in the United States. Qual Life Res. 2000;9(8):887–900.CrossRefGoogle Scholar
  6. 6.
    Denniston AK, Kyte D, Calvert M, Burr JM. An introduction to patient-reported outcome measures in ophthalmic research. Eye. 2014;28(6):637–45.CrossRefGoogle Scholar
  7. 7.
    McGrath RE. Conceptual complexity and construct validity. J Pers Assess. 2005;85(2):112–24.CrossRefGoogle Scholar
  8. 8.
    Tavakol M, Dennick R. Making sense of Cronbach's alpha. Int J Med Educ. 2011;2:563–55.Google Scholar
  9. 9.
    Ishak AH, Osman MR, Mahaiyadin MH, Tumiran MA, Anas N. Examining unidimensionality of psychometric properties via Rasch model. Int J civil. Eng Technol. 2018;9:1462–7.Google Scholar
  10. 10.
    Le JT, Viswanathan S, Tarver ME, Eydelman M, Li T. Assessment of the incorporation of patient-centric outcomes in studies of minimally invasive glaucoma surgical devices. JAMA Ophthalmol. 2016;134(9):1054–6.CrossRefGoogle Scholar
  11. 11.
    National Eye Institute. National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25), version 2000. Available from: https://eprovide.mapi-trust.org/instruments/national-eye-institute-visual-function-questionnaire-25. Accessed on: 01/09/2019.
  12. 12.
    Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050–8.Google Scholar
  13. 13.
    Senthil M, Khadka J, Pesudovs K. Assessment of patient-reported outcomes in retinal diseases: a systematic review. Surv Ophthalmol. 2017;62(4):546–82.CrossRefGoogle Scholar
  14. 14.
    Marella M, Pesudovs K, Keeffe JE, O'Connor PM, Rees G, Lamoureux EL. The psychometric validity of the NEI VFQ-25 for use in a low-vision population. Invest Ophthalmol Vis Sci. 2010 Jun;51(6):2878–84.CrossRefGoogle Scholar
  15. 15.
    Pesudovs K, Gothwal VK, Wright T, Lamoureux EL. Remediating serious flaws in the National Eye Institute Visual Function Questionnaire. J Cataract Refract Surg. 2010;36(5):718–32.Google Scholar
  16. 16.
    Mogil S, Tirsi A, Lee JM, Tello C, Park SC. Glaucoma patient-reported concerns and associated factors. Am J Ophthalmol. 2017 Jun;178:9–17.CrossRefGoogle Scholar
  17. 17.
    Hasebe Y, Kashiwagi K, Tsumura T, Suzuki Y, Yoshikawa K, Suzumura H, et al. Changes in adherence and associated factors among patients on newly introduced prostaglandin analog and timolol fixed-combination therapy. Patient Prefer Adherence. 2018;12:1567–77.CrossRefGoogle Scholar
  18. 18.
    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):533–40.CrossRefGoogle Scholar
  19. 19.
    Friedman DS, Quigley HA, Gelb L, Tan J, Margolis J, Shah SN, et al. Using pharmacy claims data to study adherence to glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci. 2007;48(11):5052–7.Google Scholar
  20. 20.
    US Food and Drug Administration. Glaukos iStent Trabecular Micro-Bypass Stent (models: GTS-100R, GTS-100L) and inserter (GTS-100i). 2012 June 25. Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf8/P080030a.pdf. Accessed on: 10/31/2018.
  21. 21.
    Krezel AK, Hogg RE, Azuara-Blanco A. Patient-reported outcomes in randomised controlled trials on age-related macular degeneration. Br J Ophthalmol. 2015;99(11):1560–4.CrossRefGoogle Scholar
  22. 22.
    Amadio M, Govoni S, Pascale A. Targeting VEGF in eye neovascularization: What's new? A comprehensive review on current therapies and oligonucleotide-based interventions under development Pharmacol Res. 2016;103:253–69.PubMedGoogle Scholar
  23. 23.
    Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123(8):1751–61.CrossRefGoogle Scholar
  24. 24.
    Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57–65.e5.Google Scholar
  25. 25.
    Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.CrossRefGoogle Scholar
  26. 26.
    Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98.CrossRefGoogle Scholar
  27. 27.
    Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258–67.CrossRefGoogle Scholar
  28. 28.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419–1431.Google Scholar
  29. 29.
    Singer MA, Awh CC, Sadda S, Freeman WR, Antoszyk AN, Wong P, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175–83.Google Scholar
  30. 30.
    Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States. Ophthalmology Retina. 2018;2(7):645–53.CrossRefGoogle Scholar
  31. 31.
    Mitchell J, Bradley C. Summary of the MacTSQ: a measure of treatment satisfaction in patients with macular degeneration. Health Psychology Research Ltd.Google Scholar
  32. 32.
    Gohil R, Crosby-Nwaobi R, Forbes A, Burton BJ, Hykin P, Sivaprasad S. Treatment satisfaction of patients undergoing ranibizumab therapy for neovascular age-related macular degeneration in a real-life setting. Patient Prefer Adherence. 2016;10:949–55.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Boyle J, Vukicevic M, Koklanis K, Itsiopoulos C, Rees G. Experiences of patients undergoing repeated intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration. Psychol Health Med. 2018;23(2):127–40.CrossRefGoogle Scholar
  34. 34.
    The definition and classification of dry eye disease: Report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf 2007;5(2):75–92.Google Scholar
  35. 35.
    Gomes JAP, Santo RM. The impact of dry eye disease treatment on patient satisfaction and quality of life: a review. Ocul Surf. 2018.Google Scholar
  36. 36.
    Walt JG, Rowe MM, KL S. Evaluating the functional impact of dry eye: The Ocular Surface Disease Index. Drug Inf J. 1997;31.Google Scholar
  37. 37.
    Guillemin I, Begley C, Chalmers R, Baudouin C, Arnould B. Appraisal of patient-reported outcome instruments available for randomized clinical trials in dry eye: revisiting the standards. Ocul Surf. 2012;10(2):84–99.CrossRefGoogle Scholar
  38. 38.
    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.Google Scholar
  39. 39.
    Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index Arch Ophthalmol. 2000 May;118(5):615–21.Google Scholar
  40. 40.
    Minsk A, Blakely J, Cohen D. FDA issues final guidance on patient-reported outcome measures used to support labeling claims. Regulatory Focus; 2010. Available from: https://www.agg.com/media/interior/publications/Minsk_Blakely_Cohen-FDA_Issues_Guidance_Patient-Reported_Outcome.pdf. Accessed on: 10/29/2018.
  41. 41.
    US Food and Drug Administration. Guidance for industry: patient-reported outcome measures: use in medical product development 2009. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf Accessed on: 10/29/2018.
  42. 42.
    Observational registry study of Leber hereditary optic neuropathy (LHON) affected patients. Clinicaltrials.Gov identifier: NCT03295071. Clinicaltrials.gov Available from: https://clinicaltrials.gov. Accessed on: 10/31/2018.
  43. 43.
    Vitamin A palmitate supplementation in patients with age-related macular degeneration (and without reticular pseudodrusen) and delayed dark adaptation. Clinicaltrials.Gov identifier: NCT03478865. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  44. 44.
    A staged study incorporating a Phase 1b, multicenter, unmasked, dose escalation evaluation of safety and tolerability and a Phase 2, multicenter, unmasked, randomized, parallel group, controlled, proof of concept investigation of efficacy and safety of ASP7317 for atrophy secondary to age-related macular degeneration. Clinicaltrials.Gov identifier: NCT03178149. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  45. 45.
    A two-year, two-arm, randomized, double masked, multicenter, Phase III study assessing the efficacy and safety of brolucizumab versus aflibercept in adult patients with visual impairment due to diabetic macular edema. Clinicaltrials.Gov identifier: NCT03481660. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  46. 46.
    A two-year, three-arm, randomized, double-masked, multicenter, Phase III study assessing the efficacy and safety of brolucizumab versus aflibercept in adult patients with visual impairment due to diabetic macular edema. Clinicaltrials.Gov identifier: NCT03481634. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  47. 47.
    Development of novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration. Clinicaltrials.Gov identifier: NCT03349801. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  48. 48.
    Optical head-mounted display technology for low vision rehabilitation. Clinicaltrials.Gov identifier: NCT02983305. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  49. 49.
    Impact on daily life of patients using the subretinal implant retina implant alpha AMS. Clinicaltrials.Gov identifier: NCT03561922 Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  50. 50.
    Effect of treatment modality on psychosocial functioning of survivors of unilateral retinoblastoma. Clinicaltrials.Gov identifier: NCT03662776. Available from: https://clinicialtrials.gov. Accessed on: 10/23/2018.
  51. 51.
    Impact of red and processed meat and fibre intake on treatment outcome among patients with chronic inflammatory diseases: Protocol for a prospective cohort study on prognostic factors and personalised medicine. Clinicaltrials.Gov identifier: NCT03173144 Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  52. 52.
    Topical cadaveric-derived corneal epithelial stem cell transplant therapy for the treatment of severe dry eye disease. Clinicaltrials.Gov identifier: NCT03302273. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  53. 53.
    A multi-center, double masked, randomized, placebo-controlled, dose-ranging study of EBI-005 ophthalmic solution versus placebo in subjects with dry eye syndrome. Clinicaltrials.Gov identifier: NCT01745887. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  54. 54.
    A randomized, Phase 2, double-blind, placebo-controlled study to assess the safety and efficacy of filgotinib, GS-9876 and GS-4059 in adult subjects with active Sjogren's Syndrome. Clinicaltrials.Gov identifier: NCT03100942 Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  55. 55.
    Cost-effectiveness of immediately versus delayed sequential bilateral cataract surgery (ISBCS vs. DSBCS). Clinicaltrials.Gov identifier: NCT03400124. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  56. 56.
    Development of a new patient reported outcome (PRO) measure for refractive surgery patients as part of the national dataset in refractive surgery. Clinicaltrials.Gov identifier: NCT03655743. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  57. 57.
    Prospective, randomized, fellow eye comparison of fellow eyes undergoing Lasik with the intralase IFS150 versus the visumax. Clinicaltrials.Gov identifier: NCT03063164. Available from: https://clinicaltrials.gov. Accessed on: 10/23/2018.
  58. 58.
    Owsley C, McGwin G Jr, Scilley K, Kallies K. Development of a questionnaire to assess vision problems under low luminance in age-related maculopathy. Invest Ophthalmol Vis Sci. 2006;47(2):528–35.CrossRefGoogle Scholar
  59. 59.
    Finger RP, Fenwick E, Owsley C, Holz FG, Lamoureux EL. Visual functioning and quality of life under low luminance: evaluation of the German Low Luminance Questionnaire. Invest Ophthalmol Vis Sci. 2011;52(11):8241–9.Google Scholar
  60. 60.
    Dagnelie G, Jeter PE, Adeyemo O. Optimizing the ULV-VFQ for clinical use through item set reduction: psychometric properties and trade-offs. Transl Vis Sci Technol. 2017;6(3):12.CrossRefGoogle Scholar
  61. 61.
    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):1498–503.Google Scholar
  62. 62.
    Dauhajre J, Atallah R. Dry eye: More than a symptomatic disease. 2014. Available from: https://www.reviewofophthalmology.com/article/dry-eye-more-than-a-symptomatic-disease. Accessed on: 1/7/2019.
  63. 63.
    Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, et al. Eular Sjogren's syndrome patient reported index (ESSPIR): development of a consensus patient index for primary Sjogren's syndrome. Ann Rheum Dis. 2011;70(6):968–72.CrossRefGoogle Scholar
  64. 64.
    Lundstrom M, Pesudovs K. CATquest-9SF patient outcomes questionnaire. Nine-item short-form Rasch-scaled revision of the CATquest questionnaire J Cataract Refract Surg. 2009;35(3):504–13.PubMedGoogle Scholar
  65. 65.
    Clinical evaluation of Etafilcon a contact lenses using a novel molding process 2. Clinicaltrials.Gov identifier: NCT03701516. Available from: clinicaltrials.gov. Accessed on: 1/7/2019.Google Scholar
  66. 66.
    Wirth RJ, Edwards MC, Henderson M, Henderson T, Olivares G, Houts CR. Development of the Contact Lens User Experience: CLUE scales. Optom Vis Sci. 2016;93(8):801–8.Google Scholar
  67. 67.
    Varma R, Richman EA, Ferris FL 3rd, Bressler NM. Use of patient-reported outcomes in medical product development: a report from the 2009 NEI/FDA clinical trial endpoints symposium. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6095–103.CrossRefGoogle Scholar
  68. 68.
    American Academy of Ophthalmology. The IRIS®Registry. Available from: https://www.aao.org/iris-registry. Accessed on: 1/9/2019.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Ophthalmic Medical and Research ConsultingOmar Consulting Group, LLCPrinceton JunctionUSA

Personalised recommendations