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Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease pp 487–515Cite as

Regulatory Considerations for Early Clinical Development of Drugs for Diabetes, Obesity, Nonalcoholic Steatohepatitis (NASH) and Other Cardiometabolic Disorders

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Abstract

Advancing therapeutic discoveries through early clinical studies benefits from a working knowledge of regulatory history, practices, provisions, procedures and controversies. This chapter aims to supplement available published and web-based resources that describe current regulatory expectations and requirements. Though the Food and Drug Administration (FDA) is emphasized for illustrative purposes, the importance of the European Medicines Agency (EMA) and other regional authorities should not be minimized. Some relevant differences between EMA and FDA are also discussed. With emphasis on early studies, selected regulatory considerations are presented for developing diabetes, anti-obesity and lipid-lowering therapies towards existing therapeutic indications. Regulatory and clinical trial considerations are provided for developing novel therapeutic indications including those for nonalcoholic steatohepatitis (NASH) and related disorders.

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Notes

  1. 1.

    Ironically, the title could not be completely harmonized. The British/French spelling continues to be used in the official international title. FDA uses the American spelling.

  2. 2.

    FDA adopted the ICH reports as guidances to avoid the much longer period of time that would have been required to makes these laws or regulations.

  3. 3.

    Pharmaceuticals and Medical Devices Agency of Japan.

  4. 4.

    The current U.S. system of protection for human research subjects is heavily influenced by the Belmont Report, https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html written in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report outlines the basic ethical principles in research involving human subjects. In 1981, with this report as foundational background, HHS and the Food and Drug Administration revised, and made as compatible as possible under their respective statutory authorities, their existing human subjects regulations. The Federal Policy for the Protection of Human Subjects or the “Common Rule” was published in 1991 and codified in separate regulations by 15 Federal departments and agencies, as listed below. The HHS regulations, 45 CFR part 46, include four subparts: subpart A, also known as the Federal Policy or the “Common Rule”; subpart B, additional protections for pregnant women, human fetuses, and neonates; subpart C, additional protections for prisoners; and subpart D, additional protections for children. Each agency includes in its chapter of the Code of Federal Regulations [CFR] section numbers and language that are identical to those of the HHS codification at 45 CFR part 46, subpart A. For all participating departments and agencies, the Common Rule outlines the basic provisions for IRBs, informed consent, and Assurances of Compliance. Human subject research conducted or supported by each federal department/agency is governed by the regulations of that department/agency. The head of that department/agency retains final judgment as to whether a particular activity it conducts or supports is covered by the Common Rule. If an institution seeks guidance on implementation of the Common Rule and other applicable federal regulations, the institution should contact the department/agency conducting or supporting the research. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html

  5. 5.

    FDA Staff, Personal Communication (2017).

  6. 6.

    “In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.” https://www.fda.gov/ForPatients/Approvals/Fast/ucm405447.htm

  7. 7.

    FDA Staff, Personal Communication (2018).

  8. 8.

    FDA Staff, Personal Communication (2017).

References

  1. Congressional Record, 18 Dec 1941, p. 9988–89 (Legislative History 7:92–93).

    Google Scholar 

  2. To amend the Federal Food, Drug, and Cosmetic Act of June 25, 1938, as amended, by providing for the certification of batches of drugs composed wholly or partly of insulin, and for other purposes. 55 STAT. 77TH CONG., IST SESS.-CH. 613-DEC. 22, 1941. https://www.loc.gov/law/help/statutes-at-large/77th-congress/session-1/c77s1ch613.pdf.

  3. The FDA Modernization Act of 1997. https://www.fda.gov/RegulatoryInformation/Laws Enforced by FDA/Significant Amendments to the FDCAct/FDAMA/ucm089179.htm.

  4. The road to the biotech revolution – highlights of 100 years of biologics regulation. Linda Bren FDA Consumer magazine, Centennial Edition (Jan.–Feb. 2006). https://www.fda.gov/downloads/AboutFDA/WhatWeDo/History/ProductRegulation/UCM593490.pdf.

  5. Products. https://www.fda.gov/Drugs/Development Approval Process/How Drugs areDeveloped and Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580419.htm. Accessed 5 Apr 2018.

  6. Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry, Transition Period for Certain Biological Products, p. 4. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf. Accessed 5 Apr 2018.

  7. Heinemann L, Khatami H, McKinnon R, Home P. An overview of current regulatory requirements for approval of biosimilar insulins. Diabetes Technol Ther. 2015;17(7):510–26. https://doi.org/10.1089/dia.2014.0362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Milestones in U.S. Food and Drug Law History. http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm Accessed 12 Jan 2014.

  9. Human medicines: regulatory information. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/landing/human_medicines_regulatory.jsp&mid=WC0b01ac058001ff89. Accessed 12 Jan 2014.

  10. Rahalkar H. Historical review of pharmaceutical industry and drug regulatory affairs. Pharmaceut Reg Aff. 2012;2(S11):002.

    Google Scholar 

  11. ICH Topic E6 (R1) Guideline for Good Clinical Practice. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf. Accessed 19 Sept 2014.

  12. Human Drug Advisory Committees. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/default.htm. Accessed 18 May 2014.

  13. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs — insights from the rosiglitazone experience. N Engl J Med. 2013;369:1285–128.

    Article  CAS  PubMed  Google Scholar 

  14. Marris E. Diabetes drugs under scrutiny in a post-Vioxx world. Nat Rev Drug Discov. 2007;6:505–6.

    Article  CAS  PubMed  Google Scholar 

  15. Roy ASA. Stifling new cures: the true cost of lengthy clinical drug trials. http://www.manhattan-institute.org/html/fda_05.htm. Accessed 20 Jan 2014.

  16. ICH History. http://www.ich.org/about/history.html. Accessed 31 Jan 2014.

  17. Providing regulatory submissions in electronic format — certain human pharmaceutical product applications and related submissions using the eCTD specifications guidance for industry, April 2017. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm333969.pdf. Accessed 4 Apr 2018.

  18. FDA guidance providing regulatory submissions in electronic format — standardized study data. December 2014. https://www.fda.gov/downloads/drugs/guidances/ucm292334.pdf. Accessed 4 Apr 2018.

  19. Division of Metabolism and Endocrinology Products (DMEP). https://www.fda.gov/AboutFDA/CentersOffices/Office ofMedicalProductsandTobacco/CDER/ucm269646.htm. Accessed 5 Apr 2018.

  20. Office of Drug Evaluation I – Division of Cardiovascular and Renal Products (DCaRP). https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm290673.htm. Accessed 5 Apr 2018.

  21. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–8.. http://www.nejm.org/doi/full/10.1056/NEJM199103213241201.

    Article  CAS  PubMed  Google Scholar 

  22. Brown NJ, Vaughan DE. Cardiovascular drugs: angiotensin-converting enzyme inhibitors. Circulation. 1998;97:1411–20.

    Article  CAS  PubMed  Google Scholar 

  23. Lambers Heerspink HJ, Perkovic V, de Zeeuw D. Is doubling of serum creatinine a valid clinical ‘hard’ endpoint in clinical nephrology trials? Nephron Clin Pract. 2011;119:c195–9.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang S, Park C, Barner C. Ranibizumab, VEG-F inhibitor Ranibizumab for age-related macular degeneration: a meta-analysis of dose effects and comparison with no anti-VEGF treatment and bevacizumab. J Clin Pharm Ther. 2014;39:234–9.

    Article  CAS  PubMed  Google Scholar 

  25. Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007, Issue 4. Art. No.: CD004572. https://doi.org/10.1002/14651858.CD004572.pub2.

  26. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. Accessed 20 May 2014.

  27. Tardif J-C, Heinonen T, Orloff D, Libby P. Vascular biomarkers and surrogates in cardiovascular disease. Circulation. 2006;113:2936–42.

    Article  PubMed  Google Scholar 

  28. Rosen CJ. Revisiting the rosiglitazone story — lessons learned. N Engl J Med. 2010;363:803–6.

    Article  CAS  PubMed  Google Scholar 

  29. Endocrinologic and Metabolic Drugs Advisory Committee. https://www.fda.gov/Advisory Committees/Committees MeetingMaterials/Drugs/Endocrinologic and MetabolicDrugsAdvisoryCommittee/default.htm. Accessed 5 Apr 2018.

  30. Guidance for industry diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf. Accessed 20 May 2014.

  31. Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR. Koda-Kimble & Young’s applied therapeutics: the clinical use of drugs. Published 10th edition Lippincott Williams & Wilkins; 2012. p. 252–67. http://www.astrazeneca.com/Media/Press-releases/Article/2014056%2D%2Dus-fda-approves-epanova-for-the-treatment-adults-severe-hypertriglyceridaemia. Accessed 5 June 2014.

  32. Psaty BM, Lumley T. Surrogate end points and FDA approval: a tale of 2 lipid-altering drugs. JAMA. 2008;299:1474–6.

    Article  CAS  PubMed  Google Scholar 

  33. Kastelein J, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431–43. http://www.nejm.org/doi/full/10.1056/NEJMoa0800742.

    Article  CAS  PubMed  Google Scholar 

  34. Cannon C, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97. http://www.nejm.org/doi/full/10.1056/NEJMoa1410489.

    Article  CAS  PubMed  Google Scholar 

  35. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99.

    Article  CAS  PubMed  Google Scholar 

  36. The HPS3/TIMI55–REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217–27.. http://www.nejm.org/doi/full/10.1056/NEJMoa1706444?query=recirc_curatedRelated_article.

    Article  Google Scholar 

  37. Toklu B, et al. Current indications, cost, and clinical use of Anti-PCSK9 monoclonal antibodies. Am Coll Cardiol. 2016. http://www.acc.org/latest-in-cardiology/articles/2016/05/18/14/34/current-indications-cost-and-clinical-use-of-anti-pcsk9-monoclonal-antibodies.

  38. Robinson J, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99. http://www.nejm.org/doi/full/10.1056/NEJMoa1501031; Sabatine M, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22. http://www.nejm.org/doi/full/10.1056/NEJMoa1615664.

  39. Hirshberg B, Raz I. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34:s101–6.

    Article  PubMed  PubMed Central  Google Scholar 

  40. http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194879.htm. Accessed 10 June 2014.

  41. https://www.hhs.gov/about/budget/fy2017/budget-in-brief/fda/index.html.

  42. Office of Combination Products. https://www.fda.gov/AboutFDA/CentersOffices/Office of MedicalProductsandTobacco/OfficeofScienceandHealthCoordination/ucm2018184.htm.

  43. Frequently asked questions about combination products. https://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm. Accessed 5 Apr 2018.

  44. http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/MedicalFoods/default.htm. Accessed 31 Jan 2014.

  45. Degnan FH. The US Food and Drug Administration and probiotics: regulatory categorization. Clin Infect Dis. 2008;46(Supplement 2):S133–6. https://doi.org/10.1086/523324.

    Article  PubMed  Google Scholar 

  46. http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/MedicalFoods/ucm054048.htm. Accessed 31 Jan 2014.

  47. Key Legal concepts: interstate commerce, adulterated, and misbranded. https://www.fda.gov/Cosmetics/GuidanceRegulation/LawsRegulations/ucm074248.htm. Accessed 5 Apr 2018.

  48. Investigational New Drug (IND) application. https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm. Accessed 5 Apr 2018.

  49. FAQs about investigational device exemption. https://www.fda.gov/MedicalDevices/Device RegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051480.htm. Accessed 5 Apr 2018.

  50. Guidance for industry: formal meetings between the FDA and sponsors or applicants of PDUFA products. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.pdf. Accessed 5 Apr 2018.

  51. Guidance for review staff and industry good review management principles and practices for PDUFA products. https://www.fda.gov/downloads/Drugs/.../Guidances/ucm079748.pdf. Accessed 5 Apr 2018.

  52. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm079690.pdf. Retrieved January 2014.

  53. http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM153222.pdf retrieved January 2014.

  54. Office of Drug Evaluation I – Division of Psychiatry Products (DPP). https://www.fda.gov/AboutFDA/CentersOffices/Officeof MedicalProductsandTobacco/CDER/ucm290676.htm. Accessed 5 Apr 2018.

  55. http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/UCM078933.pdf.

  56. Guidance for industry, investigators, and reviewers exploratory IND studies. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078933.pdf. Accessed 5 Apr 2018.

  57. FDA guidance for clinical investigators, sponsors, and IRBs – Investigational New Drug Applications (INDs) — determining whether human research studies can be conducted without an IND (Sept. 2013). http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm229175.pdf.

  58. FDA guidance for industry – content and format of Investigational New Drug Applications (INDs) for phase 1 studies of drugs, including well characterized, therapeutic, biotechnology-derived products (Nov. 1995). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074980.pdf.

  59. FDA guidance for industry S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by Human Pharmaceuticals. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074963.pdf. Accessed 5 Apr 2018.

  60. Federal policy for the protection of human subjects (‘common rule’). https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html. Accessed 5 Apr 2018.

  61. Safety assessment for IND safety reporting guidance for industry. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm477584.pdf. Accessed 5 Apr 2018.

  62. Menikoff J, et al. The common rule, updated. N Engl J Med. 2017;376:613–5. http://www.nejm.org/doi/pdf/10.1056/NEJMp1700736.

    Article  PubMed  Google Scholar 

  63. FDA CFR – Code of Federal Regulations Title 21 (Apr. 2017). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=56.

  64. Manual of policies and procedures center for drug evaluation and research. https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffPoliciesandProcedures/ucm082024.pdf. Accessed 4 Apr 2018.

  65. Meekings KN, Williams CS, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today. 2012 Jul;17(13–14):660–4.

    Article  PubMed  Google Scholar 

  66. Designating an orphan product: drugs and biological products. https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm. Accessed 5 Apr 2018.

  67. Wizemann T, Robinson S, Giffin R. 7 strategies for facilitating clinical trials breakthrough business models: drug development for rare and neglected diseases and individualized therapies: workshop summary; 2008. p. 82–97.

    Google Scholar 

  68. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm387060.htm.

  69. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011;17(6):922–32.

    Article  PubMed  PubMed Central  Google Scholar 

  70. FDA guidance for industry – designating an orphan product: drugs and biological products (updated: 02/16/2018). http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm.

  71. Fast track, breakthrough therapy, accelerated approval, priority review. https://www.fda.gov/ForPatients/Approvals/Fast/default.htm.

  72. Mittermayer F, Caveney E, De Oliveira C, Fleming GA, Gourgiotis L, Puri M, et al. Addressing unmet medical needs in type 1 diabetes: a review of drugs under development. Curr Diabetes Rev. 2017;13(3):300–14. https://doi.org/10.2174/1573399812666160413115655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fleming GA. Regulatory and policy issues for T1DM immunotherapy. Hum Vaccin. 2011;7(1):1–6.

    Article  Google Scholar 

  74. FDA CDER guidance for industry diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention (Feb. 2008). http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071624.pdf.

  75. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Intercept announces phase 3 REVERSE trial evaluating OCA for the treatment of NASH patients with compensated cirrhosis, February 12, 2018. http://ir.interceptpharma.com/node/11576/pdf. Accessed 9 June 2018.

  77. Galmed Announces ARRIVE Study Data, February 14, 2018. http://galmedpharma.investorroom.com/2018-02-14-Galmed-Announces-ARRIVE-Study-Data. Accessed 9 June 2018.

  78. Akcea initiates phase 2 study of AKCEA-ANGPTL3-LRx in patients with hypertriglyceridemia, type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), December 14, 2017. http://ir.ionispharma.com/news-releases/news-release-details/akcea-initiates-phase-2-study-akcea-angptl3-lrx-patients-0. Accessed 9 June 2018.

  79. Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, Most MM, Fryburg DA. Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring). 2010;18(8):1646–51.

    Article  CAS  Google Scholar 

  80. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311(1):74–86. https://doi.org/10.1001/jama.2013.281361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. FDA CDER guidance for industry developing products for weight management. http://www.fda.gov/downloads/Drugs/Guidances/ucm071612.pdf. Accessed 6 June 2014.

  82. Petrie JR, Peters AL, Bergenstal RM, Holl RW, Fleming GA, Heinemann L. Improving the clinical value and utility of CGM systems: issues and recommendations. Diabetes Care. 2017;40:1614–21.

    Article  PubMed  Google Scholar 

  83. Ceriello A. Postprandial hyperglycemia and cardiovascular disease: is the HEART2D study the answer. Diabetes Care. 2009;32(3):521–2. https://doi.org/10.2337/dc08-2209. 1935-5548

  84. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881–5.

    Article  PubMed  Google Scholar 

  85. Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and postprandial hyperglycemia over a wide range of A1c levels before and after treatment intensification in type 2 diabetes. Diabetes Care. 2011;34(12):2508–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rosenson RS, Underberg JA. Systematic review: evaluating the effect of lipid-lowering therapy on lipoprotein and lipid values. Cardiovasc Drugs Ther. 2013;27:465–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. FDA guideline for industry – the extent of population exposure to access clinical safety for drugs intended for long-term treatment of non-life-threatening conditions (ICH-E1A March 1995). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073083.pdf. Accessed 6 June 2014.

  88. Cosentino G, Conrad AO, Uwaifo GI. Phentermine and topiramate for the management of obesity: a review. Drug Des Devel Ther. 2013;7:267–78.

    CAS  PubMed  Google Scholar 

  89. Ornellas T, Chavez B. Naltrexone SR/bupropion SR (Contrave): a new approach to weight loss in obese adults. P T. 2011;36:255–62.

    PubMed  PubMed Central  Google Scholar 

  90. FDA guidance biosimilars (updated: 11/14/2017). http://www.fda.gov/Drugs/DevelopmentApproval Process/HowDrugsareDevelopedandApproved/Approval Applications/TherapeuticBiologicApplications/Biosimilars/default.htm.

  91. FDA guidance Electronic Common Technical Document (eCTD) (updated: 03/20/2018). http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm153574.htm.

  92. FDA guidance – CDER data standards program (Updated: 03/30/2018). http://www.fda.gov/Drugs/Development ApprovalProcess/Forms SubmissionRequirements/ElectronicSubmissions/ucm249979.htm.

  93. Rodgers RJ, Tschöp MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Model Mech. 2012;5(5):621–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Colombo IO, Ferretti VV, Ferraris C, Trentani C, Vinai P, Villani S, Tagliabue A. Is drop-out from obesity treatment a predictable and preventable event? Nutr J. 2014;13:13.

    Article  PubMed  PubMed Central  Google Scholar 

  95. The prevention and treatment of missing data in clinical trials. National Research Council (U.S.). Panel on Handling Missing Data in Clinical Trials; National Research Council (U.S.). Committee on National Statistics; National Academies Press (U.S.). Washington, DC: National Academies Press; c2010. NLM ID: 101555711 [Book].

    Google Scholar 

  96. FDA guidance for industry – oversight of clinical investigations — a risk-based approach to monitoring. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm269919.pdf. Accessed 10 June 2014.

  97. Krentz AJ, Morrow L, Hompesch M. Developing new drugs for diabetes and cardiometabolic disorders: a changing paradigm. Drugs. 2012;72(13):1709–11.

    Article  PubMed  Google Scholar 

  98. Svensson A. Sponsors viewpoint – the T2DM regulatory guidances and implications for drug development presentation at development of type 2 diabetes mellitus drugs: state-of-the-art cardiovascular safety assessments. October 5–6, 2010. L’Enfant Plaza Hotel, Washington, DC. http://www.diahome.org/Tools/Content.aspx?type=eopdf&file=%2fproductfiles%2f23808%2f10035%2Epdf.

  99. Ratziu V, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference EASL. J Hepatol. 2010;53 j:372–84. http://www.journal-of-hepatology.eu/article/S0168-8278(10)00414-9/pdf.

    Article  Google Scholar 

  100. Ekstedt M, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes AASLD. Hepatology. 2006;44:865–73. http://onlinelibrary.wiley.com/doiDB17E9A321FEB71FC.f04t01.

    Article  CAS  PubMed  Google Scholar 

  101. Targher G, et al. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341–50. https://doi.org/10.1056/NEJMra0912063.. https://www.ncbi.nlm.nih.gov/pubmed/20879883.

    Article  CAS  PubMed  Google Scholar 

  102. Diehl A, et al. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377:2063–72. https://doi.org/10.1056/NEJMra1503519. http://www.nejm.org/doi/abstract/10.1056/NEJMra1503519.

    Article  CAS  PubMed  Google Scholar 

  103. Sanyal A, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis hepatology. Hepatology. 2011;54(1):344–53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014460/.

    Article  PubMed  Google Scholar 

  104. Division of Gastroenterology and Inborn Errors Products (DGIEP). https://www.fda.gov/AboutFDA/CentersOffices/Office ofMedicalProductsandTobacco/CDER/ucm252065.htm. Accessed 5 Apr 2018.

  105. The Fifth Liver Forum was held on November 10, 2016 in Boston, MA. http://www.hivforum.org/projects/liver-forum/liver-forum-meetings/1358-liver-forum-5.

  106. Regulatory considerations Lara Dimick-Santos, U.S. Food and Drug Administration. http://www.hivforum.org/storage/documents/2016/LF5/02_Dimick-Santos.pdf. Accessed 5 Apr 2018.

  107. Guidance for industry expedited programs for serious conditions – drugs and biologics. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. Accessed 5 Apr 2018.

  108. MELD score for end-stage liver disease. http://reference.medscape.com/calculator/meld-score-end-stage-liver-disease?src=ppc_google_rsla_ref&gclid=CIuS-9LV-9ACFRZMDQodOCQGMA. Accessed 5 Apr 2018.

  109. Brunt EM. Nonalcoholic fatty liver disease: pros and cons of histologic systems of evaluation. Lonardo A, Targher G, editors. Int J Mol Sci. 2016;17(1):97. https://doi.org/10.3390/ijms17010097.

  110. FDA’s plan to engage the public in the agency’s new effort to strengthen and modernize FDA’s regulatory framework. https://blogs.fda.gov/fdavoice/index.php/2017/09/fdas-plan-to-engage-the-public-in-the-agencys-new-effort-to-strengthen-and-modernize-fdas-regulatory-framework/. Accessed 5 Apr 2018.

  111. Guidance for industry: providing clinical evidence of effectiveness for human drug and biological products. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072008.pdf. Accessed 5 Apr 2018.

  112. Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment (REGENERATE). https://clinicaltrials.gov/ct2/show/NCT02548351. Accessed 15 Apr 2019.

  113. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377:2063–72.

    Article  CAS  PubMed  Google Scholar 

  114. Afdhal NH. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol. 2012;8(9):605–7.

    Google Scholar 

  115. 510 (k) Summary Apr 5 2013 Echosens’ FibroScan® System https://www.accessdata.fda.gov/cdrh_docs/pdf12/K123806.pdf. Accessed 5 Apr 2018.

  116. Guidance for industry: FDA staff qualification process for drug development tools https://www.fda.gov/downloads/Drugs/Guidance Compliance RegulatoryInformation/Guidances/UCM230597.pdf. Accessed 5 Apr 2018.

  117. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf. Accessed 5 Apr 2018.

  118. Sanyal A. Endpoints and clinical trial design for nonalcoholic steatohepattis NIH. Hepatology. 2011;54(1):344–53. https://doi.org/10.1002/hep.24376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014460/pdf/nihms289374.pdf.

  119. Guidance for industry: codevelopment of two or more new investigational drugs for use in combination. https://www.fda.gov/downloads/drugs/guidances/ucm236669.pdf. Assessed 5 Apr 2018.

  120. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–68. https://doi.org/10.1001/jama.2011.520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57–64. https://doi.org/10.3892/br.2012.18.

  122. Graham R, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60:1577–85.

    Article  Google Scholar 

  123. The voice of the patient: a series of reports from FDA’s patient-focused drug development initiative (Mar. 2018). https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm368342.htm.

  124. Public workshop on patient-focused drug development: guidance 1 – collecting comprehensive and representative input. https://www.fda.gov/Drugs/NewsEvents/ucm574725.htm.

  125. Patient-focused drug development: disease area meetings held in fiscal years 2013–2017. https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm347317.htm.

  126. FDA Commissioner Page. https://www.fda.gov/AboutFDA/CommissionersPage/default.htm.

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Acknowledgements

The authors thank Charles Alexander, Frances Mielach, Asoke Mukherjee, Lynn Schaich, Thomas Seoh, and Knut Zellerhoff for helpful suggestions and Brandon Jones for editorial assistance.

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  1. Kinexum, Harpers Ferry, WV, USA

    G. Alexander Fleming

  2. Global Liver Institute, Washington, DC, USA

    Brian E. Harvey

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  2. ProSciento, Chula Vista, CA, USA

    Christian Weyer

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    Marcus Hompesch

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Fleming, G.A., Harvey, B.E. (2019). Regulatory Considerations for Early Clinical Development of Drugs for Diabetes, Obesity, Nonalcoholic Steatohepatitis (NASH) and Other Cardiometabolic Disorders. In: Krentz, A., Weyer, C., Hompesch, M. (eds) Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-11748-1_19

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