The Forum for Collaborative Research (The Forum – previously The Forum for Collaborative HIV Research(1)) contribution to resolving regulatory issues in HIV, HCV, NAFLD/NASH,TAVI and Rare Diseases includes consensus reports and reports of collaborative data analyses.
Issues in HIV drug development addressed by the Forum include the revision of clinical trial designs to adapt trials to evolving patient populations (with increasing levels of drug resistant HIV(2-4); re-thinking approaches for expanded access programs(5); recommendations on HIV screening and testing algorithms(6); consensus for endpoints for clinical trials to treat lipodystrophy(7); addressing drug class specific safety concerns for chemokine antagonists(8); appropriate use of observational databases derived information for assessing post-marketing safety signals(9), and specifically, cardiovascular events(10); international pharmacovigilance(11, 12); consensus on Risk Evaluation and Mitigation Strategies (REMS) for use of antiretrovirals in HIV-uninfected individuals to prevent HIV infection(13);and forging a feasible and pragmatic regulatory/development path for new PrEP interventions(14). Collaborative analyses addressed the standardization of HIV drug resistance testing and interpretation(15-19). The Forum has also highlighted the need for continued commitment and solidarity to advancing clinical research in Africa for infectious diseases, including HIV/AIDS (40).
In the area of HCV drug development, the Forum’s HCV Drug Development Advisory Group (HCV Forum) outputs include consensus on new clinical trial designs that adapt to the rapidly changing treatment landscape(20); guidance on HCV screening and testing algorithms(6); consensus and standardization of drug resistance information for inclusion in IND packages(21) and a comprehensive analysis of resistance-associated substitutions for Direct Acting Antivirals (DAAs)(22); recommendations for standardized nomenclature and definitions of treatment response(23); and a review and discussion which clarifies the definition of viral endpoints(24). We collaborated with FIND to develop a target product profile for point-of-care HCV diagnosis(25).
In the area of Transplantation Associated Virus Infections (TAVI), the TAVI Forum updated definitions to standardize clinical research for CMV(26, 27); reviewed the current state of drug development and regulatory issues(28); and performed a systematic review of the literature and meta-analysis concluding that CMV viral load is an appropriate surrogate end-point for CMV trials in organ transplant recipients(29).
In the area of HBV drug development, the HBV Forum published a review of stakeholder perspectives on needs and gaps in HBV drug development(30); a consensus paper on principles and best practices for development of combination therapy for chronic HBV infection(31) and recommendations for differentiating between drug induced liver injury associated flares vs. “therapeutic” flares(32).The HBV Forum’s Surrogate Endpoints Working Group completed and published a systematic review and meta-analysis documenting the association of HBsAg seroclearance and long-term clinical outcome(33).
In the area of NAFLD and NASH, the Liver Forum has evaluated case definitions from a regulatory science perspective and generated recommendations for case definitions to be used in NASH clinical trials(34); developed consensus recommendations to harmonize the collection of baseline data in NASH clinical trials(35); and reviewed available data on exploratory histologic, blood-based and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during post-marketing monitoring trials. Following the publication of the baseline case definition and baseline parameters paper, the Liver Forum evaluated how to define improvement in NASH(36); discussed the attribution of NASH as an etiology of cirrhosis for clinical trial eligibility(37); recommended a standardization for diet and exercise data in clinical trials of NAFLD-NASH(38); and discussed special considerations for drug development to treat NASH in pediatric populations (39).
In the area of Rare Diseases, the Rare Diseases Forum published a review of FDA regulatory approval decisions for drug and biologic products to improve the understanding of the use of external controls to support product development and approval, which will allow for continued use and broader application of innovative approaches to clinical trial design (41).
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REFERENCES
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2.Struble K, Murray J, Cheng B, Gegeny T, Miller V, Gulick R. Antiretroviral therapies for treatment-experienced patients: current status and research challenges. AIDS 2005;19:747-756.
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7.Snyder S, Cheng B, Miller V. Regulatory considerations for the treatment of lipodystrophy. A roundtable discussion amongst clinical investigators and representatives from industry, advocacy and government. Annals of the Forum for Collaborative Research 2004;7.
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21.Kwong AD, Najera I, Bechtel J, Bowden S, Fitzgibbon J, Harrington P, Kempf D, et al. Sequence and phenotypic analysis for resistance monitoring in hepatitis C virus drug development: recommendations from the HCV DRAG. Gastroenterology 2011;140:755-760.
22.Lontok E, Harrington P, Howe A, Kieffer T, Lennerstrand J, Lenz O, McPhee F, et al. Hepatitis C virus drug resistance-associated substitutions: State of the art summary. Hepatology 2015;62:1623-1632.
23.Wedemeyer H, Jensen DM, Godofsky E, Mani N, Pawlotsky JM, Miller V, Definitions/Nomenclature Working Group* of the Hcv DrAg utaotFfCHIVR. Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents. Hepatology 2012;56:2398-2403.
24.Lontok E, Mani N, Harrington PR, Miller V. Closing in on the target: sustained virologic response in hepatitis C virus genotype 1 infection response-guided therapy. Clin Infect Dis 2013;56:1466-1470.
25.Ivanova Reipold E, Easterbrook P, Trianni A, Panneer N, Krakower D, Ongarello S, Roberts T, et al. Optimising diagnosis of viraemic hepatitis C infection: the development of a target product profile. BMC Infect Dis 2017;17:707.
26.Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis 2017;64:87-91.
27.Chemaly RR, Chou S, EInsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, et al. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clinical Infectious Disease 2018;In press.
28.McIntosh M, Hauschild B, Miller V. Human cytomegalovirus and transplantation: drug development and regulatory issues. J Virus Erad 2016;2:143-148.
29.Natori Y, Alghamdi A, Tazari M, Miller V, Husain S, Komatsu T, Griffiths P, et al. Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis. Clin Infect Dis 2018;66:617-631.
30.Liu J, Goicochea P, BLock T, Brosgart CL, Donaldson EF, Lenz E, Lim SG, et al. Advancing the regulatory path on hepatitis B virus treatment and curative research: a stakeholders' consultation. Journal of Virus Eradication 2017;3:1-6.
31.Anderson RT, Lim SG, Mishra P, Josephson F, Donaldson E, Given B, Miller V. Challenges, Considerations, and Principles to Guide Trials of Combination Therapies for Chronic Hepatitis B Virus. Gastroenterology 2019;156:529-533 e524.
32.Fontana RJ, Avigan MI, Janssen HLA, Regev A, Mishra P, Gaggar A, Brown N, et al. Liver safety assessment in clinical trials of new agents for chronic hepatitis B. J Viral Hepat 2020;27:96-109.
33.Anderson RT, Choi HSJ, Lenz O, Peters MG, Janssen HLA, Misha P, Donaldson E, et al. Association between HBsAg seroclearance and long-term clinical outcome in chornic hepatitis B: a systematic review and meta-analysis. Clinical Gastro Hep 2020;In Press.
34.Siddiqui MS, Harrison SA, Abdelmalek MF, Anstee QM, Bedossa P, Castera L, Dimick-Santos L, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology 2018;67:2001-2012.
35.Patel YA, Imperial JC, Muir AJ, Anstee QM, DeBrota D, Dimick-Santos L, Filozof C, et al. Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum. Gastroenterology 2017;153:621-625 e627.
36.Cheung A, Neuschwander-Tetri BA, Kleiner DE, Schabel E, Rinella M, Harrison S, Ratziu V, et al. Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum. Hepatology 2019;70:1841-1855.
37.Noureddin M, Chan JL, Barradas K, Dimick-Santos L, Schabel E, Omokaro SO, Anania FA, et al. Attribution of nonacloholic steatohepatitis as an etiology of cirrhosis for clinical trials eligibility. Recommendations from the multi-stakeolder Liver Forum. Gastroenterology 2020;Accepted for Publication.
38.Glass O, Filozof C, Noureddin M, Berner-Hanssen M, Schabel E, Omokaro SO, Schattenberg JM, et al. Standardization of diet and exercise in clinical trials of NAFLD-NASH. Recommendations from the Liver Forum. J Hepatol 2020;Accepted for publication.
39.Vos MB, Dimick-Santos L, Mehta R, Omokaro SO, Taminiau J, Schabel E, Kleiner DE, et al. Factors to Consider in Development of Drugs for Pediatric Nonalcoholic Fatty Liver Disease. Gastroenterology 2019;157:1448-1456 e1441.
40. Mbichila T, Kumwenda G, Yola N, et al. Commentary title: COVID-19 research, Africa, and global health. J Virus Erad. 2021;7(1):100030.
41. Jahanshahi M, Gregg K, Davis G, et al. The Use of External Controls in FDA Regulatory Decision Making [published online ahead of print, 2021 May 20]. Ther Innov Regul Sci. 2021;10.1007/s43441-021-00302-y.
