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Monitoring Drug Safety in Rheumatoid Arthritis Prevention Trials

      Abstract

      This commentary discusses issues particular to drug safety monitoring in prevention trials. Although the general approach to safety assessment applies across all clinical trials, prevention trials pose special challenges given that the patient population is currently asymptomatic or experiencing only mild symptoms of the targeted disease. This sways the risk-benefit analysis balance toward minimal acceptable risk. Definition of the predisease state with validated biomarkers or other assessment tools is essential. The timing and required length of exposure to the disease intervention to produce an effect requires special methodologic considerations. In addition, prevention trials generally have a longer duration with higher dropout rates. As a result, there is an enhanced focus on lessening patient burden in regard to data collection and finding ways to minimize the safety signal to noise ratio to enable product causality assessment. To meet these challenges, clinical safety monitoring in prevention trials involves 3 essential steps: safety planning, systematic data collection and evaluation, and transparent communication of safety information. We discuss some of these issues using historical experience with primary prevention cardiovascular trials and then focus on unique issues surrounding patient populations at risk for rheumatoid arthritis.

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      References

        • Doan T.
        • Rao R.M.
        • Kracht K.
        • Pauff J.M.
        • Hendrickson B.
        Chapter 3: Product Safety Monitoring in Clinical Trials in Pharmacovigilance: A Practical Approach. 1st ed..
        in: Doan T. Renz C. Lievano F. Bhattacharya M. Scarazzini L. Elsevier, 2018 (eBook ISBN: 9780323581172(Paperback ISBN:9780323581165))
        • Colditz G.A.
        • Taylor P.R.
        Prevention trials: their place in how we understand the value of prevention strategies.
        Annu Rev Public Health. 2010; 31: 105-120
        • Deane K.D.
        • Striebich C.C.
        • Holers V.M.
        Editorial: prevention of rheumatoid arthritis: now is the time, but how to proceed?.
        Arthritis Rheumatol. 2017; 69: 873-877
        • VI C.W.G.
        Management of Safety Information from Clinical Trials. vol. 2005. 2005 (Geneva)
        • Darpo B.
        • Garnett C.
        • Benson C.T.
        • et al.
        Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.
        Am Heart J. 2014 Sep; 168 (Epub 2014 Jun 6. PubMed PMID: 25173536): 262-272https://doi.org/10.1016/j.ahj.2014.06.003
        • FDA
        U.S. FDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation.
        Drug Safety, July 2009 (2009)
        • Tovey M.G.
        • Lallemand C.
        Immunogenicity and other problems associated with the use of biopharmaceuticals.
        Ther Adv Drug Saf. 2011; 2: 113-128
        • Doran M.F.
        • Crowson C.S.
        • Pond G.R.
        • O'Fallon W.M.
        • Gabriel S.E.
        Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study.
        Arthritis Rheum. 2002 Sep; 46 (PubMed PMID: 12355475): 2287-2293
        • Radovanović-Dinić B.
        • Tešić-Rajković S.
        • Zivkovic V.
        • Grgov S.
        Clinical connection between rheumatoid arthritis and liver damage.
        Rheumatol Int. 2018 May; 38 (Epub 2018 Apr 7. Review. PubMed PMID: 29627896): 715-724https://doi.org/10.1007/s00296-018-4021-5
        • Simon T.A.
        • Thompson A.
        • Gandhi K.K.
        • Hochberg M.C.
        • Suissa S.
        Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis.
        Arthritis Res Ther. 2015 Aug 15; 17 (Erratum in: Arthritis Res Ther. 2016;18(1):100. PubMed PMID: 26271620; PubMed Central PMCID: PMC4536786): 212https://doi.org/10.1186/s13075-015-0728-9. Review
        • Mori S.
        • Yoshitama T.
        • Hirakata N.
        • Ueki Y.
        Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals.
        Clin Rheumatol. 2017 Dec; 36 (Epub 2017 Sep 7. PubMed PMID: 28884373; PubMed Central PMCID: PMC5681610): 2673-2682https://doi.org/10.1007/s10067-017-3804-5
        • England B.R.
        • Thiele G.M.
        • Anderson D.R.
        • Mikuls T.R.
        Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications.
        BMJ. 2018 Apr 23; 361 (Review. PubMed PMID: 29685876): k1036https://doi.org/10.1136/bmj.k1036
        • Schieir O.
        • Tosevski C.
        • Glazier R.H.
        • Hogg-Johnson S.
        • Badley E.M.
        Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis.
        Ann Rheum Dis. 2017 Aug; 76 (Epub 2017 Feb 20. Review. PubMed PMID: 28219882): 1396-1404https://doi.org/10.1136/annrheumdis-2016-210275
        • Robertson J.
        • Peters M.J.
        • McInnes I.B.
        • Sattar N.
        Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm.
        Nat Rev Rheumatol. 2013 Sep; 9 (Epub 2013 Jun 18. Review. PubMed PMID: 23774906): 513-523https://doi.org/10.1038/nrrheum.2013.91
        • Maradit-Kremers H.
        • Crowson C.S.
        • Nicola P.J.
        • Ballman K.V.
        • et al.
        Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study.
        Arthritis Rheum. 2005 Feb; 52 (Review. PubMed PMID: 15693010): 402-411
        • Barbarroja N.
        • Pérez-Sanchez C.
        • Ruiz-Limon P.
        • et al.
        Anticyclic citrullinated protein antibodies are implicated in the development of cardiovascular disease in rheumatoid arthritis.
        Arterioscler Thromb Vasc Biol. 2014 Dec; 34 (Epub 2014 Sep 25. PubMed PMID: 25256232): 2706-2716https://doi.org/10.1161/ATVBAHA.114.304475
        • López-Longo F.J.
        • Oliver-Miñarro D.
        • de la Torre I.
        • et al.
        Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis.
        Arthritis Rheum. 2009 Apr 15; 61 (PubMed PMID: 19333979): 419-424https://doi.org/10.1002/art.24390
        • EMA
        • Guideline on Data Monitoring Committees
        Committee for Medicinal Products for Human Use, 2005.
        June 2005
        • Bell M.L.
        • Kenward M.G.
        • Fairclough D.L.
        • Horton N.J.
        Differential dropout and bias in randomised controlled trials: when it matters and when it may not.
        BMJ. 2013 Jan 21; 346 (PubMed PMID: 23338004; PubMed Central PMCID: PMC4688419): e8668https://doi.org/10.1136/bmj.e8668
        • E2A I.E.W.G.
        Clinical Safety Data Management: Definitions and Standards for Expedited Reporting ICH Harmonized Tripartite Guideline.
        1994
        • Schubert C.
        • Desai M.
        • Patwardhan M.
        • Lievano F.
        • Islam S.S.
        • Chand D.H.
        • Bacher H.P.
        • Green S.P.
        • Shabbir A.
        • Fareed J.
        • Verghese M.
        Doan T. Renz C. Lievano F. Bhattacharya M. Scarazzini L. Chapter 4: Causality Assessment and Examples of Adverse Drug Reactions (Drug-Induced Liver Injury, Renal, Skin, and Major Adverse Cardiac Events). 1st ed. Elsevier, 2018 (eBook ISBN: 9780323581172(Paperback ISBN: 9780323581165))
        • Council for International Organizations of Medical Sciences (CIOMS) Working Groups III and IV
        Guidelines for Preparing Core Clinical-Safety Information on Drugs.
        (Geneva)2nd ed. 1999
        • Hill A.B.
        The environment and disease: association or causation?.
        Proc R Soc Med. 1965; 58: 295-300
        • Naranjo C.A.
        • Busto U.
        • Sellers E.M.
        • et al.
        A method for estimating the probability of adverse drug reactions.
        Clin Pharmacol Ther. 1981 Aug; 30 (PubMed PMID: 7249508): 239-245
        • Centre T.U.M.
        The Use of the WHO-UMC System for Standardised Casse Causality Assessment.
        2018
        • FDA
        U.S. FDA Guidance for Industry and Investigators. Safety Reporting Requirements for INDs and BA/BE Studies.
        December 2012
        • FDA
        U.S. FDA Informed Consent Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Draft Guidance.
        July 2014
        • Buse J.B.
        • Bigger J.T.
        • et al.
        • ACCORD Study Group
        Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods.
        Am J Cardiol. 2007 Jun 18; 99 (Epub 2007 Apr 16. PubMed PMID: 17599422): 21i-33i
        • Gerstein H.C.
        • Miller M.E.
        • et al.
        • Action to Control Cardiovascular Risk in Diabetes Study Group
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008 Jun 12; 358 (PubMed PMID: 18539917; PubMed Central PMCID: PMC4551392): 2545-2559https://doi.org/10.1056/NEJMoa0802743. Epub 2008 Jun 6
        • Bonds D.E.
        • Kurashige E.M.
        • Bergenstal R.
        • et al.
        Severe hypoglycemia monitoring and risk management procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
        Am J Cardiol. 2007 Jun 18; 99 (Epub 2007 Apr 17. PubMed PMID: 17599428): 80i-89i
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • et al.
        JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008 Nov 20; 359 (Epub 2008 Nov 9. PubMed PMID:18997196): 2195-2207https://doi.org/10.1056/NEJMoa0807646
        • Ridker P.M.
        The JUPITER trial: results, controversies, and implications for prevention.
        Circ Cardiovasc Qual Outcomes. 2009; 2: 279-285
        • Ridker P.M.
        • MacFadyen J.G.
        • Fonseca F.A.
        • et al.
        Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER).
        Circ Cardiovasc Qual Outcomes. 2009 Nov; 2 (Epub 2009 Sep 22. PubMed PMID: 20031900): 616-623https://doi.org/10.1161/CIRCOUTCOMES.109.848473
        • van Dongen H.
        • van Aken J.
        • Lard L.R.
        • et al.
        Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial.
        Arthritis Rheum. 2007 May; 56 (PubMed PMID: 17469099): 1424-1432
        • Burgers L.E.
        • Allaart C.F.
        • Huizinga T.W.J.
        • van der Helm-van Mil A.H.M.
        Brief Report: Clinical Trials Aiming to Prevent Rheumatoid Arthritis Cannot Detect Prevention Without Adequate Risk Stratification: A Trial of Methotrexate Versus Placebo in Undifferentiated Arthritis as an Example.
        Arthritis Rheumatol. 2017 May; 69 (Epub 2017 Mar 31. PubMed PMID:28217975): 926-931https://doi.org/10.1002/art.40062
      1. van Schaardenburg, D.I., Statins to prevent rheumatoid arthritis (STAPRA) prevention of rheumatoid arthritis by atorvastatin in seropositive arthralgia patients: a multicenter double-blind randomized placebo-controlled trial. Trial NL5036 (NTR5265).

        • Gerlag D.M.
        • Safy M.
        • Maijer K.I.
        • et al.
        Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study.
        Ann Rheum Dis. 2019 Feb; 78 (Epub 2018 Dec 1. PubMed PMID: 30504445; PubMed Central PMCID: PMC6352407): 179-185https://doi.org/10.1136/annrheumdis-2017-212763
        • Al-Laith M.I.
        Arthritis Prevention in the Pre-clinical Phase of RA with Abatacept (APIPPRA).
        2014 (ISRCTN No. 46017566)
      2. Deane, K.D., Holers, M, Striebich, C. Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis (StopRA). ClinicalTrials.gov identifier NCT02603146.

        • van der Helm A.I.
        Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis.
        Treat Earlier, 2015 (Trial NL4599 (NTR4853))