Intraindividual Comparisons to Determine Comparative Effectiveness: Their Relevance for G-BA’s Health Technology Assessments

Published:February 17, 2021DOI:



      Health technology assessments (HTA) rely on head-to-head comparisons. We searched for intraindividual comparisons (IIC) qualifying as head-to-head design to develop comparative evidence.


      Gemeinsamer Bundesausschuss (G-BA) appraisals between January 2011 and April 2020 were reviewed for inclusion of IIC. Identified IIC were grouped according to disease characteristics into nonprogressive, progressive, irregular, or symmetrical conditions. Evaluation of IIC by Institut für Qualität und Wirschaftlichkeit im Gesundheitswesen (IQWIG) and acceptance of IIC by G-BA were determined, and criteria for the usage and quality of IIC were developed.


      A total of 483 appraisals finalized between January 2011 and April 2020 were reviewed. Eleven appraisals included IIC: nonacog beta (hemophilia B), turoctocog alpha (hemophilia A), emicizumab (2 appraisals: hemophilia A), pasireotide (unresectable pituitary tumor), lomitapid (homozygous familial hypercholesterolemia), glycerol phenylbutyrate (2 appraisals: urea cycle disorders), asfotase alfa (hypophosphatasia), lumacaftor (cystic fibrosis), and larotrectinib (NTRK+ solid tumors). All those appraisals related to rare genetic conditions with hemophilia and its bleeding rate are considered mainly a nonprogressive condition. All the other diseases show progressive disease characteristics. None of the identified IIC has been accepted by G-BA. Inconsistencies of before/after study design, lack of clarity on treatments prior to the switch, and different time intervals were among the most commonly cited methodological concerns.


      IICs provide a rare opportunity to determine comparative effectiveness in distinct clinical settings that are not suitable or difficult to randomize into parallel groups. While manufacturers and researchers should aim for highest methodological standards when running an IIC, HTA bodies should accept IIC in distinct settings when determining relative effectiveness.


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        • Altman D.G.
        • Bland J.M.
        Treatment allocation in controlled trials: why randomise?.
        BMJ. 1999; 318: 1209
        • Park M.
        • Chung Y.E.
        • Lee H.S.
        • et al.
        Intraindividual comparison of diagnostic performance in patients with hepatic metastasis of full-dose standard and half-dose iterative reconstructions with dual-source abdominal computed tomography.
        Invest Radiol. 2014; 49: 195-200
      1. Yim JH, Kim YK, Min JH, Lee J, Kang TW, Lee SJ. Diagnosis of recurrent HCC: intraindividual comparison of gedoxetic acid MRI and extracellular contrast-enhanced MRI.

        • Schley G.
        • Köberle C.
        • Manuilova E.
        • et al.
        Comparative analysis of diagnostic and predictive performance of novel renal biomarkes in plasma and urine of acute kidney injury patients.
        Intensive Care Med Experiment. 2015; 3: A258
        • Tzelikis P.F.
        • Morato C.S.
        • Neves N.T.
        • Hida W.T.
        • Alves M.R.
        Intraindividual comparison of nepafenac 0.3% for the prevention of macular edema after phacoemulsification.
        J Cataract Refract Surg. 2018; 44: 440-446
        • Gonnermann J.
        • Bertelmann E.
        • Pahlitzsch M.
        • Maier-Wenzel A.B.
        • Torun N.
        • Klarmann M.K.
        Contralateral eye comparison study in MICS & MIGD: Trabectome vs iStent inject.
        Graefes Arch Clin Exp Opthalmol. 2017; 255: 359-365
        • Augustin M.
        • Maier K.
        • Sommer B.
        • Sattler G.
        • Herberger K.
        Double-blind, randomized, intraindividual comparison study of the efficacy of prilocaine and lidocaine in tumescent local anesthesia.
        Dermatology. 2010; 221: 248-252
        • Lecompte F.
        • Vignion-Dewalle A.S.
        • Vicentini C.
        • et al.
        Evaluating the noninferiority of a new photodynamic therapy (Flexitheralight) compared with conventional treatment for actinic keratosis: protocol for a phase 2 study.
        JMIR Res Protoc. 2019; 26
        • Vrani F.
        • Sotiriou E.
        • Lazaridou E.
        • et al.
        Short incubation fractional CO2 laser-assisted photodynamic therapy vs. conventional photodynamic therapy in field-cancerized skin: 12-months follow-up results of a randomized intraindividual comparison study.
        J Eur Acad Dermatol Venereol. 2019; 33: 79-83
        • Dirschka T.
        • Ekanayake-Bohlig S.
        • Dominicus R.
        • et al.
        A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis.
        J Eur Acad Dermatol Venerol. 2019; 33: 288-297
        • Matowe L.K.
        • Leister C.A.
        • Crivera C.
        • Korth-Bradley J.M.
        Interrupted time series analysis in clinical research.
        Ann Pharmacother. 2003; 37: 1110-1116
        • Young G.
        • Liesner R.
        • Chang T.
        • et al.
        A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.
        Blood. 2019; 12: 2127-2138
      2. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Emicizumab. 2018.
      3. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Emicizumab (neues Anwendungsgebiet). 2019.
      4. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Turoctocog alfa pegol. 2020.
      5. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Nonacog beta pegol. 2018.
      6. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Lomitapid. 2015.
      7. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Glycerol phenylbutyrate. 2018.
      8. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Glycerol phenylbutyrate (neues Anwendungsgebiet.
      9. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Asfotase alfa. 2016.
      10. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Lumacaftor/ Ivacaftor. 2021.
      11. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Pasireotid. 2012.
      12. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Larotrectinib" before the the year 2020.
        • Risal A.
        • Carpenter S.L.
        Hemophilia A and B: an overview: hospital physician.
        Hematology/Oncology. 2017; 12: 15-31
        • Cuchel M.
        • Bruckert E.
        • Ginsberg
        • et al.
        Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society.
        Eur Heart J. 2014; 35: 2146-2157
        • Mornet E.
        Orphanet J Rare Dis. 2007; 2: 40
        • Mew N.A.
        • Simpson K.L.
        • Gropman A.L.
        • Lanpher B.C.
        • Chapman K.A.
        • Summar M.K.
        Urea Cycle Disorders Overview. GeneReviews.
        University of Washington, Seattle, Seattle (WA)2003
        • Goetz D.
        • Ren C.L.
        Review of cystic fibrosis.
        Pediatr Ann. 2019; 48: e154-e161
        • Nieman L.K.
        • Ilias I.
        Evaluation and treatment of Cushing’s syndrome.
        Am J Med. 2005; 118: 1340-1346
        • Vaishnavi A.
        • Le A.T.
        • Doeble R.C.
        TRKing down an old oncogene in a new era of targeted therapy.
        Cancer Discov. 2015; 5: 25-34
        • Oldenburg J.
        • Mahlangu J.N.
        • Kim B.
        • et al.
        Emicizumab prophylaxis in hemophilia A with inhibitors.
        NEJM. 2017; 377: 809-818
        • Mahlangu J.
        • Oldenburg J.
        • Paz-Priel I.
        • et al.
        Emicizumab prophylaxis in patients who have hemophilia A without inhibitors.
        NEJM. 2018; 379: 811-822
        • Haendel M.A.
        • Chute C.G.
        • Robinson P.N.
        Classification, ontology, and precision medicine.
        NEJM. 2018; 379: 1452-1462
        • IQWiG
        General methods; draft version 6.0.
      13. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Aflibercept. 2015.
      14. Gemeinsamer Bundesausschuss. Nutzenbewertungsverfahren zum Wirkstoff Aflibercept (neues Anwendungsgebiet). 2015.
        • Werner S.
        • Lechterbeck L.
        • Rasch A.
        • Merkesdal S.
        • Ruof J.
        Analysis of acceptance rate and rationales for rejection of indirect comparisons in IQWIG’s benefit assessments.
        Gesundh ökon Qual Manag. 2020; 25: 24-36
        • Wolff-Holz E.
        • Tiitso K.
        • Vleminchx C.
        • Weise M.
        Evolution of the EU biosimilar framework: past and future.
        BioDrugs. 2019; 33: 621-634
        • European Medicines Agency
        Assessment Report Hemlibra.
        • Yeh R.W.
        • Valsdottir L.R.
        • Yeh M.W.
        • et al.
        Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial.
        BMJ. 2018; 363: k5094