Reconsideration of the balance between efficacy and side-effects of newly introduced drugs shows that for most of them, the assessment given in 2006 has remained unchanged or has to be downgraded. All the money and efforts that went into their development and production have not benefited patients at all.
This new survey comes to the same conclusion as the previous annual surveys, namely that at the time when a new drug is introduced, relatively little is known about its efficacy and side-effects, so that caution needs to be exercised when prescribing such new drugs. Ten years after their introduction, remarkably little long-term research has been conducted into these drugs. Nevertheless, the indications for four of these drugs have been extended, based on very limited research. The relevant authorities can rightly be reproached for not requiring such research as a precondition for registration. For a number of drugs, some evidence has emerged for (albeit rare) serious side-effects, and these drugs should be avoided at least for relatively innocent and non-life-threatening conditions. Another striking aspect is that EMA has not decided to withdraw the market authorisation for strontium ranelate, in view of its serious side-effects.
It is also striking that there have been relatively few publications about side-effects. For some drugs, the number of reports to the Dutch adverse effects reporting centre Lareb is also low. It is not just the pharmaceutical industry and the reporting centres which are to blame for this, however. Care providers could play a far more proactive role in this respect, by actively following patients using new drugs and reporting any side-effects to reporting centres like Lareb (www.lareb.nl).
The number of drugs given market authorisation on the basis of a shortened and simplified registration procedure is expected to rise considerably over the next few years. In such procedures, the manufacturer is obliged to supplement the missing studies after the drug has already been admitted to the market. It is to be hoped that the trend towards diminishing post-marketing research reported in this Gebu article will be reversed by this obligation. If not, the percentage of drugs which have been authorised without sufficient data on efficacy and side-effects will only rise. The exposure of more and more patients to such drugs as guinea pigs is an undesirable development.
Four of the six drugs discussed in the article are mentioned in Dutch guidelines. It is good to see that none of these are being recommended as the treatment of first choice, as the authors of these guidelines rightly concluded that their benefits do not outweigh the disadvantages. It may be concluded that none of the new drugs discussed in Gebu in 2006 has since then proved to offer added value. It is high time to revise the current views on drug development, drastically reducing the role of the pharmaceutical industry and expanding the role of universities and university-affiliated research centres. Public institutions ought to take the lead, so that the influence of market forces can be reduced.
Unfortunately, we will have to wait another year to find a new drug that has proved its value after ten years.
- Productinformatie adapalene (Differin®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- Cunliffe WJ, Danby FW, Dunlap F, Gold MH, Gratton D, Greenspan A. Randomised, controlled trial of the efficacy and safety of adapalene gel 0.1% and tretinoin cream 0.05% in patients with acne vulgaris. Eur J Dermatol 2002; 12: 350-354.
- EMA starts review of retinoid medicines. EMA, 2016. Via: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Retinoids_31/Procedure_started/WC500209971.pdf.
- Smeets JG, Grooten SJ, Bruinsma M, Jaspar AHJ, Kertzman MG. NHG-Standaard ’Acne’ (Tweede herziening). Huisarts Wet 2007; 50: 259-268.
- Productinformatie atomoxetine (Strattera®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- Cheng JY, Chen RY, Ko JS, Ng EM. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis. Psychopharmacology 2007; 194: 197-209.
- Hanwella R, Senanayake M, Silva V de. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry 2011; 11: 176.
- Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, Wyk GW. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 2011; 15: 674-683.
- Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. J Am Acad Child Adolesc Psychiatry 2014; 53: 174-87.
- Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, et al. Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45: 919-927.
- Bangs ME, Wietecha LA, Wang S, Buchanan AS, Kelsey K. Meta-analysis of suicide-related behaviour or ideation in child, adolescent, and adult patients treated with atomoxetine. J Child Adolesc Pscyhopharmacol 2014; 24; 426-434.
- Cortese S, Panei P, Arcieri R, Germinario EAP, Capuano A, Margari L, et al. Safety of methylphenidate and atomoxetine in children with attention-deficit/hyperactivity disorder (ADHD): data from the Italian national ADHD registry. CNS Drugs 2015; 29: 865-877.
- Boyd I. Atomoxetine and dystonia in paediatric patients. WHO Pharmaceutical Newsletter 2015; no. 4: 20-23.
- GGZ-richtlijn ’ADHD bij kinderen en jeugdigen’, versie 1.0. Landelijke stuurgroep/Trimbos-instituut, 2005. Via: http://www.ggzrichtlijnen.nl/.
- Richtlijn ’ADHD bij volwassenen’, fase I. Nederlandse Vereniging voor Psychiatrie, 2015. Via: http://www.nvvp.net/.
- Productinformatie cargluminezuur (Carbaglu®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- Website Orphanet The portal for rare diseases and orphan drugs, 2016. Via: http://www.orpha.net/consor/cgi-bin/home.php?Lng=GB.
- De ziektes die de hielprik opspoort. Website RIVM, 2016. Via: http://www.rivm.nl/Onderwerpen/H/Hielprik/De_ziektes_die_de_hielprik_opspoort#z11.
- Informatie over methylmalonzuuracidemie. Website Volwassenen, kinderen en stofwisselingsziekten (VKS) 2016. Via: https://www.stofwisselingsziekten.nl/toon-ziekte/methylmalonacidurie__methylmalonyl_coa_mutase_/.
- Assessment report for paediatric studies submitted according to Article 46 of the Regulation (EC) No 1901/2006 - Carbaglu. Procedurenr. EMEA/H/C/000461/P46/033. EMA, Londen, 2016. Via: http://www.ema.europa.eu/.
- Valayannopoulos V, Baruteau J, Delgado MB, Cano A, Couce ML, Del Toro M, et al. Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study. Orphanet J Rare Dis 2016; 11: 32.
- GIP/Zorginstituut Nederland. Databank, via: www.gipdatabank.nl/.
- Productinformatie gammahydroxyboterzuur (Xyrem®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- The US Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002; 25: 42-49.
- Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005; 6: 415-421.
- Scrima L, Hartman PG, Johnson FH Jr, Thomas EE, Hiller FC. The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double blind study. Sleep 1990; 13: 479-490.
- Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G, Troost J. Gamma hydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 1993; 16: 216-220.
- Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev 2012; 16: 431-443.
- Alshaikh MK, Tricco AC, Tashkandi M, Mamdani M, Straus SE, BaHammam AS. Sodium oxybate for narcolepsy with cataplexy: systematic review and meta-analysis. J Clin Sleep Med 2012; 8: 451-458.
- Poli F, Ricotta L, Vandi S, Franceschini C, Pizza F, Palaia V, et al. Catathrenia under sodium oxybate in narcolepsy with cataplexy. Sleep Breath 2012; 16: 427-434.
- George CF, Feldman N, Inhaber N, Steininger TL, Grzeschik SM, Lai C, et al. A safety trial of sodium oxybate in patients with obstructive sleep apnea: Acute effects on sleep-disordered breathing. Sleep Med 2010; 11: 38-42.
- Productinformatie lanthaancarbonaat (Fosrenol®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R et al. Long-term efficacy and tolerability of lanthanum carbonate: results from a 3-year study. Nephron Clin Pract 2006; 102: c61-c71.
- Navaneethan SD, Palmer SC, Vecchio M, Craig JC, Elder GJ, Strippoli GF. Phosphate binders for preventing and treating bone disease in chronic kidney disease patients. Cochrane Database Syst Rev 2011: CD006023
- Zhang C, Wen J, Li Z, Fan J. Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol 2013; 14: 226.
- Habbous S, Przech S, Acedillo R, Sarma S, Garg AX, Martin J. The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis. Nephrol Dial Transplant 2016. pii: gfw312.
- Richtlijn ’Mineraal- en botstoornis’. Nederlandse Federatie voor Nefrologen 2010. Via: https://www.nefro.nl/richtlijnen/mineraal-en-botstoornis-2010.
- Productinformatie strontiumranelaat (Protelos®), via: www.cbg-meb.nl, Geneesmiddeleninformatiebank.
- Meunier PJ, Roux C, Ortolani S, Diaz-Curiel M, Compston J, Marquis P, et al. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int 2009; 20: 1663-1673.
- Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C et al. Strontium ranelate reduces the risk of nonvertebral fractures in post-menopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005; 90: 2816-2822.
- Kaufman JM, Audran M, Bianchi G, Braga V, Diaz-Curiel M, Francis RM, et al. Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men. J Clin Endocrinol Metab 2013; 98: 592-601.
- CHMP scientific conclusions and PRAC Assessment report of the Review under Article 20 of Regulation (EC) No 726/2004, Protelos and Osseor. Procedurenr. EMEA/H/A20/1371/C/000560/0039. EMA, Londen, 2014. Via: http://www.ema.europa.eu/.
- European Medicines Agency recommends that Protelos/Osseor remain available but with furtherrestrictions. EMA, Londen, 2014. Via: http://www.ema.europa.eu/.
- Anonymous. Strontium still authorised despite an unfavourable opinion of the European pharmacovigilance committee. Rev Prescrire 2014; 34: 743.
- Anonymous. Strontiumranelat (PROTELOS) - Arzneimittelbehörde EMA jahrelang untätig. A-T 2016; 47: 96-97.
- Richtlijn ’Osteoporose en Fractuurpreventie’, derde herziening (2011). Nederlandse Vereniging voor Reumatologie, Utrecht 2011.
*The literature refers to the Dutch text