Pharmaceutical Medicine

, Volume 25, Issue 5, pp 285–291 | Cite as

Diabetes Drugs

Historical Regulatory Decisions Over the Past 17 Years
Current Opinion


Diabetes mellitus is a common chronic disease that is already pandemic, and hyperglycaemia plays a key role in the development of diabetes complications. In the last 15–20 years, we have witnessed a dramatic improvement of the ‘armamentarium’ developed by the pharmaceutical industry for treating diabetes. The objective of this review is to examine cases of relevant differences for these compounds in terms of approval, rejections, withdrawals and different labelling, between the US FDA and the European Medicines Agency (EMA) that have occurred since 1994, which was the date of the US approval of metformin. Cited examples include troglitazone, vildagliptin, liraglutide and the class of thiazolidinediones (TZDs) or ‘glitazones’. We looked at the labelling of TZDs and the different evaluative approaches for rosiglitazone performed by the FDA and EMA last year. The latest assessment on pioglitazone from both agencies is also included in this review.

It is difficult to understand the reasoning behind different decisions in these two regions. They might relate to the approval itself, likely due to a different benefit/risk assessment approach, or to the use of different guidances or guidelines. Differences in timing are also notable between the regions, even when licensing applications are submitted at the same time in both the US and Europe. It is easy to understand the need for a prolonged assessment time for the approval of a drug when more data are required by a regulatory agency (e.g. specific race-related findings from phase I studies or safety data in a specific target population, such as the elderly); however, many delays are not related to such requests. In addition, we looked at the timing of withdrawals of some new diabetes medicines, which also sometimes vary between regions.

These different assessments have a negative impact on patients with diabetes, in terms of finding their own medications if they travel or live abroad, understanding their use and ultimately feeling reassured by a worldwide consistent safety profile. Regulatory agencies should be aligned in their requirements to clearly guide manufacturers in the clinical development of future innovative medicines in order to improve the treatment of diseases such as diabetes that present on a very large and costly scale and are growing in prevalence. We would welcome in the new millennium, the harmonization of criteria for the assessment of experimental antidiabetic therapies and the timing of approvals and withdrawals, as well as a uniformed labelling of diabetes drugs from the FDA, EMA and from any other regulatory agency.


Metformin Bladder Cancer Rosiglitazone Pioglitazone Liraglutide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No funding was provided for the writing of this review. Dr Domenico Merante is an employee of Daiichi Sankyo. Professor Antonio Ceriello had no conflicts of interest to declare that are directly relevant to the content of this review.


  1. 1.
    Center Watch. FDA approved drugs for endocrinology [online]. Available from URL: [Accessed 2011 Jun 15]
  2. 2.
    Nathan DM. Finding new treatments for diabetes: how many, how fast … how good. N Engl J Med 2007; 356 (5): 437–43PubMedCrossRefGoogle Scholar
  3. 3.
    Diabesity Drugs. Your online resource for obesity and non-insulin type 2 diabetes drugs [online]. Available from URL: [Accessed 2011 Jun 15]
  4. 4.
    European Medicine Agency. EMA latest news index [online]. Available from URL: [Accessed 2011 Jun 15]
  5. 5.
    US Food and Drug Administration [online]. Available from URL: [Accessed 2011 Jun 15]
  6. 6.
    UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65CrossRefGoogle Scholar
  7. 7.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2467–71Google Scholar
  8. 8.
    Guidance for Industry. Diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes [online]. Available from URL: [Accessed 2011 Mar 10]
  9. 9.
    The European Agency for the Evaluation of Medicinal Products. Note for guidance for clinical investigation of medicinal products in the treatment of diabetes mellitus. 2002 May 30: CPMP/EWP/1080/00 [online]. Available from URL: [Accessed 2011 Jun 15]Google Scholar
  10. 10.
    Committee for Medicinal Products for HumanUse. Concept paper on the need for revision of the note for guidance on clinical investigation on medicinal products in the treatment of diabetes mellitus [online]. Available from URL: [Accessed 2011 Jun 15]
  11. 11.
    European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus: draft. 2010 Jan 20 — CPMP/EWP/1080/00 Rev. 1 [online]. Available from URL: [Accessed 2011 Jun 15]
  12. 12.
    Kolata GB. The phenformin ban: is the drug an imminent hazard? Science 1979; 203: 1094–6PubMedCrossRefGoogle Scholar
  13. 13.
    Kumar A, Nugent K, Kalakunja A, et al. Severe acidosis in a patient with type 2 diabetes mellitus, hypertension, and renal failure. Chest 2003; 123: 1726–9PubMedCrossRefGoogle Scholar
  14. 14.
    Mariano F, Benzi L, Cecchetti P, et al. Efficacy of continuous venous venous hemofiltration (CVVH) in treatment of severe phenformin-induced lactic acidosis. Nephrol Dial Transplant 1998; 13: 1012–5PubMedCrossRefGoogle Scholar
  15. 15.
    Bailey CJ, Campbell IA, Chan JCN, et al, editors. Metformin: the gold standard: a scientific handbook. Chichester: J Wiley & Sons, Ltd, 2007Google Scholar
  16. 16.
    Misbin RI. Lessons from the Avandia controversy. Diabetes Care 2007 Dec; 30 (12): 3141–4PubMedCrossRefGoogle Scholar
  17. 17.
    WHO Drug Information. Regulatory matters — Vol. 13, No 2, 1999 [online]. Available from URL: [Accessed 2011 Jul 25]
  18. 18.
    ICH. History and future of ICH [online]. Available from URL: [Accessed 2011 Jun 15]
  19. 19.
    US Food and Drug Administration. Information for healthcare professionals rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) [online]. Available from URL: [Accessed 2011 Jun 16]
  20. 20.
    Dormandy JA, Charbonnel B, Eckland DJ, et al., PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro- Vascular Events): a randomised controlled trial. Lancet 2005; 366 (9493): 1279–89PubMedCrossRefGoogle Scholar
  21. 21.
    Woodcock J, Sharfstein JM, Hamburg M. Regulatory action on rosiglitazone by theU.S. Food and Drug Administration. N Engl J Med 2010; 363: 1489–91PubMedCrossRefGoogle Scholar
  22. 22.
    First World. Germany follows France in suspension of Takeda’s Actos [online]. Available from URL: [Accessed 2011 Jun 14]
  23. 23.
    European Medicines Agency. EMA recommends new contra-indications and warnings for pioglitazone to reduce small increase risk of bladder cancer. Press release 2011 Jul 21 [online]. Available from URL: [Accessed 2011 Jul 25]
  24. 24.
    European Medicines Agency. EMA updates on ongoing benefit/risk review of pioglitazone-containing medicines. Press release 2011 Jun 23 [online]. Available from URL: [Accessed 2011 Jun 29]
  25. 25.
    US Food and Drug Administration. FDA actos (pioglitazone): ongoing safety review. Potential increased risk of bladder cancer [online]. Available from URL: [Accessed 2011 Jul 25]
  26. 26.
    Takeda Pharmaceutical Company Limited. Takeda receives new information on alogliptin (SYR-322) NDA. Press release 2009 Mar 6 [online]. Available from URL: [Accessed 2011 Jun 16]
  27. 27.
    Villhauer EB, Brinkman JA, Naderi GB, et al. 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003; 46 (13): 2774–89PubMedCrossRefGoogle Scholar
  28. 28.
    Hughes B. 2007 FDA drug approvals: a year of flux. Nature Reviews Drug Discovery 2008 Feb; 7: 107–9PubMedCrossRefGoogle Scholar
  29. 29.
    US Food and Drug Administration. FDA approves new treatment for type 2 diabetes [online]. Available from URL: [Accessed 2011 Jun 15]
  30. 30.
    ADA & EASD 2009 guidelines for screening, diagnosing, and treating diabetes [online]. Available from URL: [Accessed 2011 Jun 15]
  31. 31.
    Nathan DM, Buse JB, Davidson MB, et al., American Diabetes Association; European Association for the Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009 Jan; 32 (1): 193–203PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Clinical DevelopmentDaiichi Sankyo Development LtdGerrards CrossUK
  2. 2.Insititut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  3. 3.Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadis (CIBERDEM)BarcelonaSpain

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