Avandia nakaarten III

We doen nog maar eens weer een rondje Avandia. The saga continues. Op 13 en 14 juli gaan de Endocrinologic and Metabolic Drugs Advisory Committee and de Drug Safety and Risk Management Advisory Committee van de FDA nog eens goed naar Avandia/rosiglitazone kijken.

On both days, the committees will focus primarily on the cardiovascular safety of AVANDIA (rosiglitazone maleate)

Leuk. Want er ligt al weer een bommetje onder deze meeting…..

Update 03/07/2010: meer gepubliceerde studies

Waar de meeting over gaat leest u hier maar even. Behalve m.b.t. rosiglitazone wordt er ook een meta-analyse van het middel pioglitazone gepresenteerd. Niet denkbeeldig is dat men tot de conclusie komt dat het slikken van pioglitazones (Actos) minder belastend is voor de mensen met diabetes II dan het slikken van rosiglitazones (Avandia). Een vingerwijzing hiervoor kunnen we al bij een eerder BMJ onderzoek vinden.

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study [fulltext]

Er zijn veel meer meta-analyses losgelaten op de Thiazolidinediones. Voor meer info hierover beperk ik mij tot het geven van een review van deze door de American Heart Association en de American College of Cardiology Foundation. Vrij recent, volg de referenties.

Thiazolidinedione Drugs and Cardiovascular Risks, Sanjay Kaul, et al [fulltext]

More data are urgently needed to clarify the effects of all existing and future glucose-lowering agents, including thiazolidinediones, on IHD events. In the meantime, patients and clinicians will need to weigh the accepted benefits of improved glycemic control on risk for microvascular disease from glucose-lowering agents against the worrisome, inconclusive, or completely absent information about the effects of these agents on macrovascular disease.

De auteurs spreken hier, in nette gebruikelijke wetenschappelijke bewoordingen, over de noodzaak van meer gegevens m.b.t. het gebruik van deze middelen en hun relatie met hartfalen.
In een heads up trail m.b.t. Actos (pioglitazon) en Avandia (rosiglitazon) zouden deze vergeleken kunnen worden. Die trail is er. De zogenaamde TIDE-trail.

Er zijn meerdere redenen waarom de meeting van de FDA interessant is. Ik zei het al eerder. Deze discussie overstijgt de normale haarkloverij m.b.t. de onderzoeksuitkomsten. Vragen die beantwoord zullen moeten worden zijn prachtig op een rijtje gezet door Invivo-blog. Leest u daar maar even mee.

Vooral de vragen met betrekking tot het goedkeuren van medicijnen en het in de gaten houden van dezelfde medicijnen (post marketing) zijn eminent. Niet alleen m.b.t. deze geneesmiddelen. Mark Crypto’s words. Er gaan koppen rollen.

Bijvoorbeeld de TIDE-trail. Vele wetenschappers argumenteren dat deze onethisch zou zijn. Voorop onze vriend Nissen, die hierover al in gesprek schijnt te zijn geweest met Hamburger (hoofd FDA), die vind dat de studie moet worden afgeblazen. Iets waar uw Crypto in dit verband ook al eens ietwat cynisch over schreef. Even een lolletje:

Nissen on patient enrollment in TIDE: “500 patients in 14 months. To get 16,000 patients will take another 448 months.

Ik had u een bommetje beloofd. Komt die boem!!

David Graham, we kennen hem:

Rosiglitazone should be removed from the market,” one report, by Dr. David Graham and Dr. Kate Gelperin of the Food and Drug Administration, concludes. Both authors recommended that Avandia be withdrawn.

heeft een nieuwe nog ongepubliceerde studie verricht.

227571 patients with an average age of 74.4 years at entry were followed for up to 3 years after initiating a TZD during which time 7979 endpoint events were observed. For each endpoint, the hazard ratio (95% CI) was: AMI 1.06 (0.95-1.17); stroke 1.27 (1.12-1.44); HF 1.25 (1.16-1.34); death 1.13 (1.04-1.23); AMI or death 1.11 (1.03-1.18); AMI, stroke, or death 1.14 (1.07-1.21); and AMI, stroke, HF, or death 1.17 (1.12-1.23). The attributable risk for the composite of AMI, stroke, HF, or death was 1.69 excess events per 100 person-years of treatment with rosiglitazone (95% CI 1.44-1.94). The corresponding NNH was 59 person years (95% CI 51-70), and the national estimate of excess events among US elderly from 1999-2009 was 48,032.

Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone: A retrospective observational cohort study, David J. Graham et al [fulltext]

Deze studie heeft twee beperkingen. Als eerste is het nog niet gepubliceerd en daarom ook niet ‘peer reviewd’. Ten tweede is het een retrospectieve studie en dus ‘beperkt’ t.o.v. een RCT. Toch is het wel even ‘leuk’ om te kijken naar de Number need to harm. Graham stelt deze op 1 op 59 personyears.

Pakken we er eens tabelletje van de GIP databank bij:

You do the math.

Dat rekenen hebben ze trouwens bij onze oosterburen al gedaan.

Glinide und Glitazone zur Behandlung des Diabetes mellitus Typ 2 können künftig nur noch in medizinisch begründeten Einzelfällen zu Lasten der Gesetzlichen Krankenversicherung (GKV) verordnet werden […] Wir sind der Auffassung, dass Patienten sowohl vor nutzlosen als auch besonders vor schädlichen Therapien geschützt werden müssen

G-BA schließt Glinide und Glitazone zur Diabetes-Therapie von der Verordnungsfähigkeit zu Lasten der GKV aus [voor de pers]
Hier de hele handel.

We wachten het congres even af. Daarna kunnen de ambtenaren van Klink en het CvZ er misschien als de donder voor zorgen dat al die Glaxopennetjes (en/of Tenaka-schrijfmateriaal) bij onze voorschrijvers is de zak gehouden kunnen worden. Dat scheelt al weer een beetje in de eigen bijdrage, rollators, vullingen voor onze jongeren en hartcomplicaties voor onze ouwetjes met diabetes II.

Update:

Inmiddels is de besproken studie van Graham gepubliceerd.

Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone. Graham DJ et al., JAMA. 28 juni 2010;304(4). [fulltext]

Ook Nissen publiceerde een update voor zijn meta-analyse:

Rosiglitazone Revisited: An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality, Nissen SE, Wolski K. Arch Intern Med. Online gepubliceerd 28 juni 2010; 170. [fulltext]

Michaël Laurent van de Nederlandstalige journalclub (zie feed) besluit zijn bespreking hieromtrent met:

Rosiglitazon heeft geen plaats meer in de behandeling van type 2 diabetes.

En zo is het maar net.

18 Responses to Avandia nakaarten III

  1. Artikel ge-update met nieuw gepubliceerde studies.

  2. JennyJo zegt:

    Nou, ben benieuwd wat daar allemaal uit gaat komen.

  3. wilmamazone zegt:

    http://www.nytimes.com/2010/07/10/health/10diabetes.html?_r=1&partner=rss&emc=rss

    Caustic Government Report Deals Blow to Diabetes Drug
    Published: July 9, 2010

    A federal drug official on Friday dealt a severe blow to the popular diabetes drug Avandia, issuing a scathing review of a major clinical trial that its manufacturer has been using to argue that the drug was safe.

    The reviewer, Dr. Thomas Marciniak of the……….

    Reuters

    EU and U.S. weigh fate of Glaxo’s Avandia

    GlaxoSmithKline Plc’s diabetes pill Avandia came under intense scrutiny on both sides of the Atlantic on Friday, leaving the drug’s future uncertain as its maker battles a wave of lawsuits.

  4. @ Wilma:

    OMG!

    Artikel onderweg.

  5. wilmamazone zegt:

    Reuters

    High-stakes U.S. vote nears on Glaxo diabetes drug

    The fate of a GlaxoSmithKline Plc diabetes drug may become clearer on Wednesday when U.S. advisers vote on whether the widely used pill carries too much heart risk to stay on the market.

    The high-stakes decision by a panel of outside experts is designed to help the Food and Drug Administration settle a three-year safety dispute over Avandia.

    Views on Avandia’s risks are mixed within the FDA. Opinions also could be split within the 33-member panel of scientific experts after hearing hours of sharply conflicting data on Tuesday on whether Avandia causes heart attacks.

    Avandia’s U.S. sales were just 1.5 percent of Glaxo’s 2009 revenues, but……..

  6. Volare zegt:

    http://www.msnbc.msn.com/id/38235484/ns/health
    Analysis: Negative Avandia vote may bring new GSK legal woes

    A U.S. Food and Drug Administration advisory panel weighing evidence of heart risks with Avandia will recommend whether the drug should be removed from the market, one of five options that include restricting its use or keeping the drug on the market without a heart-attack warning.

    Safety concerns over heart risks have engulfed Avandia since 2007, leading to a steep sales decline for the company’s one-time second-biggest-selling drug and precipitating a flood of lawsuits.

    Glaxo appears to be trying to move past the litigation. Bloomberg News, citing unnamed sources, reported on Tuesday that Glaxo has agreed to pay about $460 million to resolve about 10,000 of an estimated 13,000 lawsuits. A company spokeswoman declined to comment on the report.

    The amount tallies with estimates from some Wall Street analysts that the company will ultimately pay less than $1 billion related to the litigation and that it is already adequately reserved.

    But a vote by the FDA advisers to pull the drug could raise new problems, including possibly another rash of lawsuits against the company, plaintiffs attorneys say. Such an event could restart the clock that began ticking in 2007 that would allow more Avandia users to sue the company.

  7. wilmamazone zegt:

    Reuters

    U.S. advisers say keep Glaxo’s Avandia on the market

    GlaxoSmithKline Plc’s diabetes drug Avandia should be allowed to stay on the market but with additional warnings, U.S. health advisers recommended on Wednesday, easing a threat of further costly litigation that could have followed a ban.

    A majority of the 33-member panel of outside experts found data raised concerns about heart attacks associated with the widely used pill, but not enough to warrant its withdrawal from the market.

    The Food and Drug Administration will make the final decision in the coming months and the agency usually follows recommendations from its advisory committees.

    But some opponents of the drug said……………

    update:
    NY-Times

    F.D.A. Panel Votes to Restrict Avandia

    A federal medical advisory panel recommended Wednesday that Avandia, a controversial diabetes drug, should either be withdrawn from the market or have sales severely restricted because it increases the risks of heart attacks.

    The panel’s votes, taken after two days of intensive scientific discussions, were a blow to GlaxoSmithKline, which makes Avandia. The company argued that Avandia is a safe and needed option in treating diabetes.

    But panel members voiced great skepticism about the company’s trustworthiness after questions were raised about its clinical trials. And internal company documents showed that the company for years kept crucial safety information about Avandia from the public.

    The panel took six votes on a variety of issues, but its most important came near the end of the meeting when asked what the Food and Drug Administration should do. Of the panel’s 33 members, 12 voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged. One member abstained, and no one voted for a final option, to weaken the label’s present heart warnings.

    Dr. Janet Woodcock, director of the drug center at the F.D.A., said that the agency took the panel’s advice seriously and that it would consider its regulatory options.

    The F.D.A. often takes the advice…………………….

    (dikgedrukt door mij)

  8. Volare zegt:

    http://money.cnn.com/2010/07/13/news/companies/avandia_fda_panel.fortune/index.htm
    What the Avandia ruling means for Big Pharma

    From an investing point of view, you’re thinking ‘Hey my drug’s approved, in eight years is it going to be pulled off the market?'” says Les Funtleyder, a health-care analyst at industrial trading firm Miller Tabak + Co. Other pharma companies that make blockbuster diabetes drugs include Takeda (TKPHF), Novo Nordisk (NVO), and Eli Lilly (LLY, Fortune 500).

    If Avandia stays on the market, the FDA will have to outline the protocol for keeping a controversial diabetes drug on the shelves. No one is questioning whether Avandia increases a patient’s risk of heart disease — it does. The question is whether it increases that risk more than Actos, another drug in the same class. If not, the FDA will have to decide if it’s worth it to leave Avandia on the market if there’s even a question of safety

    It’s more difficult now to yank an approved drug than to reject a drug for approval. The FDA needs to improve its system for monitoring drugs that have already hit the market, says Funtleyder. If that happens, drug companies and investors will need to prepare for more post-market scrutiny.

  9. wilmamazone zegt:

    Vers van de pers:

    http://www.nytimes.com/2010/07/16/business/global/16avandia.html?_r=1&partner=rss&emc=rss

    Glaxo Plans $2.36 Billion Charge for Legal Issues

    GlaxoSmithKline, the British pharmaceutical company, said Thursday that it would take a second-quarter charge of $2.36 billion related to legal cases involving its drugs, Avandia and Paxil.

    The company, based in Brentford, England, made the announcement a day after an American medical advisory panel recommended that Avandia, a controversial diabetes drug, should either be withdrawn from the market or have sales severely restricted because it increases the risks of heart attacks.

    The company said that……….

  10. Volare zegt:

    Misschien staat dit al ergens, dan nog maar een keer om aan te geven hoe men te werk gaat…
    http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1&ref=policy

    In the fall of 1999, the drug giant SmithKline Beecham secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda.
    Avandia’s success was crucial to SmithKline, whose labs were otherwise all but barren of new products. But the study’s results, completed that same year, were disastrous. Not only was Avandia no better than Actos, but the study also provided clear signs that it was riskier to the heart.

    But instead of publishing the results, the company spent the next 11 years trying to cover them up, according to documents recently obtained by The New York Times. The company did not post the results on its Web site or submit them to federal drug regulators, as is required in most cases by law.

  11. volare zegt:

    http://triangle.bizjournals.com/triangle/stories/2010/07/19/daily18.html
    Report: Avandia panelist paid by GSK

    One of the three panelists who recommended that the U.S. Food and Drug Administration allow GlaxoSmithKline to continue marketing Avandia with no further restrictions is a paid speaker for the drug company, reports The Wall Street Journal.
    The revelations about Capuzzi’s speaking deal come as the National Institutes of Health, the primary backer for medical research in the U.S., works to strengthen its ethics and conflict of interest policies to prevent medical researchers who are paid to speak by drug companies from lending their expertise in research studies. The NIH and FDA operate under different guidelines.

  12. volare zegt:

    Een filmpje waarin eigenlijk heel helder naar voren komt waarom de FDA dit middel niet van de markt haalt.

  13. JennyJo zegt:

    Science-Based Medicine van vandaag over Avandia:
    http://www.sciencebasedmedicine.org/?p=6476#more-6476

  14. Ik had het al gelezen Jenny. Mooie samenvatting. Ander onderzoek in BMJ is ook wel aardig om te lezen over deze zaak:

    http://www.bmj.com/cgi/content/full/340/mar18_1/c1344

    en hier in het Nederlands

    http://gebu.artsennet.nl/Archief/Tijdschriftartikel/Rosiglitazon-hoe-de-interpretatie-van-hetzelfde-bewijs-leidt-tot-sterk-contrasterende-opstellingen.htm

    Ik kom gewoon niet toe aan een update. De EMA is ook aan het delibreren of ze de richtlijnen gaan aanpassen las ik laatst. Even geen link

  15. JennyJo zegt:

    Ja, ik vond het een heel verhelderend stuk in SBM.

  16. Federal drug regulators ordered GlaxoSmithKline to send a letter to crucial doctors describing a hearing in July where an expert advisory panel discussed the risks of Avandia, the company’s controversial diabetes medicine. But a federal official and some members of the panel now say the company’s letter is misleading and could endanger patients.

    http://www.nytimes.com/2010/08/20/health/policy/20fda.html

  17. The Committee for Medicinal Products for Human Use (CHMP) is meeting on Wednesday 8 September to discuss the ongoing benefit-risk review of the rosiglitazone-containing medicines Avandia, Avandamet and Avaglim.

    Hierrr.

  18. Pingback: Avandia (Rosiglitazon), dood en doek « Cryptocheilus Weblog

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