The FDA announced today that it would not remove rosiglitazone (Avandia) from the market but that it would impose severe new restrictions on its use. It also put on “full clinical hold” the controversial TIDE trial. The FDA is also requiring GSK to “commission an independent re-adjudication of the RECORD study.”

The new REMS will require documentation that risk information about the drug has been received by each patient taking rosiglitazone. For patients not already taking rosiglitazone documentation will be required demonstrating that the patient was unable to achieve glycemic control with other medications and has decided not to take pioglitazone for medical reasons.

Separately, the European Medicines Agency announced it was suspending marketing authorization for rosiglitazone. FDA commissioner Margaret Hamburg discussed the difference between the decisions of the two regulatory agencies, explaining that the two agencies did not disagree about the data but about the different roles and abilities of the agencies.

In her memo, FDA’s Janet Woodcock explained the decision to suspend TIDE in the context of re-adjudication of RECORD:

While both a majority of the Advisory Committee members and OND recommend continuation of TIDE, I do not believe it should proceed at this time, given the restrictions I have determined are necessary for rosiglitazone and the level of concern about its cardiovascular safety. In many cases, when a drug safety issue arises, conduct of a randomized trial is an appropriate step to resolve the question. However, the results of RECORD, which are currently in question, directly affect the ethics of conducting TIDE. I believe that re-adjudication of RECORD is the appropriate next step, with decisions on whether to conduct further studies or take additional regulatory actions to be based on the results of the re-adjudication and any other data that may become available in the interim. FDA is not rescinding the post-market requirement for the sponsor to study the safety of rosiglitazone compared to pioglitazone, if feasible and appropriate, but is stopping the current trial until all existing information is evaluated, including the data from RECORD, if possible.

Click here to read a New England Journal of Medicine perspective on rosiglitazone by the FDA’s Janet Woodcock, Joshua Sharfstein, and Margaret Hamburg.

Click here for links to the FDA documents.

Here is the FDA press release:

FDA significantly restricts access to the diabetes drug Avandia
Makes regulatory decisions on RECORD and TIDE trials

The U.S. Food and Drug Administration today announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.

“The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks,” said FDA Commissioner Margaret A. Hamburg, M.D. “We are seeking to strike the right balance to support clinical care.”

Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.

Avandia, manufactured by GlaxoSmithKline (GSK), is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus.

The FDA will require that GSK develop a restricted access program for Avandia under a risk evaluation and mitigation strategy, or REMS. Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of Avandia significantly.

“Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the company’s clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDA’s review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.

In addition, the agency halted the GSK’s clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs.

The FDA may take additional actions after the independent re-analysis of RECORD is completed.

For more information:

Avandia Update
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm226956.htm

Here is the EMA press release:

European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim

Anti-diabetes medication to be taken off the market

The European Medicines Agency today recommended the suspension of the marketing authorisations for the rosiglitazone-containing anti-diabetes medicines Avandia, Avandamet and Avaglim. These medicines will stop being available in Europe within the next few months.

Patients who are currently taking these medicines should make an appointment with their doctor to discuss suitable alternative treatments. Patients are advised not to stop their treatment without speaking to their doctor.

Doctors should stop prescribing rosiglitazone-containing medicines. Patients taking rosiglitazone-containing medicines should be reviewed in a timely manner to amend their treatment.

The current review of rosiglitazone by the Agency’s Committee for Medicinal Products for Human Use (CHMP) was initiated on 9 July 2010 following the availability of new studies questioning the cardiovascular safety of the medicine.

Since its first authorisation, rosiglitazone has been recognised to be associated with fluid retention and increased risk of heart failure and its cardiovascular safety has always been kept under close review. Consequently, the use of rosiglitazone was restricted to a second-line treatment and contra-indicated in patients with heart failure or a history of heart failure when it was first granted a marketing authorisation as Avandia in 2000.

Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone. Further restrictions on the use of these medicines in patients with ischaemic heart disease were introduced.

The availability of recent studies has added to the knowledge about rosiglitazone and overall, the accumulated data support an increased cardiovascular risk of rosiglitazone. In view of the restrictions already in place on the use of rosiglitazone, the Committee could not identify additional measures that would reduce the cardiovascular risk. The Committee therefore concluded that the benefits of rosiglitazone no longer outweigh its risks and recommended the suspension of the marketing authorisation of the medicines.

The suspension will remain in place unless the marketing authorisation holder can provide convincing data to identify a group of patients in whom the benefits of the medicines outweigh their risks.

The Committee’s recommendation has now been forwarded to the European Commission for the adoption of a legally binding decision.

Notes

• Rosiglitazone was initially authorised as Avandia in the European Union in July 2000 as second-line diabetes type-2 treatment to be used when other treatments have either failed or are unsuitable for a patient. It was subsequently approved in combination with metformin as Avandamet and with glimepiride as Avaglim.
• The review of the marketing authorisations of Avandia, Avandamet and Avaglim was initiated on the request of the European Commission under Article 20 of Regulation (EC) No 726/2004, following the publication of two studies on 28 June 2010. References for the two studies are as follows: Graham DJ et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA doi:10.1001/jama.2010.920. Nissen SE et al. Rosiglitazone revisited. An updated meta analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med doi:10.1001/archinternmed.2010.207.

Here is the GSK statement:

GSK regulatory update on Avandia following EMA and FDA reviews

Issued: Thursday 23 September 2010, London UK, LSE Announcement

GlaxoSmithKline (GSK) confirms that following a review of Avandia® (rosiglitazone maleate) by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), each agency has today announced their individual regulatory decisions and the resulting actions.

In the European Union*, the EMA has suspended the marketing authorisation for all rosiglitazone-containing medicines (Avandia, Avandamet® and Avaglim®).  As a result, physicians in Europe are being advised that affected patients need to be transitioned to alternative treatment options.  The EMA has stated that the suspension will remain in place unless convincing data are provided that identify a group of patients in whom the benefits of the medicine outweigh its risks.

In the US, all rosiglitazone-containing medicines (Avandia, Avandamet and Avandaryl®) will remain available with additional safety labelling and restrictions for use. The FDA will also require a Risk Evaluation and Mitigation Strategy (REMS) programme with additional measures to ensure the safe use of the medicine.

Dr. Ellen Strahlman, GSK’s Chief Medical Officer, said: “Our primary concern continues to be patients with type 2 diabetes and we are making every effort to ensure that physicians in Europe and the US have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The company continues to believe that Avandia is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions.  GSK will also work closely with other regulatory agencies to comply with any decisions made by them regarding rosiglitazone-containing medicines. GSK will voluntarily cease promotion of Avandia in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.

Regarding clinical trials, the FDA has imposed a new post-marketing requirement (PMR) for GSK to commission an independent re-adjudication of the endpoints reported in the large, prospective, randomised, controlled study, RECORD. GSK will provide its full support for this review. The FDA-required TIDE study has been placed on full clinical hold by the agency.  TIDE is the only GSK-sponsored clinical trial using Avandia currently being conducted in the US and Europe.  GSK in conjunction with the TIDE steering committee will communicate this decision to local regulatory agencies, ethics committees and institutional review boards (IRBS).

Financial Information
Total sales of Avandia products in the first half of 2010 were £321m (-18%); US £164m (-23%); Europe £72m (-17%); Emerging Markets £37m (-5%); RoW £48m (-6%)**.  As a result of the regulatory updates in both the US and EU, GSK now expects global sales of Avandia products to be in a range of approximately £100m – £150m in the second half of 2010 and with minimal annual sales thereafter. These estimates are net of customer returns of product previously sold.  Associated one-off costs in 2010 comprising stock write-offs, asset write-offs and other related one-off costs are currently expected to be approximately £100m on a pre-tax basis.

To access the full EMA announcement visit www.ema.europa.eu.

To access the full FDA announcement visit www.fda.gov.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

* The 27 voting members of the EMA are Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom.  In addition, Norway, Iceland and Liechtenstein who are non-voting members of the EMA are also affected.

** All growth rates are shown at constant exchange rates and relate to the prior comparative period

Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK’ s operations are described under ‘Risk Factors’ in the ‘Business Review’ in the company’ s Annual Report on Form 20-F for 2009.