Inpharma 1636 - 3 May 2008

drug is deemed to have in effect an "approved REMS".3 InUS FDA shows its teeththis scenario, products deemed to have an approvedwith Rotarix approval REMS in effect are those that had in effect "elements toassure safe use" on 25 March. These elements of safeIn approving GlaxoSmithKline’s Rotarix, the US FDAuse include the following:exercised its authority – newly gained under the Food &• prescribers of the drug have particular training orDrug Administration Amendments Act (FDAAA), signed

experience, or are specially certifiedinto law 27 September 2007 – to require a• practitioners, pharmacies or healthcare settings thatpostmarketing safety study.1

dispense the drug are specially certifiedOn 3 April 2008, the agency approved GSK’s oral, live• drug is dispensed only in certain settingsattenuated, human rotavirus vaccine [Rotarix] for the• drug is dispensed to patients with evidence or otherprevention of rotavirus gastroenteritis in infants.2 The

documentation of safe use conditionsapproval was based on clinical data from nearly 75 000• patient registriesinfants participating in trials conducted in North and• patient monitoring programmes.South America, Europe, Asia and Africa.

Under the FDAAA, the agency is able to mandate Baby-sized bitessafety-related postmarketing studies, effective from The FDAAA also increases the requirement for one-25 March 2008. In its approval letter to GSK, the FDA year safety reviews as part of paediatric drug research.notes that it considers analyses of spontaneous Prior to the FDAAA, drugs granted exclusivity under thepostmarketing adverse events insufficient to assess the Best Pharmaceuticals for Children Act were subject topotential serious risk of postvaccination intussusception these safety reviews, to be brought to the paediatricor to identify other unexpected serious risks that, based advisory committee. Going forward, one-year safetyon current data, have the potential to occur with the reviews will be necessary whenever data from FDA-rotavirus vaccine.1 In addition, the new requested studies (under the Pediatric Research Equitypharmacovigilance system required under the FDAAA Act [PREA]) are added to product labelling. To this end,has not yet been established and is therefore not the FDA has established an internal committee to reviewsufficient to assess signals of a serious risk.1 both BPCA- and PREA-related activities.Consequently, the FDA requires GSK to conduct a US-

1. FDA. Rotarix Product Approval Information Internet Document : [4 pages], 3based postmarketing observational study of Rotarix to Apr 2008. Available from: URL: http://www.fda.gov.2. GlaxoSmithKline. FDA APPROVES ROTARIX(R) [Rotavirus Vaccine, live,assess the potential serious risk of intussusception and

oral], THE FIRST VACCINE LICENSED TO COMPLETE THE ROTAVIRUSother serious adverse effects among vaccine recipients.IMMUNIZATION SERIES BY FOUR MONTHS OF AGE. Media Release : 3

The study will be designed to detect an increased Apr 2008. Available from: URL: http://www.gsk.com.3. Shuren J. Identification of drug and biological products deemed to have riskrelative risk of intussusception due to Rotarix with a

evaluation and mitigation strategies for purposes of the food and Drugrelative risk of ≥ 2.5 and with 80% power. The letter also Administration amendements Act of 2007. Federal Register 73: 16313-16314,lists the expected number of study subjects No. 60, 27 Mar 2008.

4. Vadheim KL. Clinical trial updates: critical changes in US and EU regulations(approximately 44 000, with adjustments made basedand guidance. Internet Document : [1 page], 23 Apr 2008. Available from: URL:on the background rate of intussusception) and the http://www.orcanw.org.

5. Juneja V. ESAs in Oncology and Management of Risks. Internet Document : [1agreed schedule (start date June 2009, with final reportpage], 13 Mar 2008. Available from: URL: http://www.fda.gov/ohrms/dockets/submission by March 2012).AC/08/slides.

6. FDA outlines revised product labelling for recombinant erythropoietins. 1579:Taking a bigger bite22, 17 Mar 2007.

Under the FDAAA, the agency can now require risk 7. Amgen Inc. Amgen Announces Update to U.S. Prescribing Information forAranesp (Rm) and EPOGEN (Rm). Media Release : 8 Mar 2008. Availableevaluation and mitigation strategies (REMS) for newfrom: URL: http://www.amgen.com.products if it determines such schemes are necessary to 801075236

ensure the benefits of a drug outweigh the risks.3,4

Notably, the FDA can withhold product approval untilREMS are in place.

The legislation also allows the FDA to require REMSfor approved products if the agency becomes aware ofnew information on a serious or unexpected risk.4 Itseems quite likely that erythropoiesis-stimulating agents(ESAs) will become the first group of marketed productsto face mandatory postmarketing safety studies andREMS.5 In March 2007, the FDA issued a Public HealthAdvisory concerning serious life-threatening adverseeffects associated with the use of ESAs, which includeAmgen’s darbepoetin-α [Aranesp] and epoetin-α[Epogen] and Ortho Biotech’s Procrit [epoetin-α].6Product labelling was amended to include updatedwarnings, a new boxed warning and modifications to thedosing instructions. There was a concern that ESAsshortened overall survival and/or time to tumourprogression in clinical studies involving patients withbreast, cervical, head and neck, lymphoid and non-smallcell lung cancers, when dosed to target a haemoglobinlevel ≥ 12 g/dL.7

For companies with products approved before25 March 2008, there is a requirement to submit aproposed REMS by 21 September 2008 if the approved

1

Inpharma 3 May 2008 No. 16361173-8324/10/1636-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved