The European Medicines Agency (EMA) has announced it is conducting a review of Medtronic's implantable bone-development product, InductOs, after Spanish and Dutch inspectors discovered contamination issues at a US manufacturing site which makes one of its components.
InductOs was authorized via the centralized procedure in 2002 and is marketed by Medtronic BioPharma B.V., headquartered in the Netherlands. InductOs is used to promote bone development in patients undergoing lower back spinal fusion and surgery to repair broken tibia.
InductOs is sold as a kit containing its active ingredient dibotermin alfa, a solvent and an absorbable collagen sponge (ACS). EMA has classified the ACS as an excipient of InductOs, and it is thus subject to inspection under EU good manufacturing practice (GMP) guidelines.
The ACS included with InductOs is manufactured by Integra LifeSciences at one of Integra's US locations. In January 2014, an inspection of Integra's site uncovered "a number of major deficiencies." As a result, Integra was handed a corrective action plan and was restricted from importing the ACS to the EU, until inspectors could return to "assess the progress in eliminating the major deficiencies."
When inspectors returned to conduct their follow-up inspection in April 2015, they found Integra had not taken adequate steps to eliminate "contamination of ACS with particulate matter."
As a result, the Netherlands issued a draft statement of non-compliance in July 2015, and notified the European Commission (EC) and EMA's Committee for Medicinal Products for Human Use (CHMP).
On 23 July, the Netherlands finalized its statement of non-compliance, after which the EC initiated an Article 20 procedure, requesting EMA "assess the [issues] and their impact on the benefit risk balance for … InductOs." Under Article 20 of Regulation (EC) No 726/2004, the commission has the authority to request EMA conduct an assessment of a manufacturer or importer in relation to non-compliance issues raised by national regulators.
Healthcare providers are being told to continue using InductOs as usual, and the agency is advising that there is "no indication of risk to patients linked to the inspection findings." EMA says it expects a shortage of InductOs to occur as a result of the ongoing import restriction.
From here, EMA will begin its review of InductOs in light of the contamination issues found at Integra's facility and issue a recommendation for any changes necessary to InductOs' marketing authorization.
In the interim, EMA has prepared a series of questions for Medtronic to address. In particular, the agency wants to know if there have been any "safety reports or complaints … related to the contaminating particulate matter," and if there are "any patient population(s) for whom there is no other treatment option available."
EMA is also asking Medtronic for a timeline for steps taken to "ensure that the manufacturing of the ACS will be GMP compliant." The agency is also requesting the batch numbers of InductOs already distributed in the EU, and for information on InductOs' use per EU member state, in ongoing clinical trials, and forecast demand.
EMA Press Release, Notification to CHMP/EMA, CHMP List of Questions