India’s drug controller is allowing Abbott’s coronary stent, Absorb BVS, to start fresh clinical trials, though it has been red-flagged by the US and Australia.
New Delhi: Reacting to growing safety concerns, India’s drug controller is going to direct healthcare company Abbott to do Phase IV clinical trials in India for their controversial cardiac stent Absorb GT1-Bioresorbable Vascular Scaffold (Absorb BVS). The Central Drugs Standard Control Organisation (CDSCO) will also be ordering the stent to be on “restricted access” and to be sold and used only in “major-volume hospitals.” Abbott will be asked to submit a list of these hospitals.
This comes after a series of red flags were raised on the stent since March 2017 by drug regulators in the US, Australia and Denmark. Abbott is one of the largest healthcare products company in India and has operated in India since 1910.
A senior official in the health ministry confirmed this on April 26. The device has been under review by the ‘expert committee on cardio-vascular devices.’ The committee has just taken a decision on this and an office memorandum is due to be issued by next week. The committee consists of eminent cardiologists from around the country, including from the All India Institute of Medical Sciences (AIIMS).
With concerns being raised about safety from around the world, Indian health watchers had been waiting for action from the Indian regulatory side as well. CDSCO, India’s drug controller, is charged with ensuring the safety of drugs in India. On April 7, CDSCO issued a “Medical Device Alert” for the same Absorb BVS. India’s alert said, “Based on the three years clinical data analysis from ABSORB II it has been observed that there is an over elevated rate of major adverse cardiac events, specifically, myocardial infarction and scaffold thrombosis.” CDSCO asked patients and professionals to report all adverse events to CDSCO or to Abbott Healthcare in the US and Maharashtra.
The decision of the expert committee doesn’t change things drastically for Abbott as it effectively means that the contentious stent will continue to be in production and circulation in India, but the data will be collected and monitored as part of Phase IV trials, especially for any adverse events following the implanting of this stent.
Global safety concerns on Abbott’s Absorb stent
It has been a bad year for Abbott’s Absorb stent with a torrent of concerns and criticism coming in from all over the world. In March 2017, the US Food and Drug Administration (FDA) wrote a letter to health care providers, informing them that the agency was investigating the “increased rate of major adverse cardiac events” with Absorb BVS. This was based on the FDA’s initial review of two year data from the ABSORB III trial. Patients could experience cardiac symptoms such as “irregular heartbeats, chest pain, or shortness of breath.”
Shortly after that, Australia’s Therapeutic Goods Administration also issued a “Safety alert” for the same stent, in March. Like their US counterpart, they said there is an “increased rate of major adverse cardiac events” including cardiac death, heart attack and the need for an additional procedure to re-open the treated heart vessel.
The Danish Medicines Agency uploaded a letter from Abbott Vascular titled, “Urgent Field Safety Notice/ Physician Advisory.” This letter was leaked on the internet earlier this month, and written by Abbott where they stated they were withdrawing the contentious stents from the market, “No further BVS stents will be provided to non-registry sites after March 31, 2017 and these sites are instructed to cease implants and existing inventory will be removed.” The company was clear on the reason for the move: “These important containment measures are being undertaken in light of recent concerns over elevated rate of major adverse cardiac events, specifically, myocardial infarction and scaffold thrombosis,” said the letter.
And this month, a study in the New England Journal of Medicine added more pressure on Abbott’s credibility. In fact the investigators wrote that they were so alarmed by the safety issues that they in fact released an early report of their data. “Given the lack of putative benefit in the ABSORB Japan and ABSORB II trials, the advantage of bioresorbable technology over metallic stents remains to be established,” they said.
Abbot’s stent has been marketed as a medical innovation in the area of coronary stents, at it is supposed to be a fully dissolving stent, which disappears after the artery is healed. In 2010, it received the Conformité Européenne mark in the European Union. In July 2016, US FDA approved this stent. In November 2016, Japan approved the stent. Absorb was first introduced into India in December 2012.
NPPA bars Abbott from withdrawing their Absorb stent
A curious underlying tension came to focus on Wednesday. On April 21, Abbott had in fact written to the National Pharmaceutical Pricing Authority (NPPA) – and not to CDSCO – and asked for the withdrawal of this very contentious stent from the market. In February, the NPPA had passed landmark orders, capping the price of stents in the country.
However, Abbott’s application for the withdrawal of this stent was not on the ground of safety but on the ground of pricing. Abbott cited the “commercial unviability post fixation of ceiling price.”
But on April 26, the NPPA issued a memorandum to Abbott and another company Medtronic, over its stents. NPPA has rejected all three applications for withdrawal, meaning that their stents must continue to be produced and stocked in the market. Abbott had applied to withdraw Xience Alpine and Absorb GT1 Bisoresorbable Vascular Scaffold and Medtronic wanted to withdraw Resolute Onyx Zotarolimus Eluting Coronary Stent System.
Although the notices are nearly identical to all three, NPPA made one specific observation to Abbott on Absorb BVS. NPPA made a reference to the global safety concerns on Abbott’s stents, and gave Abbott a tricky option: “However, if M/s. Abbott Healthcare India Ltd. finds that ‘Absorb BVS’ cannot address the ‘safety concerns’ already raised by USFDA, EU, TGA-Government of Australia, CDSCO and others, the company can approach NPPA at any time before the period mentioned in 5(a) above, clearly stating the reasons for withdrawal to be ‘safety concerns’.”
An Abbott spokesperson confirmed that they do not plan on withdrawing the stent on the ground of safety. “We have taken this step because of commercial unsustainability of Alpine and Absorb. The CDSCO medical device alert of 7 April does not restrict the use of Absorb in India. When Absorb is implanted according to training and instructions for use, results are comparable to Xience.” said Abbott’s spokesperson.
Health watchers find the timing of Abbott’s application for withdrawal of the stent from India surprising, as it coincides with the safety concerns being raised globally. “Abbott seems to be trying a backdoor-exit from India. Their attempt to withdraw the same stent via NPPA citing price control, seems to be a way for them to remove their product without admitting that it is due to safety,” says Malini Aisola of All India Drug Action Network.
A backdoor for Abbott?
Not much will change for Abbott in the immediate future in India, even while patient-safety remains a concern. Abbott enjoyed access to the Indian market even before it had received US FDA approval. “It is horrifying to imagine for a patient, that a stent which is failing globally is still being implanted here. CDSCO is effectively allowing Abbott to stay in the market instead of suspending the stent and show-causing the company, until we are sure of safety. So far, this is all in favour of Abbott,” says Aisola.
The government’s proposal to allow the Absorb stent to be used in major-volume hospitals, is taken from US guidelines, which explains that “major-volume hospitals” should be preferred for angioplasties, and they must have an annual volume of over 400 procedures. However, these same recommendations were earlier downgraded as “they represent expert opinion and lack strong and consistent evidence from the literature.” Researchers have raised caution on reliance on volume as, “Volume is not a surrogate for quality and should not be substituted for risk-adjusted outcomes and other measures of quality.”
On this, an Indian stent manufacturer asks, “How can the company itself decide which hospitals should use this stent? Unlike in the west, there is no organised system here where major-volume hospitals are identified. Patients in a major-volume hospital will still face the same problems of safety.” Abbott has also said in its global communications that the fault is not with their BVS stent but with the implantation procedure done by doctors. The Indian manufacturer says, “Their trials have failed even in a country like Japan where procedures for implantation are followed with precision and ethical standards are very high.”
“How is it ethical to do a trial for a device which is already found to be controversial and unsafe? What remains to be proved? Patients participate in Phase IV trials when studies have already shown the drug or device to be safe in a controlled environment, and for its high benefit and low risk. Here it will be the opposite,” says another Indian stent manufacturer.
However, a Phase IV trial will bring some regulation to the company, in that patients will have to be informed before implantation, that this stent is still under testing, and will have to sign consent forms. This would be different from post marketing surveillance, which is also a part of Phase IV trials, but does not require consent and can be done retrospectively as well. This measure will make the sale of the stent somewhat more difficult for Abbott, while not destabilising the company’s operations too much, but safety concerns on the part of patients will remain.