FDA-Maharashtra and DCGI lock horns on status of medicated stents

Uncertainty looms on stent manufacturers and importers

Rita Dutta - Mumbai

The over 150-crore Drug Eluting Stents (DES) market in India still reeling under the jolt of Food and Drug Administration (FDA) Maharashtra’s crackdown on “illegal” DES at Mumbai’s JJ Hospital, now stands to witness the unfolding of another drama as FDA-Maharashtra and Drug Controller General of India (DCGI) lock horns debating whether DES is a device or a drug.

Post-JJ Hospital incident, where 60 patients were treated with Netherland-based Axxion stents, which were non-FDA and non-CE approved, the FDA continued its crusade against “illegal” stents by issuing notices to companies manufacturing, importing or distributing DES to abstain from marketing their products in Maharashtra till they secure drug license from DCGI within two months. This was followed by notices to major Mumbai private and government hospitals for refraining from use of medicated stents unapproved by US-FDA or CE, till the companies secure license from DCGI.

While uncertainty looms largely over the future of 20 manufacturers, importers and distributors of drug coated stents in India, DCGI has given a twist to the tale. In a letter dated June 7 (a copy of which is in possession of this reporter), A B Ramteke of DCGI, states: “DES for cardiac patients is considered as a medical device, which has not been notified under Drugs and Cosmetics Act and Rules thereunder. Therefore, manufacturing and marketing of the said DES is presently not within the purview of this office.”

FDA's stringency may lead to strangulation of indigenous market Dr A B Mehta, director, cardiology, Jaslok Hospital

DCGI’s stance is not an immediate response, but as revealed in a letter to Surat-based Sahajanand Medical Technologies Pvt. Ltd dated September 2002 (a copy is with Express Healthcare Management), it had echoed the same verdict.

So is DES a drug or a device? Dr Ganesh Kumar, head, interventional cardiology, Hiranandani Hospital, says, “It’s a blend of both, as it a metal coated with drug.” This thought was echoed by many interventional cardiologists.

Endorsing DCGI’s views, Dr D G Shah, secretary general, Indian Pharmaceutical Alliance, says, “It definitely does not come under the Indian Drugs and Cosmetic Act, 1941. In the US, it comes under the FDA, and if we are talking about regulation, then it should come under the purview of the FDA.”

Negating all views, Ramesh Kumar, commissioner, FDA, Maharashtra, emphatically says, “Coated with drugs, DES cannot just be a medial device. A Supreme Court order states that drugs not notified under section 3B2 and 2B3 of Drugs and Cosmetics Act, can be notified under section 3B1 of the same Act. Hence, DCGI should look into the issue.”

The debate has left cardiologists in a tizzy. Says an interventional cardiologist on conditions of anonymity, “We are sandwiched between the FDA’s and DCGI’s contradictions. If we stop using non-FDA and non-CE approved stents, we will be depriving a large population of patients who prefer cost-effective stents, but non-FDA and non-CE approved.” Abiding FDA order, interventional cardiologists in Maharashtra claimed to have stop ped using the unapproved DES stents.

If cardiologists are baffled, then the predicament of manufactures, distributors and importers of DES are worse. Sahajanand, growing at a rate of five per cent annually and having sold 3800 DES last year in India and 10,000 worlwide, is making its last ditch effort to convince cardiologists and hospital authorities of its credibility by issuing clarifications. Complains Manish Doshi, MD, Sahajanand, “Our image has been tarnished. While we are selling our product in 24 countries, and our product is in the last stages of getting CE approval, it’s sad that we are questioned in our own country.”

Stents which have undergone trials and have data comparable to historical studies are effective and safe Dr Sudhir Vaishnav, interventional cardiologist, Asian Heart Institute

He added that Sajahanand DES had undergone human and animal trials and the data has been presented at various national and international conferences. “Why is FDA picking on us, when there is no such regulatory body in India?” Doshi enquires.

Officials of Vascular Concepts (VC), whose DES Pronova holds 30 per cent of DES market in India, and 15,000 of which have already been deployed so far, were equally distraught. Laments Swaminathan Jayaraman, CEO, VS, “ FDA’s action was shocking. There are thousands of medical devices in India, why crack the whip on DES? Only 5 per cent of DES is drug, the rest 95 per cent has mechanical function.”

Agrees Rajesh Shrivas, zonal incharge, Mumbai, VC, “After two years of presence in the market, having conducted human and animal trials, it’s sad that overnight FDA had decided to take such an action. Such measures should stem from the centre and not be decided at the state level.” After receiving FDA’s notice, VC, which has an annual growth rate of 25 per cent, stopped marketing its product in Maharashtra.

The manufactures feel the ripples of the impact would be felt in the rest of the country, as it has alarmed cardiologists across the country.

If FDA is allowed to have their way, then out of over 20 DES companies, the market would have presence of only two players: Boston Scientific and Johnson and Johnson. “With FDA or CE approval taking years to come by and DCGI holding that DES does not come under its purview, it would be a boom time for Boston Scientific and Johnson and Johnson,” says an industry expert. Some are apprehensive that the market would be badly hit by an acute shortage of stents, if the supply is suddenly halted.

Though the need for regulation is underscored by interventional cardiologists, most of them have been unsparing in criticising FDA’s sudden crackdown. Padmashree Dr A B Mehta, director, cardiology, Jaslok Hospital, flays FDA for limiting patients choice. “A major chunk of patients prefer the inexpensive non-FDA and non-CE approved DES priced at Rs 60,000 and above, in comparison with FDA and CE-approved costing Rs one lakh and above,” says he.

Dr Mehta, who pioneered DES in India in 2002, also flayed FDA for its rules, which he believes, may lead to strangulation of indigenous market. “We are succumbing to the concept of everything which is foreign is good by being so stringent. I would certainly favour standardised procedure of obtaining FDA approval, but does such procedure exist?,” says he. Others have objected FDA’s dubbing some stents as illegal, in the absence of an existing regulatory body.

According to Dr K R Shetty, medical director, Cumballa Hill Hospital and Heart Institute, “Though FDA has taken the right step in asking the companies to get approvals, we also have patients asking for unapproved stents because of affordability issue.”

To which Dr Ganesh Kumar adds, “We always inform patients about the various stents available for use, the superiority of a DES over a non DES stent and the cost of each of them. Relatives of the patient want a DES on most occasions because of a clear superiority projected to them.” The bottomline, according to Dr Kumar is, a DES, approved or unapproved, is always better than a non-DES stent because of its lower restenosis rates.

He futher added, in this age of evidence-based medicine, if finance is the determining factor in choosing a stent, then stents with more clinical data should obviously be the first choice, but if finance is an issue, then the indigenous DES which are much cheaper should be still preferred over a non DES.

Will the controversy affect medical tourism? “Foreign tourists are affording patients and they don’t look for inexpensive stents. It’s the Indians, who will suffer,” says an expert.

With the DES market suddenly turning topsy turvy, the inevitable question is why did not FDA chart out a proper strategy before taking up the crusade against “illegal” stents? Why it did not consult DCGI before asking manufacturers to procure license? “We conducted research by studying literature on DES, understanding the market and also consulted interventional cardiologists. We even had a meeting with the DES companies on June 4, before we conducted the raid,” says the FDA commissioner.

When asked on the need for FDA and DCGI to work together, he commented, “We have not requested or consulted DCGI, but referred to them.” About restricting the market to two players, he says, “What would you prefer: two players who have approvals or 20 players with no approval?” All that DCGI Ashwini Kumar said, when contacted was: We are looking into the issue.

This is not the sole episode where state FDA and DCGI had conflicting opinion, point out sources. “Some state FDAs have high standards and DCGI does not direct control over them,” says an expert, “giving rise to conflicts.”

According to another interventional cardiologist, there is not much difference between a FDA-CE approved and unapproved DES as the drugs and the metal are the same, the difference lies only in the design. Objection has also been raised with FDA’s insistence on FDA and CE approval. “Why should we get US-FDA approval, when we don’t intend to sell my product in the US? Why cant we have a regulatory authority in the country?” enquires Doshi, adding that even US-FDA and CE approved stents are not above flaws. “Cypher was reported with stent thrombosis and Boston Scientific had to recall its stocks for some problem,” reveals an expert.

Some experts accord importance to both trials and approvals. Avers Dr Sudhir Vaishnav, interventional cardiologist, Asian Heart Institute, “Stents which are non-FDA or CE approved, but have undergone trials and whose data is comparable to historical studies are effective and safe.” According to him, companies deterred by cost-prohibitive randomised trials, should go for pilot studies. Others like Dr Mehta stresses the need of having ‘head to head studies’, where two kinds of stents are used on two different variety of people and their results compared.

Meanwhile, the coronary stent market is undergoing a dramatic transition, with DES threatening to engulf Bare Metal Stents (BMS) market. In comparison with last year, where a meagre 10 to 15 per cent of angioplasties were with DES, today DES has augmented its position to occupy 50 to 80 per cent of angioplasties in private hospitals and around 20 to 30 per cent in government institutes, say analysts. Of the over 40,000 angioplasties conducted evert year, around 90 to 95 per cent are conducted with stents. Says Padmashree Dr B K Goyal, director, interventional cardiology, Bombay Hospital, Mumbai, “Of around 1000 angioplasties conducted last year in our institute, around 40 per cent were DES. This year, till May, of the 450 angioplasties conducted, 50 per cent is DES.”

Similarly, Asian Heart Institute, Jaslok Hospital, Hiranandani Hospital and Hinduja Hospital in Mumbai, Woodland in Kolktata, Manipal Heart Foundation in Bangalore and Escorts Heart Hospital in Delhi confirmed a dramatic rise in use of DES. Says Ravi Kasliwal, director, cardiology, Escorts Hearts, New Delhi, “From 20 per cent patients choosing DES last year, today more than 80 per cent prefer it.”

So, what has tipped the market in favour of DES? The low restenosis rate of DES is the predominant factor. “The restenosis rate for DES is seven to eight per cent in comparison with 10 to 15 per cent of BMS. Additionally, for patients, who have advanced diabetes, an artery size less than 3 mm, length of block more than 15 mm and having block at proximal LAD, DES is the safest bet with the restenosis being eight per cent,” says Dr Vaishnav. Bare metal stents are a complete no-no for this category of patients as restenosis is an alarming 25 to 33 per cent.

Interventional cardiologists are happy with the turnaround in the market, as more complex patients can now be treated. “Now patients with complex blocks, having diabetes and multiple blocks, who would earlier be sent for bypass surgery, can now benefit from angioplasty. The ARTS-2 study corroborates this,” says Dr Kumar.

With the rise of DES, angioplasty has become more reliable. “With low restenosis rate, angioplasty would draw more patients, who otherwise would prefer bypass surgery,” says Dr Goyal.

Our image has been tarnished. While we are selling our product in 24 countries, and our product is in the last stages of getting CE approval, it’s sad that we are questioned in our own country Manish Doshi, MD, Sahajanand

With superiority of DES being established, it is mostly affordability that decides whether a patient would go for DES or BMS. In cases of multiple stents, cardiologists compromise and use a combination of DES and BMS just to cut down on the costs. However, where affordability is not a problem, patients prefer DES. Says Dr A K Bardhan, director, cardiology, Woodland Hospital, Kolkata, “A 53-year-old patient of mine went for nine DES.”

How will the growth rate of DES be in future? “DES, which occupies 40 per cent stake in the coronary stent market today, will double up within next two years,” says an analyst.

Will DES erase BMS completely from the market? Avers Dr Rajesh Rajani, head, interventional cardiology, Hinduja Hospital, “With increasing demand of DES, prices would plunge further and DES would be more affordable. I would not be surprised if BMS vanishes from the market five years down the line.”

However, Dr C N Manjunath, professor of cardiology, Bangalore does not think so. “BMS would still be used for patients with artery size more than three mm, not having diabetes with reasonable success with restenosis rate of 10 to 15 per cent. The restenosis rate with DES for this category of patients, which constitute around 25 per cent of patients requiring angioplasty of the over 40,000 angioplasties conducted every year, is seven to eight per cent. BMS would also continue to be used for emergency cases, when patients cannot pay for BMS.”

In anticipation of the change, companies have already started changing their strategies. “Now, we will of course focus more on DES,” says Shrivas.

In line with the pace of the growing market, experts suggest formation of a centralised authority for regulation of medical devices like DES, pacemakers, etc, as suggested by the Mashalker committee report. “We already have a centralised authority for new drug approval and now we need the same for DES,” avers Dr Shah. Concurs Dr Kumar, “It is always good to have our own central regulatory body for monitoring the ever increasing entry of newer DE stents into the country based on the various ethical trials.”

To curb malpractices like charging patients while undergoing trials, which JJ Hospital is reported to be doing during the recent FDA raid, experts emphasise on the importance of ethics committee of hospitals in charting out stringent ethical guidelines.

While the organisations focus on strategies, and experts suggest a regulated market, one can only wish that, as for all confusion, there would be a favourable outcome for a patient who with all hope looks forward to live healthy.

rita@expresshealthcaremgmt.com