Tuesday 7 March 2017

IMA White Paper on Stent Controversy

IMA White Paper on Stent Controversy Report of the Core-Committee for Revision of National List of Essential Medicines November 2015 A Core-Committee was constituted by the Ministry of Health & Family Welfare (MOHFW), Government of India, under the chairmanship of Dr VM Katoch, the then Secretary, Department of Health Research (DHR) and Director General, Indian Council of Medical Research (ICMR), and Dr YK Gupta, Professor and Head, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS) as the Vice Chairman. The Core-Committee in its initial meetings deliberated and decided on the criteria for inclusion and deletion of medicines in National List of Essential Medicines (NLEM). The criteria for inclusion of a medicine in NLEM are as follows: 1. The medicine should be approved/licensed in India 2. The medicine should be useful in a disease, which is a public health problem in India. 3. The medicine should have proven efficacy and safety profile based on valid scientific evidence. 4. The medicine should be cost effective. 5. The medicine should be aligned with the current treatment guidelines for the disease. 6. The medicine should be stable under the storage conditions in India. 7. When more than one medicines are available from the same therapeutic class, preferably one prototype/ medically best suited medicine of that class to be included after due deliberation and careful evaluation of their relative safety, efficacy and cost-effectiveness. 8. Price of total treatment to be considered and not the unit price of a medicine. 9. Fixed Dose Combinations (FDCs) are generally not included unless the combination has unequivocally proven advantage over individual ingredients administered separately, in terms of increasing efficacy, reducing adverse effects and/or improving compliance. 10. The listing of medicine in NLEM is based according to the level of health care, i.e. Primary (P), Secondary (S) and Tertiary (T) because the treatment facilities, training, experience and availability of health care personnel differ at these levels. The criteria for deletion of a medicine from NLEM are as follows 1. The medicine has been banned in India. 2. There are reports of concerns on the safety profile of a medicine. 3. A medicine with better efficacy or favorable safety profiles and better cost-effectiveness is now available. 4. The disease burden for which a medicine is indicated is no longer a national health concern in India. 5. In case of antimicrobials, if the resistance pattern has rendered a medicine ineffective in Indian context. The Core-Committee in its first two meetings, discussed in detail the modalities to be followed for revision of NLEM and prepared guiding principles and criteria for the revision of NLEM 2011 as under Criteria for Inclusion of a Medicine into NLEM 2015: For inclusion of a medicine into NLEM, the medicine should: 1. Be licensed/ approved in the country by Drugs Controller General (India) 2. Be useful in a disease, which is a public health problem in India 3. Have proven efficacy and safety profile based on valid scientific evidence 4. Be comparatively cost effective 5. Be aligned with the current treatment guidelines for the disease 6. Be stable under the storage conditions in India Medicines recommended under National Health Programmes of India are considered for inclusion in NLEM. In addition, the following criteria were also considered: 1. When more than one medicine are available from the same therapeutic class, preferably one prototype/ medically best suited medicine of that class to be included after due deliberation and careful evaluation of their relative safety, efficacy, cost effectiveness. 2. Price of total treatment to be considered and not the unit price of a medicine 3. FDC are not included unless the combination has unequivocally proven advantage over single compounds administered separately, in terms of increasing efficacy, reducing adverse effects and/or improving compliance 4. The medicine in NLEM will be based at P/S/T level of health care according to treatment facilities and training, experience and availability of health care personnel at these levels Criteria for Deletion of a Medicine A medicine will be deleted from NLEM 2011 in the following conditions 1. The medicine has been banned in India. 2. If there are reports of concerns on the safety profile of a medicine 3. If medicine with better efficacy or favorable safety profile and better cost-effectiveness is now available 4. The disease burden for which a medicine is indicated is no longer a national health concern 5. In case of antimicrobials, if the resistance pattern has rendered a medicine ineffective Stent Position • Stents and other devices are medicines and included in the Drugs and Cosmetics Act. • Stents have been put under NLEM and hence are an essential item and underprice capping. • Stents use drugs like sirolimus, everolimus, paclitaxel and zotarolimus • Each drug is different • Therefore, one category of each drug stent has to be in NLEM the one which is best suited • Only non-inferior latest stents of the same company with one best suited NLEM stent can be in non NLEM category • Most stents are built on a stainless-steel platform, the least-expensive stent material available. Unfortunately, stainless steel is not fully compatible with the human body and implantation usually is followed closely by restenosis and thrombosis. In addition, stainless steel can pose difficulties related to some types of imaging, such as magnetic resonance. Now alternative platform materials such as gold, titanium, cobalt-chromium alloy, tantalum alloy, nitinol and several types of polymers (Silicone, polyethylene and polyurethane) are available. • Some polymers are biodegradable, bio-absorbable, or bio-erodible. Biodegradable or bio-absorbable stents contain a major component (such as an enzyme or microbe) that degrades quickly enough to make them appropriate for short-term uses. A bio-erodible polymer is a water-insoluble polymer that has been converted into a water-soluble material. Biodegradable materials can form an effective stent coating because they can be mixed with an anti-re-stenotic drug and will degrade within a few weeks, thus releasing the drug into the surrounding tissue and reducing the risk of restenosis. • Examples of biodegradable polymers are: polyesters, polyorthoesters and polyanhydrides. Collagen is also very biocompatible and reduces the rate of restenosis and thrombosis. In addition, anticoagulants and fibrinolytic agents bound to the collagen can aid in drug delivery. How to choose a stent • Stents are characterized according to material composition, thickness of struts, and whether or not they are capable of eluting drugs for local delivery • Stent design may also be specific for certain indications such as small (<2.5 mm diameter) vessels or lesions involving a bifurcation of a main vessel and side branch. Vessels smaller than 2 mm are not suitable for stenting. • Tortuous, angulated, and calcified arterial segments pose challenges for even the newest stent designs because of difficulty delivering the stent to the target lesion. • The first two DES, called first generation stents, approved were sirolimus -eluting stent (SES) in 2003 and paclitaxel -eluting stent (PES) in 2004. • In 2008, the zotarolimus-eluting stent (ZES) and the everolimus-eluting stent (EES), called second generation stents, were approved. • EES and Resolute zotarolimus-eluting stent (R-ZES) are comparable in terms of efficacy and safety • Use newer generation DES in almost all cases, and either EES or R-ZES are preferred choices. For patients undergoing intracoronary stenting with a DES, IMA recommends an EES, either with a durable or bioresorbable polymer or R-ZES rather than a PES. • The choice between EES or R-ZES should be guided by issues such as cost, practitioner familiarity, and availability. • There have been two iterations of the ZES (Endeavor and Resolute); manufacturing of the older Endeavor-ZES has stopped internationally. • EES may have the lowest rate of stent thrombosis than all other DES, but one cannot make a recommendation to prefer EES to R-ZES based on this factor alone. • The results of the multicenter randomized ABSORB II study by Patrick Serruys and colleagues1published in The Lancet (Nov 19, p 2479) did not show non-inferiority in terms of late luminal loss (restenosis) or superiority in vasomotor reactivity of the bioresorbable vascular scaffolds compared with the drug-eluting stents. • Earlier this year, the multicenter randomized NORSTENT elective percutaneous coronary intervention trial showed no significant differences between participants receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and non-fatal myocardial infarctions. • The bare-metal stent technology has evolved into the drug-eluting stent technology that has produced a marked reduction in restenosis, at a cost of longer term dual antiplatelet therapy. Clinicians are trying to achieve the utopian 0% restenosis with more expensive technologies that present new problems such as thrombosis, neoatherosclerosis, stent recoil, and much stronger medications for longer durations. The ABSORB II and NORSTENT studies challenge the typical trend of showing the new thing to be shinier and the old thing dustier than they really are. • Clinicians should reflect and use cost-effective technologies that have stood the test of time before adopting newer technologies on a large scale. Durable Polymer • Xience (V, Prime, Xpedition): Abbott Vascular: Cobalt chromium: Everolimus • Promus (Element, Premier): Boston Scientific: Platinum chromium: Everolimus • Resolute: Medtronic: Cobalt chromium: Zotarolimus Bioabsorbable polymer: SYNERGY: Boston Scientific: Platinum chromium: Everolimus Older Cypher Cordis/J&J Stainless Steel Sirolimus Taxus Boston Scientific Stainless Steel Paclitaxel Promus Boston Scientific Cobalt chromium Everolimus Bare Metal Vision Abbott Vascular Cobalt chromium VeriFLEX Boston Scientific Stainless steel REBEL Boston Scientific Platinum chromium Integrity Medtronic Cobalt chromium Issues Can all stents be under NLEM? No. As per NLEM guidelines, when more than one medicine is available from the same therapeutic class, preferably one prototype/ medically best suited medicine of that class should be included after due deliberation and careful evaluation of their relative safety, efficacy, cost-effectiveness. Stents need to be classified in different groups; in each group, one of them must be in NLEM and the rest in non NLEM. Will the cost of the procedure increase to compensate for the loss of profit in selling stents? No. As per NLEM guidelines, the price of total treatment to be considered and not the unit price of a medicine. Are non-NLEM stents superior to NLEM stents? No. As per NLEM guidelines, a drug will be deleted from NLEM if there are reports of concerns on the safety profile of a medicine and if a drug with better efficacy or favorable safety profile and better cost-effectiveness is now available. All NLEM drugs have to be efficacious or proven safety and quality. Non-NLEM drugs should be non-inferior to the NLEM drugs. If a non-NLEM drug is superior to NLRM drug, it is likely to enter into NLEM category. Does costly means better? NLEM drugs will be cheaper and non-NLEM though costly, will be non-inferior to NLEM drugs. What do you mean by high end stents? Low end or high end stents, each will be a class. And, from each class, one drug must be in NLEM. Can hospital make profits from stents? As per NPPA clarification (20.2.2017), NPPA did not take price to hospitals (PTH) as price to retailers (PTR) & considered hospitals out of stents 'trade channel' for price fixing. That means there will be margins for the distributors but not for the hospitals. As per AIMED, the hospitals need to make income from procedure and compete with other hospitals and not from medical devices used in the procedure. Once hospitals won't make profits on Stents, their procurement will shift back to the buying price of product and quality. Can hospitals compel a patient to buy a drug only from hospital inventory? No. There are many state government, NCDRC and court decisions against it. If stent companies do not sponsor conferences, then who will? Why should drugs or stent companies sponsor conferences? Either doctors must pay for the learning and contribute or the hospitals should sponsor out of their profits. The delegation fee in any specialty conference nowadays is not less than Rs 10,000/-. How does we ensure that Indian stents are good? It is not our job to decide good or bad. Any stent approved by DCGI is good. The responsibility lies with the DCGI and the expert committee under Technical Drug Advisory Board (DTAB). In the Anuradha Saha case, the apex court said one needs to follow the label cleared by the DCGI. The DCGI also has a PvPi program (9717776514 phone number). If the department receives any report of side effects of any device, the device can be immediately taken off the market. Till today, the very fact that Indian stents can be marketed means no adverse effects have been notified to PvPI so far. What is IMA’s stand on routine pharma drugs? Write NLEM drugs and inform the patient about the reason, if prescribing non NLEM drugs. IMA campaign is “Write CAPITAL, Write NLEM”. A large segment of the society will thus be covered with affordable health care. Those who can afford can go for newer non-superior drugs with some special advantages for example longer-acting, mouth dissolvable, nanotechnology, more tasty formulations etc. How much can a cardiologist charge for the implantation? As per MCI, the only requirement is transparency and pre-procedure declaration. As per CEA, rates will be defined by the state government in consultation with organisations including the IMA. How should a prescription for a stent be written? Example: Advised Everolimus Drug Eluting stent with stable polymer. Avoid writing simply ‘advised stent’. Dr KK Aggarwal National President IMA & HCFI

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