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Avendus Pharmaworld The year 2011 took off to a slow start for the global pharma and healthcare dealscape, with M&A deals worth only USD 3.85 bn being announced. The largest M&A deal was the USD 644 million acquisition of International Dialysis Centers (IDC), Euromedic CONTENTS
International's "non-core" dialysis services business, by Germany-based Fresenius Kabi. The acquisition gives Fresenius Medical Care access to IDC's 8,200 hemodialysis patients ry Animal Tox: The Next "Big Thing"? treated through a network of 70 clinics in nine countries in CEE. Fresenius Medical Care, the world leader in renal therapy, currently serves more than 210,000 patients globally Valuation snapshot and more than 17,000 patients in Eastern Europe. The second largest deal was the USD 540 million (USD 445 mn net of tax benefits) acquisition of Paddock Labs Inc. by Perrigo Inc. Paddock is a privately held manufacturer and marketer of generic drugs and this acquisition is in line with Perrigo's long term strategy of strengthening its generics portfolio. It also solidifies Perrigo's leading position in the extended topical market. The global healthcare private equity space saw a couple of buyouts. The largest was Advent's buyout of the Priory Group, Europe's leading provider of acute mental healthcare for USD 1.5 bn. In another large transaction, CVC bought out the European hospital chain Capio's Spanish division for USD 1.2 bn. There were only 3 small M&A transactions closed in India. Fortis bought out Lifeline Hospitals, a 100-bed hospital located in Alwar, Rajasthan. This marks Fortis' third acquisition in a tier II city within the last two months. In another deal, Transasia Diagnostics acquired Diasis Diagnostic systems, a Turskish in-vitro diagnostics player for an undisclosed amount. Then, Aurobindo Pharma sold 51% stake in its Chinese subsidiary Aurobindo (Datong) BioPharma to Sinopharm. Post deal, Sinopharm will infuse funds into the company to up its stake to 80.50%, thereby reducing Aurobindo's stake to 19.5%. In one of the largest private-equity buy-outs in the Indian Healthcare space till date, Halcyon Finance and Capital Advisors, a turnaround specialist, completed its USD 44 million acquisition of hospital management services firm Integrated Health and Healthcare Services India Pvt. Ltd. (IHHS India). IHHS India is owned by Mauritius-based Integrated Health and Healthcare Services, and is in the business of developing/ redeveloping, managing and operating healthcare facilities in India. IHHS India currently manages Delhi-based Dr BL Kapur Memorial Hospital and had equity capital worth Rs. 185 crore on its Balance Sheet as on Mar 31, 2010. IHHS India had reported revenues of Rs. 1.63 lakh and total expenses of Rs. 34.4 lakh for the fiscal year ended Mar 31, 2010. Disclaimer: The news articles contained herein are Halcyon Capital founders Abhay Soi and Narayan Seshadri were appointed as Directors on only a part of the original articles from the source the Board of IHHS India in Sep 2010. mentioned and therefore are not complete. In case you need complete articles, please contact us on the In this edition of the Avendus Knowledge Series, we decided to take a closer look at the e-mail addresses provided above. safety issues plaguing the global pharma industry. The pace of withdrawals of The news contained herein has been taken from commercialized blockbuster drugs on account of safety issues has been accelerating since published sources as indicated under each item. 2004, to a level that has become worrisome. The latest debacles in this series are GSK's Avendus will not be held liable for any erroneous Avandia and Abbott's Reductil/ Meridia. Such high-profile drug withdrawals have created data as published in the source indicated. Avendus pressure on pharma regulators to "raise the bar" for safety assessment studies in also does not take any responsibility for any errors animals. We expect this new-found "sense of purpose" to provide a sharp impetus to the or omissions or results of any actions based upon market for outsourced GLP animal toxicology services. Indian toxicology services this information. providers have significant gains to be realized from this global trend, given India's cost advantages and the provision to use Dogs as the second-species in lieu of Non-Human Primates. We bring you a feature on the Toxicology-focused CROs in India and the global opportunities in store for them. Avendus Healthcare Team
Regulatory Animal Toxicology: The Next "Big Thing"?
Introduction to Toxicology Studies

Toxicology is the study of adverse effects of chemical or physical agents on biological systems. In the context of drug development, toxicology refers to the testing of a drug candidate in animals (in-vivo), assays (in-vitro), or specially designed software packages (in-silico) to decide if the candidate is safe for administration in humans. Almost 70% of the toxicology market comprises of in-vivo tests which are performed on rodents, rabbits, dogs, goats, guinea pigs, fish, and monkeys. The choice of animal for a test is very critical; ideally the chosen species should be freely available, be able to live and breed comfortably, be safe to handle, remain healthy on diets acceptable to man, and most importantly, react to a drug in a fashion as similar as possible to humans. Majority of the toxicological tests are carried out in the preclinical development phase. The standard battery of tests for pre-IND safety evaluation, and for NDA submissions are more or less defined in the regulatory guidelines. Preclinical tests used in IND filings include preliminary short term studies like in-vitro tests, acute toxicity tests (typically 14 days), sub acute toxicity tests (14-28 days), immunotoxicity, basic genotoxicity and safety pharmacology. Long term studies like sub chronic/chronic toxicity (30 days to 2 years), carcinogenicity (>12 months), additional genotoxicity and reproductive toxicity, that span the entire lifecycle of the drug development are used primarily for NDA submissions. Typically, over 25 toxicity tests are required to bring a new drug to the market. The various types of toxicology studies required over the development life-cycle of a drug candidate are depicted in Exhibit 1 below. Exhibit 1: Types of toxicology studies conducted over the development life-cycle of a drug candidate
Type of toxicology study
Phase III
In-vitro model culture and optimization, Ames study, in-vitro cellular toxicity assay General toxicity studies (Including acute, sub-chronic, and chronic studies) Immunotoxicity studies Carcinogenicity studies Reproductive and developmental toxicology studies Safety pharmacology Genotoxicity studies Specialized tox studies (drug interaction studies, focused studies indicated by prior results) Other (nontypical, but specialized tox studies) Source: Covance presentation The primary objective of safety assessment studies is to identify circumstances under which the candidate drugs produce toxic effects. It also establishes the thin line between a toxic dose and a safe dose, target organs of toxicity, onset, duration and reversibility. These studies help select safe doses for clinical trials and subsequently aid in determining therapeutic doses. The design of the studies, dose selection, number and age of samples are critical issues and the role of toxicologist together with pathologist, becomes very important in determining the progress of the new drug candidate. Just like any other step in drug development, adherence to safety guidelines is imperative to carry out toxicology studies. In 1979, the USFDA and later on in 1981, the OECD countries formalized a set of GLP guidelines to bring about uniformity in toxicity testing methods. Stringent rules and test guidelines were established to carry out preclinical toxicology evaluation of new drugs. Today, GLP guidelines have been accepted across the world including India, and accreditations from multiple monitoring agencies have become hygiene factors in the choice of a service provider. Outsourced toxicology services: On a robust footing
The ability to accurately assess the toxicity (short-term and long-term) of a drug candidate is the latest in the series of R&D
productivity issues plaguing the global pharma industry. With a ten-fold rise in R&D-cost-per-marketed-drug and a significant
fall in the number of NMEs approved year-on-year, one would expect that paying greater attention to drug safety assessment
is the least that pharma companies can do to course-correct.
Exhibit 2a: Increasing R&D expenditure and declining
Exhibit 2b: Ten-fold rise in R&D cost per marketed drug
number of NME approvals
Source: Tufts Institute Figures in USD mn Pharma R&D Investment New medicines approved Studies have demonstrated that 40% to drug attrition from Exhibit 3: Reasons for drug attrition – discovery
to launch
discovery to launch is due to toxicity issues. Preclinical studies, which comprise < 15% of drug development costs, play a critical role in screening out "less safe" candidates early on, in order to avoid wasting monies on unviable candidates in human trials. In addition, there has been a sharp acceleration in the last 6 years, in the number of high profile drugs withdrawn from the market (presented in Exhibit 4 below) due to undesirable side-effects detected during Phase IV studies. In many of these cases, the side effects were responsible for the deaths of a number of patients consuming the drugs. In addition to resulting in the termination of innocent human lives, there have been multiple instances of Big Pharma shelling out huge sums of money to settle tort-litigations/ class actions, e.g., USD 4.85 billion in the case of Vioxx (Merck) and USD 3.55 billion in the case of Avandia (GSK). Such incidents have resulted in the USFDA/ EMEA "raising the bar" for safety assessment studies in animals. Consequently, long term animal studies such as chronic safety, carcinogenicity and reproductive toxicity studies have assumed greater importance for obtaining USFDA/ EMEA approvals. Exhibit 4: List of high-profile blockbuster drug withdrawals since 2004
Withdrawn by
Safety Risk/Issue
Year withdrawn
Heart-attacks and strokes Heart-attacks and strokes Heart-attacks and strokes Heart valve damage CVS ischemic events incl. MI and stroke Post-op bleeding Post-op complications / death Pain/inflammation Depression and suicide Progressive multifocal leukoencephalopathy Cardiovascular events Veno-occlusive disease Heart attacks and death (withdrawn in EU) Source: Avendus Research Growth in the market for outsourced toxicology services

Over 75% of toxicology studies are currently conducted in-house within Big Pharma setups. It comes as no surprise then that toxicity has not been receiving the attention it requires, since Big Pharma's large and unwieldy R&D setups are not the most conducive for effective discovery and development. However, as pharmaceutical and biotech companies consolidate and step-up their focus on improving R&D productivity and drug-safety-assessment, the emphasis on outsourcing toxicology studies is bound to increase. We expect that outsourcing levels could reach 35 - 40% in 2015, driven by profit-pressures caused by patent expirations and the need to deliver consolidation benefits on pricey M&A deals. Exhibit 5a: Global toxicology market (USD bn)
Exhibit 5b: Outsourced toxicology market (USD bn)

Source: Analyst reports, Avendus research

Competitive landscape in the global outsourced toxicology services space

The global market for outsourced toxicology services is highly fragmented with only two major players, Covance and Charles River Laboratories. There are a handful of mid-sized players, including the likes of MPI, Harlan, LSR and Ricerca, followed by numerous small players. Pure in-vitro players include Ceetox, Caliper, Iconix, Celsis, etc. We also have another category of players who are engaged in developing software models to predict toxicity effects of a compound (also known as in-silico or predictive toxicology). This is a fast-growing field since innovators have started using in-silico methods to supplement traditional toxicity studies.

Exhibit 6: Global service provider landscape by type of toxicology services provided
(a) Large in-vivo players (with limited presence in
(b) Major in-vitro players
(c) In-silico players
The toxicology space has witnessed significant M&A activity in the last 24 months, driven mostly by the need for newer
services (e.g., Cyprotex - Appredica) and, in others, the need to enter low-cost geographies (e.g., PPD - Bioduro). There have
been 12 deals reported in the last 24 months, shown in Exhibit-7, spanning broad-based in-vivo tox assets and niche-
therapy-specific in-vitro companies. We believe that given the fragmented landscape and the gaps prevailing in the current
offerings of most players, consolidation in this space will continue at a brisk pace.
Exhibit 7: Mergers and acquisitions in the preclinical/ toxicology spaces in the last 24 months
Deal Size
Broad business of the Target
Preclinical ADME and toxicology services IP for offering high content tox services In-vitro ADME services DMPK & safety assessment services services Bridge Labs GLP compliant toxicology services Invitro and invivo pharmacology services Disc. chem. & biology, DMPK, safety assessment Mostly in vivo toxicology services Perry Scientific Efficacy studies, tox studies and vivarium services In vitro neurological preclinical research Preclinical efficacy testing with expertise in oncology Bioassay techniques, bioanalysis, and genetic *Earlier known as NexMed **Parent of Huntingdon Lifesciences Competitive landscape in the Indian outsourced toxicology services space

India's presence in the preclinical development domain has been historically limited to medicinal/ discovery chemistry. As of 2009, the total Indian export of preclinical services (discovery + development) was dominated by discovery chemistry (at 78% of the total), followed by discovery biology (at 15% of the total) and toxicology services trailing with a mere 8% contribution to the total kitty. However, with the expanding global requirement for low-cost and world-class toxicology

services, preclinical toxicology services are projected to account for as much as 15% of total preclinical service exports from India by 2015, with preclinical toxicology projected to grow > 30% p.a. during this period. Exhibit 8: Growth projections for Pharmaceutical contract R&D from India
2009-15 CAGR 33%
2009-15 CAGR 41%
2009-15 CAGR 15%
Discovery Chemistry Discovery Biology Preclinical Toxicology Indian companies providing pre-IND toxicology services can be divided into three broad segments. Firstly, there are over 10
CROs that provide non-GLP tox studies to aid lead optimization/candidate selection as part of the overall discovery process.
Secondly, we have 5-6 CROs that are capable of providing selected GLP tox services that enable an IND submission. Lastly, we
have CROs that provide end-to-end services required to deliver an IND package. The (GLP) Regulatory Animal toxicology
landscape in India is dominated by Advinus, which remains the "go-to" player for customers seeking a vendor who can deliver
end-to-end services from candidate-selection to IND filing.
Exhibit 9: Indian service-provider landscape in the pre-IND toxicology space

Non-GLP toxicology studies
Portions of IND enabling GLP
End to end IND enabling GLP
aiding lead optimization
toxicology studies
toxicology studies
The increasing importance of drug safety assessment, coupled with the imperative for innovators to outsource development
activities to low cost locations presents a great opportunity for Indian preclinical service providers. Toxicology as a standalone
service has not evinced too much interest from the Indian players in the past. The scenario is changing with the sector poised
to become a USD 150 mn opportunity by 2015. Most Indian CROs have a strong presence in discovery chemistry and have the
client relationships in place to be able to expand into toxicology services, if they can build up the required capability and
infrastructure. This "share-of-wallet" mindset is driving CROs like Syngene, Aurigene and GVK to step up their activities in GLP
toxicology services over the last 2-3 years. We believe that Indian CROs will soon start looking at international markets to find
tox-focused assets in order to accelerate their time-to-market. Likewise, we expect inbound interest to step-up. Global CRO
majors are expected to take in this regard, driven by their business imperative to establish global delivery capability from low-
cost locations like India.
Valuation Snapshot
(As on 31st January, 2011)
Market Cap
Enterprise Value
Stock Return
Piramal Healthcare
Jubilant Organosys Suven Lifesciences CRAMS Mean
CRAMS Median
Generics Mean
Generics Median
India Branded Formulati
IBF Mean
IBF Median
Apollo Hospitals Indraprastha Medical Hospitals Mean
Hospitals Median
Multiples based on December '10 TTM Financials
Apax, KKR in talks to acquire Blackstone stake in Emcure
Economic Times
Three investor groups, including private equity firms Apax Partners and Kohlberg Kravis & Roberts (KKR), are in separate discussions to buy Blackstone's stake in Indian drugmaker Emcure Pharmaceuticals for about USD 100 million. The Pune-based company's plan for a public issue to get listed on the stock markets has been delayed and this may have prompted Blackstone to go for a secondary transaction to exit the company. Emcure was one of the first investments made by US private equity major Blackstone in India and this could well be one of its first exits from an Indian portfolio company. It had invested USD 50 million in Emcure in an undisclosed stake in 2006. One of the persons aware of the negotiations said Blackstone holds 10-15% in Emcure and wants to sell the entire holding. Namita Thapar, CFO at Emcure, said the company is not aware of any specific discussions between PE players for any transaction. Although Thapar did not say whether the company's public issue has been delayed and whether it was expected soon, she said, "The company is evaluating various options to meet its growth as well as capital objectives." Blackstone and Apax Partners did not respond to separate e-mails, while a KKR executive declined to comment. Healthcare is one of the five sectors in which Apax Partners invests globally, besides technology & telecom, retail & consumer, media, financial & business Services. Although it has not invested in any pharmaceutical company in India it has exposure to drugmakers internationally and last September Apax sold its stake in sixth largest generic drugmaker Qualitest to Nasdaq-listed Endo Pharma. In India, Apax has healthcare investment in the country's largest hospital operator Apollo Hospitals. KKR has invested in technology, cement, consumer retail, power generation and telecom infrastructure firms in India. Earlier media reports suggested that promoter and CEO Satish Mehta, who started Emcure in 1981, has the option to buy back the securities held by Blackstone but the company CFO said no such discussions between the promoter and Blackstone is on. Emcure makes active pharmaceutical ingredients and generic medicines, besides providing contract research services to global drugmakers. It has revenues of Rs 1,600 crore, and has profits in line with the pharma industry, the company said. Most Indian pharma companies command a profit margin of 15-20% which means Emcure could have net profit of Rs 240-320 crore. If valuations in the drug industry as a multiple of earnings is a benchmark, Blackstone may get about twice its investment, said one of the persons mentioned above on condition of anonymity. Ahmedabad-based privately held Intas Pharmaceuticals, which has similar revenues of Rs 1,600 crore, has proposed to raise Rs 750-800 crore by selling 15% to the public, valuing the company at about Rs 5,000 crore. But Intas revenue grew 39% last fiscal- much faster than the industry rate. If Blackstone indeed sells its stake in Emcure, it would be among the larger private equity exits in the pharmaceutical space. ChrysCapital is set to exit at least half of its 11.5% stake in Intas Pharmaceuticals' proposed IPO. Healthcare sector has attracted significant investor interest over the last few years in India, one of the fastest growing markets for drug sales with lack of adequate healthcare services. According to audit tax and advisory firm Grant Thornton, there were a total of 23 private equity deals in India in the healthcare sector last year worth USD 320 million. New Silk Route's USD 55 million investment in Chandigarh-based Nectar Life Sciences was the biggest transaction. Cognizant signs pact with Eli Lilly
Financial Times
Cognizant, a leading provider of consulting, technology and business process outsourcing (BPO) services, announced that it has been selected by Eli Lilly and Company, one the world's leading innovation-driven pharmaceutical companies, to deliver an end-to-end set of services to help Lilly's US sales and marketing operations be more effective, efficient, and innovative. Under the multi-year contract, Cognizant will deliver a tightly bundled range of solutions spanning commercial analytics, sales force planning, sales incentive compensation, customer relationship management, business reporting, data warehousing and state compliance reporting using a consumption-based service delivery model called Business Process as a Service (BPaaS). Zydus, Bayer Healthcare enter 50:50 JV
Business Standard
Ahmedabad-based Zydus Cadila and Germany's Bayer Healthcare have signed an agreement to set up a 50:50 joint venture (JV) company, Bayer Zydus Pharma, to market pharmaceutical products in India. Both companies will be equally represented in the board. The new entity will operate in key segments, including women's healthcare, metabolic disorders, diagnostic imaging, cardiovascular disease, anti-diabetic treatments and oncology, the company said in a statement. The JV will start operations with Bayer Healthcare's pharmaceutical division contributing to its existing sales and marketing business in India to the new company. Zydus will contribute women's healthcare products, diagnostic imaging business and other products. In addition to Bayer Healthcare's existing pharmaceutical products portfolio in India the joint venture would also focus on the sales and marketing of future patented pharmaceutical products, said Zydus in a release to the Bombay Stock Exchange. Both Bayer Healthcare and Zydus will supply the joint venture with products sourced from its manufacturing operations at existing locations. Commenting on the development, Zydus Cadila managing director Pankaj Patel said, "We have always believed in partnering growth, have keenly explored new opportunities and looked at synergies in the market place." Through this transaction Bayer Healthcare will enhance its marketing capabilities in India as part of its emerging market growth strategy, while Zydus can strengthen its network with global healthcare players. "With this step, Bayer Healthcare aims to significantly accelerate its capabilities to better serve the fast growing Indian market," said Bayer Healthcare AG CEO, Jorg Reinhardt. Zydus Cadila has eight manufacturing facilities across India and is also present in the regulated markets of US, Europe and Latin America. Zydus had posted a total income of Rs 1,170 crore in the quarter ended December 31, up 18 per cent from Rs 994 crore in the corresponding period last financial year. Bayer Healthcare is part of the Bayer AG Group with annual sales of over EUR 15.9 billion in 2009. Wellcome, Merck JV to make anti-diarrhoea vaccine for babies
Economic Times
An Indian healthcare joint venture between drugmaker Merck & Co and UK-based charitable entity Wellcome Trust plans to develop heat stable oral rotavirus vaccine to prevent diarrhoea in babies in developing countries. It plans to develop oral vaccines in thin strips or granules to improve its stability, ease of use, transportation and affordability. "It will take about 2-4 years to develop the vaccine," said Altaf A Lal, CEO at MSD Wellcome Trust Hilleman Laboratories, a 50:50 joint venture between MSD ( Merck India ) and Wellcome Trust. Hilleman Laboratories was formed last year and the two partners have committed to invest GBP 45 million each over the next seven years to develop vaccines for the developing markets. The initiative to develop a rotavirus diarrhoea vaccine in collaboration with Boston-based Medicine in Need is the company's first project. If it succeeds in developing the vaccine, Hilleman Labs will look for partners to manufacture and market the product in India and other developing markets, where the disease is widely prevalent. An estimated 100,000 babies die due to rotavirus in India each year, about a fourth of the total global death among infants and babies that die due to severe diarrhoea. At present, locally available rotavirus vaccines need to be transported and stored under a certain temperature. Besides higher cost, the World Health Organization estimates that annually between 10-50 % vaccines may be wasted globally because of temperature control, shipping and other logistical issues. The proposed vaccine will be developed at Hilleman's upcoming facility in Delhi which will employ a total of about 60-70 people. It plans to spend USD 10-15 million in developing the vaccine. Sun Pharma plans its biggest buy in US
The Financial Express
Sun Pharmaceutical Industries, India's largest drugmaker by market value, is planning its biggest acquisition in the US to boost sales in the world's largest pharmaceutical market, chairman Dilip Shanghvi said. Sun, which has made 13 purchases in the past 14 years including the USD 454 million acquisition of a majority stake in Israel's Taro Pharmaceuticals completed in September, needs to buy a bigger US company to attain critical scale, Shanghvi said in a January 21 interview in Mumbai. Sun, which owns about 77% of Detroit-based Caraco Pharmaceutical Laboratories, isn't in takeover talks yet, he said. "We are still a very small player in the US," Shanghvi said. "We will have to look at a slightly bigger acquisition rather than to look at very small acquisitions that we have done in the past." A buyout may help expand Sun's capacity to sell generic medicines and enable the Mumbai-based company to gain control of manufacturing sites and sales networks, according to Shanghvi. Sun and Taro supplied less than 3% of the generic medicines prescribed in the US in November, compared with Teva Pharmaceutical Industries' 20% share and Mylan Pharmaceuticals' 13% share. Shanghvi didn't say how much Sun could spend on a US buy. Any target would need to have annual sales of more than USD 300 million for Sun to compete effectively with the top five generic-drug makers in the US market. Corex takes the crown in MNC-led Indian drug mart
The Financial Express
First the good news: the year 2010 saw for the first time the Rs 52,271-crore Indian drug market throw up a Rs 200-crore plus brand. However, this comes with a bitter pill – none of the top five Indian drug makers has a single brand in the top five in India, whose market size is over Rs 930 crore. US drug major Pfizer's cough syrup Corex is the first to become the Rs 200-crore drug brand in India by clocking sales of Rs 210 crore in the 2010 calendar year. Interestingly, Corex was also the first drug brand in India to cross the Rs 100-crore mark in 2002. Corex's 2010 achievement was achieved by beating another cough syrup brand – Phensydyl – which was the leading brand in 2009. Phensydyl is marketed by Piramal Healthcare (which had not been acquired by US drug firm Abbott Labs then). Compared to 2008 when India had only one drug brand with sales over Rs 150 crore, the domestic market now has five brands boasting a market size of over Rs 150 crore, according to the data from pharma market research firm, All India Organization of Chemists and Distributors. However, all the top five brands with the exception of one, are being marketed by MNCs like Pfizer (Corex), Danish firm Novo Nordisk (Insulin Human Mixtard distributed by Abbott in India), Swiss firm Novartis (painkiller Voveran) and UK-headquartered GlaxoSmithKline Pharma (antibiotic Augmentin). The top six Indian drug makers by market share in India — Cipla, Sun Pharma, Cadila Healthcare, Alkem Labs, Lupin, Mankind Pharma - all of which market branded generics are conspicuous by their absence in the list of top five brands. The only brand from an Indian drug maker which has made the cut is Monocef from unlisted drug firm Aristo Pharma. Since 2008, the Indian pharma market has grown 36% to cross the Rs 50,000-crore mark in 2010. On a year-on-year basis, the domestic market has grown 16.9% since 2009. Also, while India had only one Rs 100-crore drug brand till 2001, today all the top 10 brands have sales of over Rs 100 crore. While multinationals have historically dominated top drug brands in the country, it is the larger transformation in the pharma space with increasing market share of foreign drug makers that is troubling certain quarters of the government. Vishal Gandhi, Vice-president, life sciences and technology, Yes Bank said: "We expect MNCs to hold close to 50% market share in the Indian drug market by the end of 2012-2013." Compare this with the situation that prevailed in 2007, when only 15% market share was in the hands of multinational pharma firms. Today, three of the top five drug firms in the country are either of foreign origin or are domestic firms which have been acquired by MNCs in the last two years. Concerned that such ‘MNCisation' of the pharma space could eventually lead to a rise in drug prices, the ministry of health has been insisting on capping the FDI limit in the Indian pharma sector. Currently, 100% FDI is allowed in the pharma space. Among the top ten drug brands, Ranbaxy's vitamin supplement Revital has seen the highest annual growth (27%) in value terms. This drug contributed almost double to Ranbaxy's kitty (Rs 138 crore) in 2010 viz-a-viz the amount it contributed two years back. Piramal Healthcare's cough syrup has seen a year-on-year negative growth rate of 24.7%. Among the top 10 drug brands, three products witnessed an annual growth of over 20%, while eight drugs recorded growth in double digits in 2010. Data exclusivity still key hurdle to India-EU FTA
Business Standard
Despite all official assurances, the path towards a free trade agreement (FTA) between India and the European Union (EU) this year remains ambiguous, as both sides are unwilling to relax their stand on the biggest stumbling block — the issue of "data exclusivity". While the commerce ministry, the government arm responsible for scripting policy framework for intellectual property rules in the country, says there is no let-down in this matter, its EU counterpart insist that data exclusivity is integral to the trade deal. The rigid stand taken up by the negotiating sides and simultaneous assurances of a timely agreement are sending conflicting signals to various stakeholders, including the domestic pharmaceuticals industry and public health groups that oppose the inclusion of any clauses that go beyond India's World Trade Organization (WTO) commitments under the FTA. Data exclusivity provides protection to the technical data generated by innovator companies to prove the merit of usefulness of their products. In the case of pharmaceuticals, it means the data generated by drug companies through expensive global clinical trials to prove the efficacy and safety of their new medicine. By gaining exclusive rights over this data, innovator companies can prevent their competitors from obtaining marketing license for low-cost versions during the tenure of this exclusivity. Indian drug firms that make generic versions of innovator medicines get their approvals after proving that their product is bio-equivalent to the original drug. In other words, they do not repeat the same clinical trials conducted by the innovator company to generate data needed to prove its safety under current laws. "The most serious impact is likely to be on drugs that are not under patent. In such cases, data exclusivity will create a "patent-like" barrier that will prevent generic entry of new formulations during the entire period of exclusivity. For instance, traditional medicine ‘colchinine', which cannot be patented as it has been used as a therapeutic agent in the treatment of gout for thousands of years, was awarded data exclusivity in the United States. Once the US drug regulator accepted the one-week trial of the drug, the company was able to enforce data exclusivity to block affordable generics. It enforced its exclusive rights, raised the price from USD 0.09 per pill to USD 4.85, and sued to remove other competitors off the market," Indian Drug Manufacturers' Association Secretary General Daara B Patel said. Commerce ministry officials say they are aware of the seriousness of the issue. "There is no question of data exclusivity. We are under no pressure from anyone (to include this provision under FTA). EU and their negotiators are well aware of India's sensitivities and we have made our position very clear to them," a senior commerce department official involved in the negotiations told Business Standard. However, earlier in the week, Daniele Smadja, head of the delegation of EU to India, said the India-EU FTA had to include data exclusivity. "This is a very important issue and it has to feature prominently in the trade deal," she said. Global pharmaceutical giants say data exclusivity is essential for their future investments and research on developing country needs. "Data exclusivity is very good as it will encourage innovation. It will also make companies do clinical trials before they launch their products thereby ensuring patient safety," said Ranga Iyer, consultant to Pharmaceutical Research and Manufacturers of America. Jupiter Biosciences in talks to buy Swiss pharma co for USD 10 mn
The Economic Times
Hyderabad-based Jupiter Biosciences is in talks to buy privately held Swiss pharma company SynphaBase AG for about USD 10 million as it looks to boost research capabilities and front-end sale of its products internationally, a person familiar with the development said. If successful, this will be Jupiter's second acquisition in Switzerland after it bought Merck Biosciences' manufacturing facilities in 2008 to service customers in the heavily regulated markets abroad, especially Europe. Basel-based SynphaBase, backed by Novartis Venture Fund, the investment arm of Swiss drugmaker Novartis AG, has annual revenues of USD 7 million and employs 25 people. "It can become the front-end to supply products to developed markets," the person said, requesting anonymity. Jupiter, which plans to bring the management of the two firms under one roof, could seal the deal next month, he said. A Jupiter Biosciences spokesman declined comment while SynphaBase AG did not respond to ET's mail query. Jupiter plans to ship raw material to the Swiss company, which will process and supply organic and chiral API—the basic raw materials used in drugs— to both generic drugmakers and innovator companies in the US, Europe, and Japan. Jupiter Biosciences' board had approved a proposal last month to raise USD 100 million for funding business projects, including acquisitions in India and overseas. It plans to raise the money through a preferential issue of shares. SynphaBase provides contract research and development services specialising in organic and medicinal chemistry, besides manufacturing intermediates and APIs for other drugmakers. The small-sized Indian pharma company specialises in synthesis of peptides, a type of protein. It also makes specialty and fine chemicals, drug intermediates, bulk drugs and nutraceuticals. Sanofi, Abbott win trial over Glenmark's generic Tarka
Sanofi-Aventis and Abbott Laboratories won a U.S. jury trial in which the drugmakers sought to halt Glenmark Pharmaceuticals Ltd.'s sales of a generic version of their hypertension medicine Tarka. Abbott was awarded USD 16 million in damages. A federal jury in Newark, New Jersey, rejected Glenmark's challenge to the validity of a Sanofi patent that expires in February 2015. Glenmark argued that the patent covered an invention that was protected by an expired patent. James Galbraith, a Glenmark attorney, declined to comment after the verdict. Jurors awarded USD 15.2 million for lost profits and USD 803,514 for higher prices Abbott would have been able to charge had Glenmark not infringed the patent. Abbott, which paid USD 290 million for an exclusive license to Tarka, was seeking USD 25 million as compensation for profit it lost because of Glenmark's sale of the generic drug. Paris-based Sanofi owns the patent on Tarka, first approved by drug regulators in 1996. Glenmark had received U.S. Food and Drug Administration approval to market the copy, and notified Sanofi and Abbott that it wouldn't wait for the results of the trial. Mumbai-based Glenmark began sales in June after U.S. District Judge Dennis Cavanaugh in Newark rejected a request by Sanofi and Abbott to stop sales. As the first to challenge the patent, Glenmark had exclusive rights to the generic market for Tarka for six months. Glenmark reported in October a 26 percent jump in sales of generics in the U.S., a market that accounts for 68 percent of the company's generic-drug revenue. The introduction of the Tarka copy helped boost sales, the company said. The patent is for an angiotensin-converting enzyme inhibitor with a calcium channel blocker. Tarka combines the ACE inhibitor trandolapril with verapamil hydrochloride. Glenmark said the patent differed little from ones covering other ACE inhibitors, including the compounds quinapril and ramipril. Abbott argued that Tarka was different than the earlier combinations, and pointed to the success of the drug as evidence that it was unique. The Abbott Park, Illinois-based company doesn't break out sales of the drug. Abbott has said a competing generic version of Tarka would cost the company USD 150 million to USD 270 million in business during the remaining life of the patent, according to court records. Abbott reported USD 30.8 billion in sales in 2009. The case is Sanofi-Aventis Deutschland GmbH v. Glenmark Pharmaceuticals Inc. USA, 07cv5855, U.S. District Court for the District of New Jersey (Newark). Wockhardt and arm's nutrition biz to merge
Business Standard
Drug maker Wockhardt's board approved a plan to merge the nutrition business of Vinton Healthcare, its wholly-owned subsidiary, with itself. "As Vinton Healthcare Ltd is a wholly-owned subsidiary of the company, no shares would be issued by the company pursuant to the aforesaid scheme of demerger," the company said in a filing to the stock exchanges. Sources said Vinton Healthcare owned a manufacturing unit and also partly owned Wockhardt's nutrition business along with two other subsidiaries — Wockhardt EU Operations (Swiss) AG and Carol Info Service Ltd, promoted by Chairman Habil Khorakiwala. Earlier, Wockhardt had decided to sell its nutrition business to Abbott for Rs 630 crore, but the deal was jointly aborted. "The demerger is part of simplifying and streamlining the processes and assets and to make Wockhardt more profitable in future," said a company spokesperson. According to the company's 2009-10 annual report, Vinton Healthcare had Rs 184.3 crore worth assets and liabilities worth Rs 109 crore. The unit also made a loss of Rs 5.4 crore during 2009-10. The debt-ridden company's lenders had allowed a debt restructuring scheme in 2009. Biocon's insulin pill falls short on testing
Business Line
Biocon's potential insulin pill did not fully meet the primary goal of lowering blood sugar levels to the desired level, according to a clinical study just completed in the country. The data obtained from trials on 264 patients at multiple centres was being assessed further, the company said in a release. The drug, tentatively called IN-105, however proved safe, or without serious side-effects, and did not increase the patients' weight (as generally happens with insulin use), it said. However, Ms Kiran Mazumdar-Shaw, Biocon's Chairman and Managing Director, called the outcome "encouraging" for going ahead with collaborative global development with a global partner. Biocon would start discussions to find a partner, she was cited in a release. Company officials were not available to clarify and the spokeswoman said this was its ‘silent period' before third-quarter results are announced on January 20. Dr Harish Iyer, Biocon's Vice-President, R&D, was quoted as saying, "These results build on the now considerable body of data generated for IN-105, strengthening our conviction of the promise of oral insulin. The lessons learned here will be fully utilised in designing future studies for the global clinical development programme." Sometime last year, Biocon undertook what is called a "double-blind placebo-controlled trial." Patients poorly controlled on metformin, an established anti-diabetic drug, were randomised to receive either IN-105 or placebo. The patients in both arms of the study continued with metformin as background therapy. It said some subsets of patients under study showed lower glucose levels as desired; and some others may have made some behavioural changes that affected the trial outcome. The company said, "Initial data analyses show that IN-105 did not meet its primary end point of lowering HbA1c levels by 0.7 per cent compared to placebo, although an unexpectedly high placebo response was also observed. Post hoc analysis of self-monitored blood glucose levels in the IN-105 arm and the placebo arm indicated large reductions in pre-meal glucose levels in the placebo arm, strongly suggestive of behavioural modification and which might have confounded the primary endpoint outcome." (HbA1c is a current test for diabetes and is based on glucose in haemoglobin.) It said, "Additionally, in further post hoc analyses, significant reductions in HbA1c levels compared to placebo, and HbA1c reductions of up to 0.8 per cent were observed in the IN-105 arm of several subsets of the studied patient population. Further assessment of the data is on-going." A drug candidate is also studied for safety or adverse side-effects in patients. Biocon said, "On secondary safety endpoints IN-105 demonstrated an excellent overall safety profile with no incidence of serious adverse events, and no occurrences of clinical hypoglycaemia (or glucose levels below normal). Data also show that the drug is weight neutral and non immunogenic." A diabetologist and former medical director of a large pharma company said the announcement of trial outcome may have been premature; the HbA1c criterion to test a drug's efficacy using the HbA1c levels, which are measured every three months, should take at least a year's trials or 3-4 quarters. The study may have been done for six months. Yet, it cannot be dismissed and would need further assessments, he said. Biocon had earlier said once the drug successfully completed the trials, it would market the drug globally by tying up with a global pharma major. The release cited Ms Mazumdar-Shaw as saying, "Based on these encouraging results, Biocon is committed to continuing its global development of IN-105 in partnership with a global pharmaceutical partner for which we plan to initiate partnering discussions." IN-105, it said, met multiple secondary endpoints on both efficacy and safety, "further strengthening the emerging profile of IN-105. Most notably on efficacy, the IN-105 patient arm demonstrated a statistically significant reduction in post-prandial glucose levels compared to placebo throughout the duration of the study." Elder Pharma set to supply to Japan
Business Line
Elder Pharmaceuticals Ltd has its eyes set on supplying to the Japanese market. The Mumbai-based drug-maker's API (active pharmaceutical ingredients) plant at Patalganga, Maharashtra, has received accreditation from Japan's Ministry of Health, a note from the company said, thereby opening up the fast-growing Japanese market for its products. The company is in talks with Japanese generic companies for supply contracts, the note added. "Elder is positioning itself to be an API and advanced intermediate supplier to the Japanese market. This accreditation for the API plant is a step towards strengthening Elder's position as a supplier of APIs and intermediates in the Japanese market," said Elder Pharma's Director Mr Alok Saxena. The company has also developed two products, going off-patent in the Japanese market in 2014 in the central nervous system and gastro-intestinal segments. Elder has already filed an international patent application for one of the advanced intermediates, targeting the Japanese market. The Japanese pharmaceutical market, valued at USD 69.4 billion in 2009, is the world's second largest pharmaceutical market. In an effort to rationalise its healthcare costs, Japan is increasingly looking at pro-generic drugs policies, including increasing its healthcare-spend in this segment. Dr Reddy's in drug discovery pact with UK research firm
The Economic Times
Pharma major Dr Reddy's Laboratories and Argenta, a UK-based contract research firm, have entered in to an agreement for collaboration in drug discovery. The collaboration will be in the area of pain and inflammation, according to Argenta. Commercial terms of the agreement were not disclosed. Argenta will apply its integrated drug discovery platform and expertise on multiple Dr Reddy's discovery targets in pain and inflammation. The aim of the collaboration is to deliver high quality development candidates to support Dr Reddy's research efforts for proprietary products. "We are excited to be working with Dr Reddy's in identifying novel and differentiated drug candidates for multiple targets meeting unmet clinical needs in pain and inflammation," said John Montana , Managing Director, Argenta. Four years ago, the Indian company had announced a similar agreement with Argenta in the area of respiratory treatment, including chronic obstructive pulmonary disease and severe asthma. Merck ends pact with Ranbaxy
The Economic Times
American drugmaker Merck has terminated its two-year-old partnership to develop anti-infective medicines with Ranbaxy Laboratories that could have brought payments of over USD 100 million to the Indian pharma company over five years. Separate reports have said the world's second largest drugmaker has now shifted the research programme to Aurigene , a wholly-owned drug discovery subsidiary of Dr Reddy's. But this could not be independently verified. The spokesmen for Ranbaxy and MSD, the Indian arm of Merck & Co, said they have terminated the drug discovery programme to develop anti-bacterial and antifungal medicines. Dr Reddy's spokesman declined comment. An analyst with a global brokerage firm said that the news was expected. "Ranbaxy has no intentions of doing new drug research." He said the termination should not have any significant financial implication for Ranbaxy and it would be premature to estimate any gains for Dr Reddy's. Lupin signs strategic deal with Brazilian firm Farmanguinhos
The Economic Times
Pharma Major, Lupin announced that it has entered into an agreement with Farmanguinhos, Brazil's largest PSU in health care for the supply of its 4 in 1 combination drug of Rifampicin, Isoniazide, Ethambutol and Pyrazinamide for tuberculosis. Lupin will supply the product for the next five years and also provide Farmanguinhos with the desired support for the set up of its local manufacturing in future, a company statement said here. With this agreement between Lupin and Farmanguinhos in place, Farmanguinhos has entered into a commitment to produce and supply the 4 in 1 combination drug to the Department of Health (Brazil), which will result in substantial savings for the government, the release said. The 4 in 1 combination reduces the pill burden on the patient drastically, particular as the treatment lasts for at least six months. As per WHO, the treatment abandonment rate has fallen from 8 per cent to only 5 per cent due to this reduced pill burden provided by the combination drug. WHO estimates indicate that globally there are 9.2 million new cases each year resulting in 1.7 million deaths. In Brazil alone, it is estimated that approximately 57 million people have already been infected by this disease with 83,000 new cases annually. Fortis to add 12 hospitals in 2 years
The Economic Times
Fortis Healthcare is working on an expansion plan that could lead to the addition of more than a dozen hospitals to its existing network over the next two years. The group which operates a network of 52 hospitals with more than 8,000 beds intends to add a further 2,000 beds to its existing capacity and increase its presence in tier-II and tier-III towns and cities. Fortis Healthcare's managing director Shivinder Mohan Singh told ET NOW, "Our target is to have at least 25 hospitals in tier-II and tier-III towns and cities in the next couple of years. The economics of operating hospitals in smaller locations has worked out quite well for us as operating costs are lower and the infrastructure that we put in place is more basic in nature, which helps us maintain healthy margins." The hospital chain already has a presence in smaller towns and cities like Mohali, Moradabad, Kota and Pondicherry and has tied up with the Jindal Group to operate a hospital in Raigarh. "Our tie-up with the Jindal Group has worked well for us and we hope to have similar partnerships in future," Mr Singh said. The company is likely to invest Rs 1,000 crore for the roll-out of various projects in the next two years, most of which will be financed through a combination of internal accruals and debt. Fortis has also embarked on an international expansion plan currently being executed through an entity called Fortis Global Healthcare, which is wholly-owned by the promoters, brothers Malvinder Mohan Singh and Shivinder Mohan Singh. Fortis lost out to Malaysian sovereign wealth fund Khazanah in a bidding battle that saw the company eventually tender shares it owned in Singapore-based Parkway Holdings to the fund. Parkway is amongst the largest hospital chains in Asia. However, the Singh brothers continue to have global aspirations for their healthcare business. They recently acquired assets from Hong Kong-based Quality Healthcare and a significant strategic interest in Australia and New Zealand's largest dental practice, Dental Corporation. Both acquisitions were made through Fortis Global Healthcare. "We are evaluating the option of listing in Singapore and other international markets but haven't taken a decision yet," Mr Singh confirmed without giving further details on which entity will be listed. Fortis is likely to launch its largest project so far in the current calendar year, a 1,000-bed hospital in Gurgaon. "The Gurgaon project will be a world-class facility. It will be like the Parkway Novena and all our attention is focused on getting that project up and running," Mr Singh said. Parkway Novena is a hospital project being set up by Parkway Holdings in Singapore, now a company 100%-owned by Khazanah. Max Healthcare to open 4 hospitals this year
The Economic Times
Max Healthcare is in the process of investing nearly Rs 540 crore to open four new hospitals in North India by September this year. "Max Healthcare will be opening four new hospitals with an average bed capacity of 250-300 with an average bed cost of nearly 45 lakh," Max healthcare CEO and managing director Pervez Ahmed said. The new hospitals, which will be multi-speciality, would come up at Shalimar Bagh in Delhi, Bhatinda and Mohali in Punjab and Dehradun. These would focus on heart diseases, trauma and cancer, he said, adding the hospitals at Bhatinda and Mohali would be under a public-private partnership mode with the Punjab government. Max Healthcare, which presently runs six hospitals and two centres, is also planning to enter into medical education in near future. "We are also planning to foray into medical education space but that would be three years from now," Ahmed said. One of the prominent hospital chains in the country, Max Healthcare at present has a capacity of over 930 beds. Apollo Hospitals to invest Rs 1,000 cr to set up 12 hospitals
The Economic Times
Healthcare chain Apollo Hospitals Enterprise will invest nearly Rs 1,000 crore to set up twelve new hospitals in small towns across the country over the next two years. "We will be investing up to Rs 1,000 crore to set up 12 ‘Apollo Reach' hospitals in tier-II and tier-III cities. The investment per hospital will be in the range of Rs 80 to 100 crore," Apollo Hospitals Chairman Prathap Reddy told reporters. Apollo Reach Hospitals is an initiative of the Apollo Hospitals Group to expand its tertiary healthcare business into semi-urban and rural areas. While construction work has already started on six hospitals, the company is still in the process of finalising sites for six more. It has already short-listed 14 locations. The company has started construction work at Trichi, Varanasi , Visakhapatnam, Nashik , Allahabad and suburban Mumbai ."We have already tied up funds for the first six hospitals. It would be in the form of debt and internal accruals. As we have an excellent debt-equity ratio, funding the next round of investment would not be an issue," Reddy said. The twelve new hospitals will also house training institutes for nurses and paramedical staff. The company also plans to invest Rs 100 crore on setting up another 500 pharmacies across the country over the next fifteen months. At present, it has nearly 1,200 pharmacies in India. Apollo Hospitals is one of the largest healthcare chains in the country and currently has 9,000 beds available at its hospitals. The company plans to increase its bed capacity to 12,000 by 2015. It also plans to augment the size of its workforce to 85,000 employees. Indians pay 78% of medical expenses from their own pocket
The Economic Times
Most of the medical expenses incurred by an average Indian are paid from their own pocket. According to an analysis published in the medical journal Lancet', private expenditure on health in India is close to 78% compared to 14% in the Maldives, 29% in Bhutan, 53% in Sri Lanka, 31% in Thailand and 61% in China. Only Pakistan is worse off with private expenditure being as high as 82.5%. The paper, "Financing health care for all: challenges and opportunities", says two features of the private out-of-pocket expenditure in India are noteworthy. First, most of the expenditure (74%) was incurred for outpatient treatment, and not for hospital care. Only 26% was for inpatient treatment. Secondly, purchasing drugs accounted for 72% of the total private out-of-pocket expenditure. According to Dr A.K Shiva Kumar, one of the primary authors of the paper, nearly 39 million people in India are pushed to poverty because of ill health every year. Around 30% in rural India actually didn't go for any treatment for pure financial reasons in 2004, up from 15% in 1995. Similarly, in urban areas, 20% of ailments were untreated for financial reasons in 2004, up from 10% in 1995. Shockingly, 47% of hospital admissions in rural India and 31% in urban India were financed by loans and the sale of assets. Dr Kumar, who is part of Prime Minister Manmohan Singh's high level expert group on universal health coverage, told TOI, "The health sector at present is a rip off for the common man. The future has to be tax funded. Preventive, primary and some part of secondary treatment has to be completely free, cashless and provided by the government and funded through taxes." Medical insurance too has a meager market share. According to the National Commission for Enterprises in the Unorganised Sector, only 7% of India's workforce is in the organised sector. The remaining 93% are cultivators, agricultural labourers, artisans and workers who typically do not have a regular or assured source of income. Analysis of per person public spending on health has also thrown up bleak results. While the government spent just 19 purchasing power parity (PPP) dollars on every person for health, the figure stood at 207 in Thailand, 122 in China, 88 in Sri Lanka, 751 in Maldives and 60 in Bhutan. "The per person government spending on health in India was about 22% of that in Sri Lanka, 16% of that in China and less than 10% of that in Thailand," the paper says. Public spending on health, 0.94% of the gross domestic product (GDP), is among the lowest in the world. Between 1986 and 2004, the average real expenditure per hospital admission increased three times in government and private hospitals. The sharp increase in the prices of drugs has been the main reason for the rising costs of medical care, which more than tripled between 1993-94 and 2006-07, says the paper. Dr Kumar added, "Between 1993-94 and 2004-05, compared with a 67% increase in real per person income and an 82% increase in per person tax collections, real per person public health expenditure rose from Rs 84 to Rs 125 -- an increase of 48%." RJ Corp plans 3 cos to scale up health biz
The Economic Times
The Jaipuria family-owned RJ Corp that runs cord blood stem cell banking venture, Cryobanks International India, plans to
float three privately-held companies to expand presence in healthcare business in India and Africa.
It plans to set up a stem cell research firm in collaboration with US-based Da Vinci Laboratories with an initial investment of Rs
50 crore, Dhara Jaipuria, chairperson, Cryobanks International India said. The American firm will share technological expertise
to conduct research in cell culture, cell differentiation and cell expansion to support its stem cell banking arm. "Globally, there
has been a lot of research in stem cell banking and we want to leverage this knowledge," CV Nerikar, CEO, Cryobanks
International India said.
RJ Corp also intends to form a chain of boutique maternity centres in Africa and India. The first set of centres in India will be
located in the north. Another venture is to start a diagnostic chain in Africa this calendar year to tap demand for healthcare
services in the region. This will run in line with its plans to scale up its operations across neighbouring countries and few other
emerging markets located in Middle East, Morocco and Zambia.

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The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society A Randomized Trial Comparing Levothyroxine withRadioactive Iodine in the Treatment of SporadicNontoxic Goiter MARIA F. T. WESCHE, MONIQUE M. C. TIEL-V BUUL, PAUL LIPS,NICO J. SMITS, AND WILMAR M. WIERSINGA Departments of Endocrinology and Metabolism (M.F.T.W., W.M.W.), Nuclear Medicine (M.M.C.T.-v.-B.),and Radiodiagnostics (N.J.S.), Academic Medical Center, University of Amsterdam,1105 AZ Amsterdam; and Department of Endocrinology (P.L.), AcademicHospital of the Free University, 1007 MB Amsterdam, The Netherlands


ARTICLE IN PRESS Basic Research—Technology Comparative Evaluation of Antimicrobial Efficacy ofSodium Hypochlorite, MTAD, and Tetraclean AgainstEnterococcus faecalis Biofilm Luciano Giardino, MD, DDS,* Emanule Ambu, MD, DDS,† Enrico Savoldi, MD, DDS,*Roberto Rimondini, PhD, MS,‡ Clara Cassanelli, MD,§ and Eugenio A. Debbia, MD§ AbstractThe aim of this study was to compare the antimicrobialefficacy of 5.25% NaOCl, BioPure MTAD (Dentsply