4 web lsi_aug_sep_2013

Mr. Apurva ShahGroup Managing Director Veeda Clinical Research

Mr. Arun SawhneyChairman, CII National Committee on Drugs & Pharamaceuticals and CEO & Managing Director Ranbaxy Laboratories Ltd

Dr. Arvind LalChairman and Managing Director Dr Lal PathLabs

Dr. Devi ShettyChairmanNarayana Hrudayalaya

Prof. N.K. GangulyPresident, JIPMER, Distinguished Biotechnology Research Professor, DBT & Former DG, ICMR

Mr. Hari BhartiaCo-Chairman and Managing DirectorJubilant Life Sciences Ltd

Dr. Kiran Mazumdar-ShawChairman and Managing Director Biocon Limited

Dr. R.A MashelkarNational Research Professor and Former DG, CSIR

Dr. Mrutyunjay SuarDirector, School of Biotechnology &CEO, KIIT-Technology Business Incubator

Dr. Naresh TrehanChairmanMedanta-The Medicity

Dr. Nitya AnandFormer Director, CDRI

Dr. Rajesh JainJoint Managing Director Panacea Biotec Ltd

Managing Editor: Vipin Balakrishnan

Editor: Hareeni Mageswaran

Consulting Editor: Shikha Dhawan

Consulting Editor: Dr Saji Salam

Copy Editor: Gouri Athale, Shekhar B

CII-Life Sciences Division

Dr. Sengupta

([email protected])

+91 99531 30050

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Editorial Advisory Board

August - September 2013

In an era of PPP’s, we must be prepared to innovate, collaborate and be consistent in deal-

ing with our Public Health issues. This issue has insights into the near mirage called NCD

management, we have to understand that the only way to tackle our public health issues is by

meaningful collaboration, as multi stakeholder relationship management and disease man-

agement is a challenge in a diverse country like ours . With the rise in non communicable

diseases, lifestyle related diseases we have to innovate ways of creating awareness, while

also fi nding innovating ways of creating pools of money consistently and effi cient manage-

ment of the resource pools. As a solution to this interesting yet mammoth task, we should

infuse communication, marketing and social media professionals in this Endeavour. Profes-

sionals with experience in Brands, Marketing, Advocacy, Public Relations, Events and Social

media professionals will make a huge difference.

These band wagon of professionals will catalyze collaboration infuse creativity and add a

fl avor of consistency. Constancy of purpose is the fi rst principle to success on such large scale

mandates like NCD, and uniting all efforts. In our country one of the greatest setbacks has

been the meeting eye to eye of policy makers and other stakeholders, and rigorous interac-

tions between them are the road to engagement, involvement and fi nally success. The large

scale benefi ts can be reaped by creating credible data pools and creating a cohesive working

environment. Corporate must be endowed with this responsibility by the Government, and

set as a premise for working.

Currently, our Country’s Public Health campaigns are more for the campaign sake not for

the Health sake. This attitude shift will call for a lot more participation of Corporate. Corpo-

rate with deep pockets and business interests must become eligible partners, as it takes the

corporate to make the partnership more engaging. The Ministry of Corporate Affairs must

device a Communication framework which actually captures the demographic challenges

of such campaigns, and thus stopping PPP’s parties from reinventing the wheel. The newly

passed CSR bill will help us see more responsible Corporate divas.

Hareeni Mageswaran

[email protected]

EDITOR'S NOTE

PPP’s– The Three C’s Collaboration,

Creativity and Consistency

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CONTENTSLSI | August - September 2013

Cover stories on NCD

Cover Story Interviews

17 Dr Jain DC

20 Dr W.D. Bhutia

21 Prof N.K. Ganguly

33 Dr Kamlesh Jain

26 CII White paper NCD

The researchers and this white paper clearly demonstrate the fact that each state has its own strengths, weaknesses and priorities which di! er from other states in many ways. Over the last two years, Diabetes management interventions under NPCDCS have reached more than 17.6 million patients, but with the incidence still going up, it is essential to scale up the e! ective interventions. The Government plans to scale up the response to the Diabetes epidemic by expanding the NPCDCS from 100 districts at present to cover all districts in the country during the 12th National Five Year Plan is appropriate and timely

10 NOT SO SWEET - The Indian diabetes saga: By 2030, India's diabetes burden is expected to cross the 100 million mark. Considering the rising burden of non-communicable diseases and existing risk factors, Government of India initiated the integrated National Program for Prevention and Control of Cancers, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS). It is essential to have the key public health facilities well sta! ed with appropriately skilled and equipped manpower to provide access to treatment services. It is also vital to have and follow standard treatment protocols for disease management.

35 HERBAL NEEM

FORMULATIONHerbal formulations which have reached widespread acceptability as therapeutic agents in India include nootropics,

antidiabetics, hepatoprotective agents and lipid lowering agents.

CONTENTS

Technology

55 Improving Vaccine Development

and Production Using Rapid Virus

Quanti! cation

There are many points during the process of developing, optimizing and producing vaccines that would bene� t from rapid enumeration of viral particles. One of the most signi� cant is tracking e� ciency following harvest from egg- and cell-based systems

60 NMR spectroscopy:

Creating waves in life sciencesNuclear magnetic resonance or NMR spectroscopy is a modern day tool that is used to delve deep into the intricate machinery that operates within each cell. Initially developed by physicists to gain insight into the magnetic properties of atom.

48 OPINION

Future of healthcare - IT OutsourcingThe US provider IT market is set to grow drastically, with a $19 billion investment into the sector as part of the US recovery plan signed by the President. However the Indian IT vendors may not be in a good position to leverage the growth in this market as most vendors have not made the right preparations/investments to address this market

Policy Watch

46 FDI in pharma need for a clear policy

regime The Government recently decided to take stock of the de-cade-old FDI policy for the pharma sector. This decision was in response to the potential threat of dominance from foreign players and a general rise in overall drug prices in the country, arising from a spate of acquisitions of Indian companies by MNCs starting in 2006. The most notable ones are the acquisi-tion of Matrix Labs by Mylan, followed by Daichii Sankyo’s acquisition of Ranbaxy, Sano� Aventis’s acquisition of Shanta Biotech and Abbott Labs’ takeover of Piramal Healthcare

43 Realizing the opportunity from

Pharmaceutical Patents in India The urgency of India’s need for access to advanced medical interventions including innovative pharmaceutical products cannot be overstated.

51 SPOTLIGHT Bio pesticides The Central Insecticide Board under the Department of Agriculture was established by Government of India, which is a regulatory authority for registering Insecticides. The Insecticides were covered under Insecticides Act 1968, whose names were included in the Insecticides Schedule from time to time by publishing in the Gazette of India, by the Govern-ment of India. Biopesticides are also governed by the Insecti-cide Act 1968, included in the Schedule. For any Biopesticide to be manufactured, which are included in the Insecticides in Schedule, it should be mandatory to register at Central Insec-ticide Board (CIB), Faridabad. Only after obtaining registration from CIB, then State Agriculture Departments of respective States will issue license for manufacturing of Biopesticides and Principle certi� cates for Marketing of Biopesticides.

40 Dr Vijayraghavan an academic turned policy makers shares some of his views on the Industry

Exclusive Interview

38 Academic Showcase

Dr Kumar Principal of Kumara Guru College of Technology Coimbatore shares their inspiring journey in innovation.

10 LIFESCIENCE INDIA | August - September 2013

LSI COVER STORY

-Jisha Krishnan

India will be home to more than 100 million diabetics, approximately, one-fifth of the global diabetes population, by 2030. We need to do everything we can and more to curb the exploding epidemic

The Indian diabetes saga

NOT SO SWEET

LIFESCIENCE INDIA | August - September 2013 11

LSI COVER STORY

“I don’t have a sweet tooth,” was the prompt response of a 30-something software engineer to the doctor’s suggestion of getting his blood sugar levels tested.

Ask any practicing physician and he is sure to share simi-lar experiences of patient ignorance and/indifference. And this is the educated, urban population in India we are talk-ing about. As we venture into the hinterlands, a majority of medical practitioners, too, fall into this category. For a country that is home to over 63 million diabetes patients - second only to China - the ground realities are more than shocking. According to International Diabetes Federation, 50 percent of Indians are unaware if they suffer from dia-betes. And among the other half, 50 percent do not take any treatment.

The silver lining, if any, is the latest buzz in the pharmaceu-tical industry: Over 15 new anti-diabetic drugs are ready to hit the market over the next couple of years. Also, an In-dian pharmaceutical company beat its global competitors to develop the fi rst of its kind anti-diabetic medication that holds immense promise for diabetics across the globe.Whether these drugs will succeed in meeting the hitherto unmet needs of diabetic patients, reduce the huge econom-ic burden, help improve the quality and quantity of life…these are questions only time will answer. For now, the saga continues.

Ground zeroEstimates suggest that 9.2 percent of adults in India have diabetes, making its prevalence second only to that in Chi-na. The country is home to over 63 million diabetes pa-tients, an increase from 50.8 million in 2010, says the Inter-national Diabetes Federation’s ‘Diabetes Atlas 2012’.The population with pre-diabetes (those with glucose lev-els higher than normal, and at increased risk to develop diabetes) is estimated to be approximately three times the size of the diabetic population. By 2030, India's diabetes burden is expected to cross the 100 million mark. “In clinical practice, a lot of patients we see today are in their late 20s and early 30s. The patient profi le has defi nite-ly got younger,” says Dr Arpandev Bhattacharyya, HOD, Department of Diabetes and Endocrinology at Manipal Hospital, Bangalore.

Diabetes mellitus – diabetes in common parlance – is caused either because the pancreas can’t produce insulin (type 1 diabetes) or the insulin that is produced isn't effec-tively shuttling sugar into the organs (type 2 diabetes). The latter is more common and preventable, courtesy sedentary lifestyles and unhealthy food habits, making it the focus of most diabetes research across the globe.

As far as the Indian scenario is concerned, we face a dual challenge. On the one hand, we are still struggling to come


LSI COVER STORY

to terms with long-standing challenges posed by commu-nicable diseases such as tuberculosis, malaria, cholera, di-arrhea, measles and leptospirosis; add to that, the current onslaught of non-communicable diseases (NCDs). As per disability-adjusted life year (DALY) which is a measure of years lost due to ill-health, disability or early death, for In-dia the topmost NCDs are cardiovascular diseases, diabe-tes, cancer and chronic obstructive pulmonary disease.

According to the Annual Report to the People on Health published by the Ministry of Health and Family Welfare, Government of India in September 2010, NCDs caused 40 percent of total deaths in rural India and 42 percent in urban India. The corresponding fi gures for communicable diseases were 40 percent and 38 percent respectively.

The World Health Report 2001 had indicated that NCDs accounted for nearly 60 percent of deaths worldwide and 75 percent of these occur in developing countries. Further, a person with NCDs is vulnerable to common infectious dis-eases like tuberculosis, community-acquired pneumonias and vaccine preventable diseases leading to poorer outcome for these diseases. “In the case of diabetes, most patients invariably also have to cope with cardiovascular disease, kidney disease, nerve damage and/or loss of limbs,” adds Dr Bhattacharyya.

As per the fi ndings of phase I of the Indian Council of Medical Research Diabetes Study, which recently covered the rural and urban settings in four states, the prevalence of diabetes in Tamil Nadu was 10.4 percent, 5.3 percent in Jharkhand, 13.6 percent in Chandigarh and 8.4 percent in Maharashtra. The prevalence of pre-diabetes was 8.3 per-cent, 8.1 percent, 14.6 percent and 12.8 percent respectively. The numbers are not small to be ignored.

Blame it on sedentary lifestyles, unhealthy dietary habits, genetic predisposition, the increasing cases of childhood obesity don’t make the picture any rosier. During the course of screening school children under the national programme for prevention and control of cancer, diabetes, cardiovas-cular diseases and stroke (NPCDCS), it was found that of the 92,047 children screened in Nainital (Uttarakhand),

Ratlam (Madhya Pradesh) and Bhilwara (Rajasthan), 1,351 (1.467%) were suspected to be diabetic.

Clinical quest What can’t be cured must be endured. For researchers and clinical practitioners across the globe, the biggest challenge is to come up with effective, affordable ways to manage the disease.

About 70 to 75 percent of diabetes patients are treated with a combination of two or more oral anti-diabetics (OADs) and 20 to 25 percent are treated with a single OAD, notes Dipak Mahajan, industry analyst, pharma & biotech, healthcare practice, Frost & Sullivan. However, due to the progressive nature of type 2 diabetes, most diabetics require insulin for glycemic control, making it unlikely to have a decrease in patient numbers.

According to Frost & Sullivan’s Competitive Intelligence re-search, Analysis of the Global Type 2 Diabetes Therapeutics Market, 15 new drugs for type 2 diabetes are in late-stage development (Phase 3 and preregistration). Metformin is expected to remain the fi rst-line therapy, in combination with Sulfonylureas; along with changes in diet and exer-cise.

The most signifi cant impact on the Indian diabetes thera-peutics market, according to Mahajan, is expected to be the launch of new Incretin Mimetics, Glucagon-like Peptide-1 (GLP-1) Agonists, and Dipeptidyl Peptidase-IV (DPP-IV) inhibitors, as well as increased use of new fi xed combina-tions and formulations of drug therapies in both insulin and non-insulin segments. “These new drug classes have better effi cacy and compliance,” he says.

New therapies are starting to address different possible roots of the condition, identifying new target areas with the potential to reverse disease progression alongside glu-cose regulation. “Therapies with the ability to preserve or restore beta cell function, postpone or prevent disease pro-gression, and allow patients to remain on a single therapy will be the game-changers in the years to come,” says Dr Subhash Kumar Wangnoo, senior consultant endocrinolo-

Therapies with the ability to preserve or restore beta cell function,

postpone or prevent disease progression, and allow patients to remain on

a single therapy will be the game-changers in the years to come

Says Dr Subhash Kumar Wangnoo, senior consultant endocrinologist and diabetologist at the Apollo Centre for Obesity, Diabe-

tes and Endocrinology, Indraprastha Apollo Hospital, New Delhi


LSI COVER STORY

gist and diabetologist at the Apollo Centre for Obesity, Diabetes and Endocrinology, Indraprastha Apollo Hospital, New Delhi.Medications which help lower blood glucose as well as manage weight - injectable thera-pies like exenatide (including the weekly once formulation) and liraglutide with lixisenatide - are good news for obese diabetic patients, especially in a country like India. “The need of the hour”, insists Dr Wangnoo, “is to individual-ise the treatment, rather than offer a blanket treatment for all”.

As far as monitoring disease progression is concerned, Dr Bhattacharyya says that contrary to popular perception, a very tight control is not such as good idea. “We have come to know from three landmark trials that exercising tighter control need not always be better; there are chances of low sugar, which can be life-threatening. So it is best to cust-omise the control depending on personal factors like the patient’s age, profession, family situation and the presence of other illnesses, among other things,” he says.

The most important unmet need of diabetes patients, ex-perts concur, remains clinically meaningful cardiovascular benefi t. Although improvements in surrogate markers such as lipids and infl ammatory biomarkers are a step in the right direction, clear demonstration of reduced risk of a car-diovascular event is critical for evidence-based medicine.

“We need robust evidence of not only effi cacy, but also of safety. Rosiglitazone was an excellent drug that had to be discontinued after years in use because of its increased risk of causing cardiovascular events. The recent controversy surrounding pioglitazone leading to its ban and re-approv-al are still fresh in the mind,” says Dr Wangnoo.

In June, the Indian government had suspended the contro-

versial drug, over concerns of the increased risk of blad-der cancer, only to revoke the suspension about a month later, after growing pressure from the medical fraternity. As one of the cheapest dia-betes medications, with a good glycemic profi le and low insulin resistance, doc-tors believe – with careful patient selection – the drug has an important role to play in the Indian scenario.

Government effortsIt is impossible to tackle an epidemic of such gigantic pro-portions without government will and action. Over the last two and half decades, though the Indian government has been making various efforts in this endeavor, the popular consensus is that it leaves a lot to be desired.

In 1987, the Government of India started the National Dia-betes Control Programme on pilot basis in some districts of Tamil Nadu, Jammu & Kashmir and Karnataka. The em-phasis was on prevention, early diagnosis and rehabilita-tion of patients. According to offi cial fi gures, Rs 12 lakh was allocated for the programme during 1995-96, while an al-location of one crore rupees was made the next year. How-ever, due to paucity of funds the programme couldn’t be expanded to cover other regions in the subsequent years.Later in 2005, the Ministry of Health spearheaded a nation-al consultation to “identify action pathways and partner-ships for implementing the Global Strategy in the context of India”. To contain the increasing burden of NCDs, the pilot phase of National Programme on Prevention and Control of Diabetes, Cardiovascular diseases and Stroke (NPDCS) was launched in January 2008. A total investment of about 350 million dollars is estimated to have been made to en-sure that every citizen over 35 years of age in the 10 selected districts of 10 states was tested for diabetes.

“India needs such concerted effort from the government to tackle the ever growing burden of diabetes. It is not only the burden which counts, but also the associated costs in-volved in diagnosis and treatment,” says Dr Wangnoo.

Medical expenditures for people with diabetes are 2.3 times


LSI COVER STORY

higher than for those without diabetes, observes Kiran Ma-zumdar Shaw, CMD, Biocon Ltd. In the U.S, direct medical costs are estimated to the tune of 176 billion dollars - which includes hospital and emergency care, doctor visits and medications – while indirect or non-medical costs come up to about 69 billion dollars. This includes costs for absen-teeism, reduced productivity and unemployment caused by diabetes-related disability.

“In India, the poorest persons with diabetes spend an av-erage of 25 percent of their family income on healthcare. Though cost of diabetes treatment in India is a tenth of that worldwide, the disease leads to severe fi nancial distress as most patients are uneducated or incapable of managing their disease by themselves because of diabetic complica-tions,” she says.

The government has been making efforts to step in. “In November 2012, the National Pharmaceutical Pricing Au-thority cut down the price of Glipizide from the erstwhile Rs 26,114 to Rs 15,946 per kg”, says Mahajan, “in a mea-sure that would ease burden on chronic patients taking the oral rapid and short acting anti-diabetic drug”. A number of multinational and generic companies currently manu-

facture and market this drug in India. Also, the National Pharmaceutical Pricing Authority (NPPA) has imposed a blanket ceiling on insulin prices, irrespective of the brand. “While the move is set to bring down insulin prices, it has left the industry upset, as it expects to lose signifi cant mar-gins due to the cap,” maintains Mahajan.

Industry initiativesTouted as one of the most attractive opportunities in the pharmaceutical segment, the global market for diabetes drugs and devices is expected to reach nearly 100 billion dollars within the next fi ve years. According to GBI Re-search’ study titled Diabetes Therapeutics Market in India to 2018 - Rapid Uptake of DPP-IV Inhibitors, GLP-1 Ago-nists and Expanding Insulin Segment to Drive Growth, the overall anti-diabetes market in India was worth 680.3 mil-lion dollars in 2011 and is projected to grow at a CAGR of 11.3 percent between 2011 and 2018 to reach 1,446 million dollars in 2018. “India has about 126 large and small com-panies, including MNCs and Indian generics players, com-

peting in the fragmented market for treatment of diabetes,” says Mahajan. Many multinational companies, such as No-vartis, Eli Lilly, are engaged in setting up strategic market-ing and distribution agreements with domestic players to improve their patient base and market share.

Differential pricing, low-cost manufacturing, introduction of innovative products, and rapid penetration into vast ru-ral markets are some of the strategies adopted by the phar-maceutical industry in India. Mahajan gives the example of Sanofi SA, which launched a low-cost, reusable insulin pen called AllStar, priced at Rs 650 in October 2012.

“Used by patients to inject insulin, this device is manufac-tured at a facility in Gujarat, one of two such plants Sanofi has worldwide. Similarly, Biocon’s IN105 is innovative oral insulin, which is expected to help overcome the challenge of invasive delivery of insulin and boost usage among both physicians and patients,” he adds.

Typically, newer class of drugs and innovative, patented products are relatively expensive, but companies are using differential pricing strategies to lower the price, making it affordable for the Indian market. In 2008, MSD launched its

patented Januvia (Sitagliptin) in India at a fi fth of its price in US. Further, patent expiries for drugs such as Glucotrol XL, Glyset, and Starlix (2009), Prandin/NovoNorm (2010), Ac-tos (2011), Lantus and Humalog (2014), and Avandia (2015) are expected to result in launch of their low-cost generic versions. In 2009, Biocon released Basalog, the generic ver-sion of Lantus in India, increasing affordability as well as usage of insulin. In 2010, Sanofi Aventis lowered the price of Lantus (patent expiry 2014) by half, making it affordable for low-income groups in Thailand and Indonesia. Reports suggest that further price reductions in other Southeast Asian countries are on the anvil.

Later this year, all eyes will be on Ahmedabad-based Zy-dus Cadila’s launch of the unique dual-action drug that is expected to help lower blood sugar as well as cholesterol levels (most diabetes patients tend to fi ght the cholesterol battle, too). As the fi rst indigenously-developed drug, Saro-glitazar, branded as Lipalyn, is the fi rst in its class of drugs called glitazars. “These drugs may also have the potential

India needs such concerted e� ort from the government to tackle

the ever growing burden of diabetes. It is not only the burden which

counts, but also the associated costs involved in diagnosis and treatmentsays Dr Wangnoo.


LSI COVER STORY

to modify the natural history of diabetes, thus portending their use in pre-diabetes,” says Dr Wangnoo.

Better awareAs far as public awareness campaigns are concerned, the industry has been proactive in partnering with government agencies. The Sanofi Diabetes Blue Fortnight 2012, for in-stance, is estimated to have reached out to over 10 million diabetics in the country.

As part of a collaborative effort by Sanofi , HEAL founda-tion, the Ministry of Health & Family Welfare India, Inter-national Diabetes Federation and Archaeological Survey of India, the campaign brought together various stakeholders in diabetes management - physicians, corporate, NGOs, media and patients - in an effort to enhance diabetes pre-vention, education and management. In June this year, Lilly India, in partnership with the Confederation of Indian Industry (CII) and Ministry of Health, hosted the inaugu-ral National Non-Communicable Disease Summit in New Delhi.

It has now become common practice for pharmaceutical companies to collaborate with hospitals to conduct diabetes awareness camps and offer free consultations. And, as Dr Bhattacharyya puts it, even if there is a ‘marketing agenda’, there’s no denying the public good that comes out of such initiatives.

Also, there are NGOs such as the Bill Gates Foundation, Wellcome Trust, as well as local organisations that have been playing a crucial role in advocating policy changes, funding constant research, spreading public awareness about prevention, early diagnosis and effi cient manage-ment of the disease. Despite all these efforts, the sad truth

remains that not enough is being done. According to a re-cent study (National programme on prevention and control of diabetes in India: Need to focus) published in the Aus-tralasian Medical Journal in June 2012, most ideas for an integrated approach to diabetes prevention and control are not fully implemented, partly because of insuffi cient fund-ing.

“Even though India accounts for about 15 percent of the world's diabetes burden, its spending on healthcare related to diabetes is only 6.4 percent of worldwide spending…Public-private partnerships are necessary at all levels of policy,” states the study. “The Public Health Foundation of India (PHFI), a partnership to address the limited institu-tional capacity for strengthening public health training, re-search, and policy development in India, is a good example. Funding comes primarily from the private sector, and the government is encouraged to match it,” it elaborates.

A laudable initiative mentioned in the study is the website www.healthy-india.org, launched in 2007, as a collabora-tive effort between PHFI and the Ministry of Health and Family Welfare, Government of India. Catering to today’s young professionals and net-savvy citizens, the online ven-ture advocates healthy living as well as prevention of dia-betes and other NCDs.

The prognosisStudies suggest that Indians aged over 30 – comprising about 40 percent of the population - are at risk of getting diabetes. Further, the population aged over 50 is expected to increase from 16 percent to 23 percent of the total popu-lation by 2030, adding signifi cantly to the number of diabe-tes cases. And then, for every diagnosed case of diabetes, there is at least one undiagnosed case of glucose intoler-ance, believe experts. In other words, the actual population at risk is much greater than our current estimate.

The need of the hour is a comprehensive policy on disease management, synergy among all healthcare stakeholders, effective public-private partnerships and increased govern-ment spending on prevention, screening, early intervention and new medical treatments to reduce the economic burden of the disease, essentially by cutting down on the associ-ated risk, morbidity and mortality. Ensuring that all doctors in rural India are qualifi ed to diagnose and treat diabetes, starting diabetes clinics at all primary health centres, en-couraging indigenous research and drug development, promoting an all-encompassing insurance coverage…the to-do list is rather exhaustive.

This is a race against time. We cannot afford ignorance. In-difference is not an option. One in fi ve diabetes patients across the globe will be an Indian. Whether or not one has a sweet tooth.


LSI COVER STORY

NCDs are surpassing communicable diseases as the most common causes of morbidity and premature mortality worldwide.

The major NCDs are cardiovascular diseases including heart diseases and stroke, diabetes, cancer and chronic respiratory diseases including chronic obstructive pulmonary disease and asthma, mental health, and injuries.

Global SituationAn estimated 36 million deaths, or 63% of the 57 million deaths that oc-curred globally in 2008, were due non communicable diseases, comprising mainly cardiovascular diseases (48%), cancer (21%), chronic respiratory dis-eases (12 %) and diabetes (3.5%) 1.

In 2008, 80% of all deaths (29 mil-lion) from NCDs occurred in low- and middle- income countries, and with a higher proportion (48%) of deaths in the latter countries are premature

(under the age of 70) compared to high-income countries (26%). As per the projections of World Health Orga-nization (WHO), the total number of deaths from NCDs will increase to 55 million by 20301, if timely and appro-priate interventions are not taken.

Magnitude of NCDs IndiaIndia is facing a great challenge of rising burden of Non Communicable Diseases resulting from rapid demographic and epidemiological transi-tions in the country. NCDs are affecting both urban and rural population and all socioeconomic strata in the country, causing signifi cant morbidity and mortality with consider-able loss in potentially years (aged 35-64 years) of life. NCDs including accidents and injuries are responsible for a larger

proportion of Disability Adjusted Life Years (DALYs) than that from com-municable, maternal and child health issues, and nutrition-related causes combined.

At present, there is no systematic re-porting system of non-communicable diseases in India; therefore it is diffi -cult to have genuine data. However, it is estimated that NCDs account for

NCDs in India: the current status,

strategy and role of corporate sector

in their Prevention and ControlDr. Jain, D.C.

(Former Deputy Director General (NCD), Ministry of Health & Family Welfare, Govt. of India)

Non-communicable diseases (NCDs) are becoming a major public health problem with leading cause of adult mortality and morbidity worldwide. NCDs are rapidly increasing globally and reached epidemic proportions in many countries, largely due to industrialization, socio-economic development, rapid urbanization, demographic and lifestyle changes. These diseases are posing a major challenge to the social and economic development, and place a tremendous demand on health systems and social welfare throughout the world especially in low/ and middle/income countries.

Figure 1

Propor� onal mortality (%of total deaths, all ages)

Source: WHO Non-communicable Diseases Country profi le 2011


LSI COVER STORY

about 53% of total deaths in 2008, and are projected to increase to 59% by 20152. The prevalence of diabetes is increasing both in urban and ru-ral population in India varying from 5-15% among urban populations, 4- 6% in semi-urban populations and 2.5% in rural populations3, 4.In 2008, a survey covering both urban and ru-ral areas reported a 5.9% of diabetes 5.

High blood pressure is major risk fac-tor for cardiovascular diseases and is directly responsible for 57% of all stroke deaths and 24% of all coro-nary heart disease deaths in India6. Several community-based studies in India have estimated the prevalence of hypertension in urban as well as rural areas. The meta-analysis of eight studies carried out in urban ar-eas gives a pooled prevalence rate of 164.18 per thousand and in rural ar-eas as 157.44 per thousand6.

Chronic Respiratory Diseases includ-ing Chronic Obstructive Pulmonary Diseases (COPD) and asthma are affecting largely younger and aging population. Projection of National Commission on Macroeconomics and Health (NCMH) report, 2005, shows

that asthma is expected to rise from 28.3 million in 2006 to 35.9 million by the year 20167.

Cancers contribute about 14% of the overall NCD mortality and 7% of the NCD/related DALYs8. According to National Cancer Registry Programme of ICMR, at any point of time, there are 28 lakh cases of cancer cases with 11 lakh new cases/ year & 5 lakh cancer deaths / year9.The most com-mon cancer are of oral cavity, lungs, oesophagus and stomach among in males, and cervix, breast and oral cavity in females. Tobacco is the most important identifi ed cause of cancer and is responsible for 30 to 50% of cancer in men and about 10 to 50 % of cancers in women.

NCD Risk Factors and Social Determinants

Causative factor for non-communica-ble disease is something other than a pathogen. It might result from he-reditary factors, improper diet, physi-cal inactivity, smoking, harmful use of alcohol, stress etc. Certain factors that increase the likelihood of getting NCDs are modifi able whereas others are non-modifi able risk factors. Fig-2

Priorities & Future Plans:The available data shows that NCDs are major contributor to high morbid-ity and mortality in the country with the risk factors; tobacco, harmful use of alcohol, lack of physical activity, un-healthy diet, obesity and stress. Most of the NCDs like Cancer, Diabetes, Cardiovascular Diseases (CVD), Men-tal Disorders and problems relating to ageing are not only chronic in nature but also have long pre-disease period where efforts of adopting healthy life style can prevent individuals from in-curring these diseases.

The Government has already given high priority to NCDs in the country and has implemented vertical pro-grammes for major non- communi-cable diseases with the objective of their prevention and control. One of these programmes is Prevention and Control of Cancer, Diabetes, CVDs and Stroke. Other programmes in-cludes on Health Care of the Elder-ly, Mental Health, Tobacco Control, Trauma Care, Blindness Control, Mi-cronutrients etc. Individually each of these programme made an effort to enhance capacity including strength-ening of physical infrastructure in a view to reduce the gap at urban and rural areas.

The National Programme for preven-tion and control of Cancer, Diabetes, CVDs and Stroke (NPCDCS) is un-der implementation in 100 districts (21 states) in the country10. The pro-gramme is being expanded to cover all districts in a uniform and phased manner during 12th Five Year Plan with integration of services at district and below level, equitable with uni-versal coverage under overall umbrella of National Health Mission. The main focus of the NPCDCS11 would be on development of data base including health management information sys-tem, promotion of healthy life styles, infrastructure development, early di-agnosis and management of diabetes, hypertension, cardiovascular diseases & common cancers e.g. cervix cancer,

Figure 2


LSI COVER STORY

breast cancer & oral cancer, and es-tablishment of linkages with tertiary care health facilities. To ensure long term sustainability of interventions, the programmes would be built with-in existing public health sector and wherever feasible introduce public private partnership models.

During 12 Five Year Pan, It is proposed to continue ongoing efforts and to introduce following key strategies:• Generating Awareness on behav-

ioural and physiological risk fac-tors for reducing exposure to life style diseases.

• Early Diagnosis through periodic/opportunistic screening of popu-lation and better diagnostic facili-ties

• Infrastructure Development and Human Resources with capacity for comprehensive management of NCDs

• Population based interventions through multi-sectoral approach

• Building evidence for action through surveillance, monitoring and research

Issues and challenges The magnitude of Non Communi-cable Diseases demands urgent at-tention. Common preventable risk factors underlie most NCDs. These include behavioural and metabolic risk factors. The prevalence of these varies between income groups and differs with gender. Till date there has been limited focus on these issues. With increasing burden of NCDs, the Health Sector will face many chal-lenges, which needs to be addressed urgently with an integrated compre-hensive framework of prevention and control of NCDs. The major issues and challenges related to prevention and control of NCDs are as under. i. Raised the priority accorded to the

prevention and control of Non Communicable Diseases in the national development agenda and the National Health Policy

ii. Develop, maintain and strengthen database and reporting system of

NCDs and their risk factors. iii. To strengthen national capacity,

leadership, governance, multisec-toral action and partnerships with stakeholders (including corporate sector, pharma ondustries and civil society) to accelerate country response for the prevention and control of NCDs

iv. Availability of cost-effective in-terventions including essential primary health care packages, and improves access to prevention programmes, essential medicines and affordable medical technol-ogy.

v. Budgetary allocations for high quality research, surveillance and monitoring systems for the pre-vention and control of NCDs.

vi. Development and availability of specialized human resource for prevention and treatment of NCDs, and establishing referral linkages and follow-up systems linkages across different levels of the health care system (primary, secondary and tertiary) to ensure timely treatment and follow-up interventions for patients suffer-ing with NCDs.

Role of Corporate Sector in Preven-tion and Control of NCDs

At the UN high-level meeting on non-communicable diseases (NCDs) in 2011, the member countries agreed that no one factor could fully address the burden of NCDs and called for collaboration with “non-health actors and key stakeholders, where appro-priate, including the corporate sec-tor and civil society, in collaborative partnerships to promote health and to reduce non-communicable dis-

ease risk factors — mainly tobacco, alcohol, and ultra-processed food and drink products

To achieve the goal of reducing the burden of NCDs both in urban as well as rural areas and all socioeco-nomic strata in the country, the cor-porate sector, pharma industries and civil society can play a crucial role by supplanting the efforts of central and state governments through public pri-vate partnership and under corporate sector responsibilities for the welfare of our citizens. The central and state governments should also involve dif-ferent stakeholders including corpo-rate sector in health promotion, early diagnosis and treatment of common NCD and availability of low cost di-agnostics, surgical procedures and medicines through suitable guide-lines and regulations. The planning commission also advocated for the partnership of government with dif-ferent stakeholders in the health sec-tor in 12th Plan Document.

After consultations and discussions at various platforms including World Health Organization’s global minis-terial conference on healthy lifestyles (April 2011) and the Global Health Council annual conference (June 2011), four areas where the private sector can have a positive impact: pro-moting workplace wellness, improv-ing access to diagnosis and treatment, creating healthy community environ-ments and strengthening education, training and research capacity. Many successful programs run by corporate sector and civil society through stra-tegic partnerships with governments and multilateral organizations.

The Government has already given high priority to NCDs

in the country and has implemented vertical programmes

for major non- communicable diseases with the objective

of their prevention and control. One of these programmes

is Prevention and Control of Cancer, Diabetes, CVDs and

Stroke


LSI COVER STORY

Dr. W.D. Bhutia, Deputy Director General, NCD, Government

of India in conversation with Shikha Dhawan

What all activities have the gov-ernment initiated under national program on prevention and control of cancers, diabetes, cardiovascular diseases and stroke (NPCDCS)?NPCDCS is being implemented in 100 districts spread over 21 states since 2010-11 and in 2011-2012 Assam and Sikkim were also included in the pro-gram. The districts have been selected keeping into account their backward-ness, inaccessibility and poor health indicators.

As on 12th August 2013, State NCD cells/ Clinics are functional at 16 sites. District NCD cell is functional in 70 districts, district NCD clinics are functional in 71 districts while 53 CHC clinics are functional in 8 dis-tricts. Cardiac Care Units are func-tional in 52 districts.

With support from private partners

(Roche and Abbott), 29,000 Glucom-eters, 5.8 crore Glucosestrips and 6.67 crore lancets have been supplied to 21 states for Diabetes screening under NPCDCS, urban health check-up and pilot phase of school health programmes.

Total 3,53,73,528 persons have been screened for diabetes and hyper-tension. Screening of all population above 30 years of age including preg-nant women and tuberculosis pa-tients is in itself a big achievement of the program. Out of the total popula-tion screened, 6.57% were found to be suspects for Diabetes and 6.37% were suspects for hypertension. The dia-betes suspects need to be confi rmed in diagnostic laboratories.

Chemotherapy services for cancer has started in 8 districts at Jorhat, dibrugarh, Rajkot, Jamnagar, Yamu-

nanagar, Darjeeling, Jalpaiguri and Dakshin Dinajpur. Cancer screening guidelines have been prepared and sent to the states.

National Institute of Health and Fam-ily Welfare (NIHFW) has trained 95 master trainers under ‘training of trainers” in 3 programme sessions. Additionally, 693 medical offi cers have been trained by states in 32 training sessions.

ANMs and other health workers have been trained about diabetes, hyper-tension and life style related issues that lead to such disorders.

A draft proposal for development of Text books on Health Education for schools from class IIIrd to Xth has been submitted to the ministry for ap-proval in collaboration with NCERT amd NIHFW.

What challenges have the gov-ernment faced in implementation of NPCDCS?The biggest challenge in implementa-tion of the NPCDCS is the availabil-ity of trained skilled manpower. As it was diffi cult to get cardiac specialists, we have appointed medical special-ists as in-charge of cardiac care units. Involvement of private partners in public health programs is also a chal-lenge as there is lack of clarity on their involvement.

Not much progress has been made in public private partnership as there are ongoing discussions on involvement of private partners in public health is-sues like mental health, tobacco con-trol and screening for diabetes.

NPCDCS was a stand-alone program so far. From 12th plan it has come under NRHM. With the availability of fl exipool under NRHM it will be much easier to get things done.

We are looking forward to the advan-tage that NRHM umbrella will offer.


LSI COVER STORY

What are the challenges to the early detection and management of diabetes, hypertension and stroke and how can these challenges be overcome?Unlike cancer, metabolic disorders like cardiovascular, stroke and dia-betes have linked with metagenom-ics signature so these can be handled together. Majority of people suffering from these diseases which have ge-netic predisposition are also affected by environment and are vulner-able from the time they are in their mother’s womb. Major environmental conditions being mother’s nutritional status as well as her exposure to nox-ious substances like tobacco, passive smoking and indoor pollution.

Children born with low birth weight grow normally for few weeks but then become obese with abnormal growth chart. They have high insulin and large proportion of them develop latent autoimmune diabetes which knocks down β cells of langerhans (insulin producing cells in pancreas). Recent advances in the understand-ing of the autoimmune process lead-ing to diabetes have generated inter-est in the potential use of vaccines to prevent type 1 diabetes.

A major challenge in diabetes is that 90% people do not know that they have diabetes. The solution is to have a surveillance system in place that can detect moderate hypertension, diabetes and cardiovascular disease. Biomarkers are also available to iden-tify these conditions. Use of a point of care device for diabetes that is reli-able and cost effective is very impor-tant. If random blood sugar levels are more than 130, further investigation is required as these may be probable prediabetics people who should be advised lifestyle management. Met-formin or Gliptins can be prescribed to people at risk for type 2 diabetes while those who cannot be managed by these drugs should be given insu-lin. It is also essential to get a baseline liver function test (LFT) for diabetes

patients. For diabetic retinopathy, proteomic signatures are used to de-tect retinopathy. At least 90% of these new cases could be reduced if there was proper and vigilant treatment and monitoring of the eyes.

Myocardial signatures like homo-cysteine, high sensitive C-reactive protein, ApoE, ApoB and triglycer-ides/HDL ratios can be monitored regularly in high risk patients. In-fact homocysteine is a common marker for diabetes, cardiovascular disease and stroke. If monitoring is done regularly, appropriate interventions can be done to control these diseases. Some major preventative measures can be mainte-nance of appropriate Vitamin-D and folate ratios in children. Cardiovas-cular disease can be prevented by use of PolycapTM developed by Cadila Pharmaceuticals Ltd. Trials conduct-

ed under the leadership of Dr. Salim Yusuf and funded by Welcome Trust have shown that PolycapTM reduces the risk of coronary heart disease by 62% and stroke by 48%. The drug has also shown to bring down the multi-ple risk factors for cardiovascular dis-ease such as lowering of blood pres-sure, heart rate, lipids and decreasing stickiness of platelets.

Another major breakthrough has been the use of endoscopic proce-dures to avoid obese bariatric surgery and stomach surgery. The procedures cause signifi cant long-term loss of weight, recovery from diabetes, im-provement in cardiovascular risk fac-tors, and a reduction in mortality from 40% to 23%. It is also very important to manage nutrition uptake appropri-ately in diabetes patients. In diabetes, higher amounts of glycosylated he-

Prof. N.K. Ganguly, Advisor, Translational Health Science and

Technology Institute and President, Jawaharlal Institute of Post

Graduate Medical Education and Research in India and former

Director General of the Indian Council of Medical Research in

conversation with Shikha Dhawan


LSI COVER STORY

moglobin, indicates poorer control of blood glucose levels and has been as-sociated with cardiovascular disease, nephropathy, and retinopathy. Moni-toring HbA1c in diabetic patients may improve their outcomes.

Another important program in the control of diabetes is tobacco cessa-tion. Tuberculosis prevalence is also high in diabetes patients. Tolerance to TB drugs can be diffi cult to manage in diabetics as side effects such as nau-sea and loss of appetite are very chal-lenging when trying to closely man-age blood sugar. In a broader sense due to the exacerbating effect many non-communicable diseases are likely to have on the existing disease burden, an integrated public health systems approach for management, better screening, diagnosis, treatment and care of communicable and non-communicable diseases is important. Effective health care fi nancing and well-trained providers are essential in our endeavors against all kinds of infection and diseases.

Is academic research in India aligned to the needs of our indus-tries?Academic research is undertaken for publication and sometimes to fi le pat-ents as well. Publications are the end point for most scientists as publica-tions are linked to their promotion. University systems have very less in-teractions with industries, except in Indian Institute of Science (IISc) in Bangalore where industry has incu-bation sites. IISc has introduced many innovative and fl exible operational modes for collaboration with indus-tries. The aim is to provide a research oriented environment coupled with hi-tech facilities and the availability of technical expertise present within the IISc community.

Industry and academic interactions can be seen as a mandate in many prestigious CSIR and DBT funded re-search institutes. Translational Health Science and Technology Institute (THSTI) is part of an emerging health

biotech science cluster and has been created for the conduct of multidisci-plinary research that translates scien-tifi c and technological advancements into medical innovations that can fi nally be taken up by industries to improve public health. In addition to IISc and THSTI, many CSIR labs have good industrial orientation. CSIR is closely working with various indig-enous industries, private and public sector undertakings to develop and commercialize its R&D results and technologies.

The government initiated New Mil-lennium Indian Technology leader-ship Initiative (NMITLI) operates in public-private partnership. NMITLI has crafted many technology projects involving industry partners and R&D institutions setting new global tech-nological paradigms in the areas such as nano material catalysts, industrial chemicals, gene based new targets for advanced drug delivery systems, bio-technology, bio-informatics, improved liquid crystal devices etc. The scheme is being implemented by CSIR.

Biotechnology Industry Research As-sistance Council (BIRAC) set up as Department of Biotechnology’s inter-face agency has many initiatives that promote industrial collaborations. Its vision is to facilitate and mentor the generation and translation of innova-tive ideas into biotech products and services by the industry, promote aca-demia and industry collaboration and enable creation and sustainability of viable bio enterprises.

In your view how successful is government’s ambitious program on management of non-communi-cable diseases?Government’s national program on prevention and control of cancers, diabetes, cardiovascular diseases and stroke (NPCDCS) is focused on health promotion and prevention, strengthening of infrastructure in-cluding human resources, early diag-nosis and management of these non-communicable diseases. NPCDCS is a hugely expensive program. Budget

is a challenge in its implementation so public-private partnerships (PPP) mode can play a very important role in all possible health care interven-tions at primary and tertiary health care centers.

Integrated surveillance systems can be set up through PPP. Diagnostic reagents and devices are generally costly and are in the hands of private sector. Inclusion of private sectors as care providers can provide cost ef-fective interventions and also pro-vide many health care options to care seekers. An insurance system that is standardized can help the marginal-ized population.

Community driven initiative by Ab-bott India Ltd with the Puduch-erry government has implemented a healthcare programme for people suf-fering with diabetes, dyslipidaemia, hypertension and thyroid disorders. Abbott provided subsidized diagnos-tics, educational support to healthcare providers, patient awareness material and conducted diet guidance camps. Random and fasting sugar levels, gly-cosylated hemoglobin, blood pressure and thyroid levels were monitored and at least 700,000 people in the union territory after screening were stratifi ed as per their need and put on interventions. Government has also taken up these initiatives in 100 dis-tricts at different health care levels in different states.

However, there are many grey areas in public-private partnerships. The gov-ernment can help by bringing in more transparency and more clarity in such collaborations. Appropriate matrixes are required so that PPP becomes the most preferred collaboration in the public health arena. The government has to make policies, processes and modalities to streamline things. PPP gains and spin-offs should be han-dled well and profi t sharing between partners should be spelled out clearly with accountability well established and audited routinely by impartial parties


LSI COVER STORY

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LSI COVER STORY

Financial Burden from Non-Communicable Diseases and the Road Ahead

-Shikha Dhawan

Non-communicable diseases (NCDs) like diabetes, cancers, cardiovascular diseases are no longer a lifestyle related disease of rich countries. With the emerging lifestyle trends and sedentary way of life, NCDs now account for a very large burden in terms of both mortality and morbidity in low and middle income countries (LMICs)

Communicable and non-communicable diseases (NCD) account for 60% of all deaths worldwide, with

80% of those taking place in develop-ing countries and in the age groups of prime productivity. As per disability-adjusted life year (DALY) which is a measure of years lost due to ill-health, disability or early death, for India the topmost NCDs are: Cardiovascular Diseases (CVDs), Diabetes, Cancer and Chronic Obstructive Pulmonary Disease (COPD) and Communicable Diseases are: Pneumonia, HIV/AIDS, Tuberculosis and Vaccine preventable diseases.

The major risk factors for non-commu-nicable diseases are smoking, alcohol abuse, a sedentary lifestyle and an un-healthy diet. The dilemma for health care system is that a person with a non-communicable disease is also vul-nerable to common infectious diseases like tuberculosis, community-acquired pneumonias and vaccine preventable

diseases leading to poorer outcome for these diseases. Direct cost for patients with co-morbidities is generally 45% higher than the direct cost for patients without co-morbidities.Burden of disease associated with NCDs and injuries is higher than that associated with the health conditions included in the Millennium Develop-ment Goals (HIV/AIDS, tuberculosis, malaria, and maternal, child and re-productive health), even in develop-ing countries. The menace of NCDs are expected to exceed communicable, prenatal and food borne diseases as the leading causes of death in all coun-tries by 2020.

NCDs pose a heavy fi nancial burden on poor households as cost of medi-cines is expensive. When it is diffi cult to meet day-to-day mundane expens-es, the treatment of NCDs has fi nan-cial implications on affected house-holds. Cost can be a major deterrent to seek medical care. For diabetes, cost of insulin represents an important source


LSI COVER STORY

of spending for patients and their families. NCDs management is not well covered under our health insur-ance systems.

There are indirect costs which also have to be borne by individuals af-fected by NCDs. These costs mainly include time and productivity loss by patients and caregivers because of the illness as well as income lost by patients and family members. Com-plications and co-morbidities related to the severity of illness increase the household fi nancial burden.

Health-fi nancing systems that im-prove fi nancial risk protection and help achieve universal health cover-age holds great potential to manage the fi nancial burden of NCDs.

The need of the hour is a comprehen-sive policy on disease management, synergy among all healthcare stake-holders, effective public-private part-nerships and increased government spending on prevention, screening, early intervention and new medical treatments to reduce the economic burden of non-communica-ble diseases by reducing risk, morbidity and mortality relat-ed to these diseases. Health promotion, prevention and early treatment would reduce some of the direct costs by appropriate mix of preven-tion and treatment according to their relative costs and im-pact.

Costs can be further reduced by rational use of medications for NCDs. Government of India has launched the am-bitious integrated National Programme for Prevention and Control of Cancers, Dia-betes, Cardiovascular Dis-eases and Stroke (NPCDCS) since 2010 with focus on health promotion and pre-vention, strengthening of infrastructure including hu-

man resources, early diagnosis and management and integration with the primary health care system through NCD cells at different levels for opti-mal operational synergies. Under the 12th Plan, the program has come un-der NRHM and the country is looking forward to the advantage the NRHM umbrella will offer.

All said and done, health promotion and prevention of chronic NCDs are yet to be adequately addressed in the country’s health system. Though many commendable targets have been achieved since the implementation of the NPCDCS program, a lot needs to be done still. The achievements of the program till date include development of Operational Guidelines and train-ing modules for Health Workers and Medical Offi cers.

Human resource has been hired for National NCD Cell while setting up of State and District NCD cells are in process. Funds for implementation of NPCDCS in 27 districts across 19 states were released in March 2011 for opportunistic screening, establish-

ment of ‘NCD clinic’ at CHCs and District Hospitals. Efforts are being taken to increase awareness for promotion of healthy lifestyle through involvement of mass media.

Training of master trainers have been done by National Institute of Health and Family Welfare (NIHFW) and Indian Nursing Counsel. Pilot proj-ect on school based diabetes screen-ing programme have been initiated in many districts. The health ministry, along with Confederation of Indian Industry (CII) and pharmaceutical company Eli Lilly and Co., is work-ing on policy interventions to control diabetes.

The health ministry is also exploring the possibilities of public private part-nership (PPP) initiatives and the in-volvement of industry to complement the government’s programme. Health Ministry has envisaged including cur-riculum on health education as part of 2014’s academic curriculum in Central Board of Secondary Education (CBSE) affi liated schools across India.

Noncommunicable

disease

Seekcare

Indirectcosts

Loss of working time of person who is ill &

caregivers

Loss of income of person who is ill &

caregivers (due to absenteeism,

missing business appointments, etc.)

Financial costs of health care (consultation,

medicines, laboratory, hospitalization, etc)

Other �nancial costs related to seeking care (transportation, special

dietary regimes, etc.)

Intra-& inter household labour

substitution

Hiring other labour & other

strategies

Reducing/delaying consumption of

non-health goods & services (food,

education, electricity, leisure, etc)

Reduced well being and increased

�nancial vulnerability for

individuals & households

Use of savings

Sale of assets

Borrowing

Delaying investments

Other strategies to cope with �nancial

costs (assistance from other, etc)

Directs costs

Yes

No

Framework for the analysis of economic impacts of NCDs on households.Ref: McIntyre D. et al (2006), Soc Sci Med


LSI COVER STORY

Research clearly indicates that countries,

states, regions with greater means of health

education and awareness have better health

outcomes, giving the healthcare providers and

policy makers the option to choose the best

interventions leads to overall improvement in

the healthcare outcomes of the community. In

practice, however, � nding the mechanism to

make this happen is di� cult. Ultimately, as in

any system, the real value of choice comes from

people having the right information to select

the option that is superior. This framework

endeavors to systematically present the available

information and options for the policy makers

and program managers. The framework has been

designed to be in synchrony with the NPCDCS

strategy that aims to strengthen prevention,

diagnosis, treatment and capacity aspects of the

health system.

CII Recommendations' based action plan(linked to NPCDCS Strategic Framework)

Issue Recommendations

Strategy 1) Prevention through behaviour change

Very little focus on "root cause" of disease

Put emphasis of health education with focus on prevention activities like exercise, dietary control and stress management in children and young adults.

Promote workplace interventions like use of stairs, no-smokingpolicies, standing desks etc should be promoted

Deploy mass media campaigns (through print, electronic and social media) for increasing community awareness regarding healthy dietary practices

Revisit media policies to discourage advertisements related to junk/fast food, tobacco and other harmful commodities while promoting messages related to exercise, healthy lifestyle etc is important.

The private partners, development agencies and Government to synergize CSR and development activities to streamline them with the NPCDCS program.

"Diabetes Education Kiosks" should be set up jointly by the government and non-governmental partners to enable community in getting key health education messages closer to their homes.

Limited involvement of community based groups

PRI (Panchayati Raj Institutions), NGOs, CBOs and community forums like Ramayan Mandalis, Saas Bahu sammelans should be involved for providing health education regarding prevention, screening, early diagnosis and timely & appropriate treatment


LSI COVER STORY

Strategy 2) Early Diagnosis (and screening)

No opportunisticscreening beingconducted at healthfacilities for DM

Cross referrals from programs like RNTCP and NPCB can help identify cases early

Non-diabetic but overweight and the high risk group people (having family history, having low birth weight) should be given a dietary plan, exercise advice and followed-up after 6 months.

Limited outreach ofscreening facilities

Glucometers to be made available at all the sub centre level and PHCs

A standardized screening system to have accurate linkages between different facilities

Integration and collaboration with screening systems established in other national programs like RNTCP, NPCB, RCH, NACP.


PPPs (Public Private Partnerships) with NGOs, CBOs and professional bodies (like IMA, IAP, OPPI, FOGSI etc) for reaching out to the community with better screening

Use of IDRS (Indian Diabetic Risk score) for screening in resource limited situations

Mobile Health Units, to be equipped with screening facilities for DM

At CHC level in addition to regular screening, HbA1c (Glycosylated Haemoglobin) estimation should be conducted and the diabetic management should be done based onHbA1C results.

No separate cadre that can be engaged for screening in urban areas.

Municipal corporations in the state often function as a separate system. There is a need to collaborate with the urban local bodies to synergize the health interventions being implemented by NPCDCS, Ministry of Health and Family Welfare and Urban Development.

System of urban dispensaries or health centres set up by urban local bodies to be equipped with screening tools and equipment

Strategy 3) Treatment

Deficiency in availability of Human resources at thefacilities

Filling up of medical specialist vacancies in medical colleges, district hospitals and CHCs..

Empanelment of senior doctors through associations, corporate and individually for tertiary care hospitals and peripheral centres for complications management


Building ICT platforms like telemedicine, GramSat for areaswhere there is lack of any skilled manpower and limitedopportunities to hire or partner with private sector

Utilizing peripheral workforce available under ICDS (Integrated Child Development Services) Scheme - Aanganwadi workers and under NRHM - ASHA workers.

Verticality in theprograms leading toartificial shortages inHR

Integrated approach to disease management, including integration of funding lines and reporting mechanisms.

Realignment of roles and responsibilities of healthcare providers aimed at multi-skilling and holistic disease management.

Continuum of care approach where a General Physician, an Ophthalmologist, an Endocrinologist, vascular surgeon neurologist work in tandem for treatment of DM


Limited reach to adolescents and other vulnerable groups

While targeting the adolescents and children, health educators should reach out to school children through National Rural Health Mission's School Health Program with messages pertaining to good dietary practices.

Health education to pregnant women could be provided at the outreach sites (MCHN days).

High incidence of LBW babies - a contributor to insulin resistance

Awareness campaign to promote better dietary practices, ante-natal care and rest during last-trimester of pregnancy etc.

Have a directory of LBW babies to screen LBW babies at regular intervals for pre-diabetes


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Ambiguous Policies Clear policy on deputation, transfer & posting, promotions etc, which also has performance linked incentives tied to clear deliverables.

Clarity on roles and responsibilities of existing manpower, with clear delegation of funds, functions and functionaries

Need for greater flexibility for the state to re-align funding for locally relevant NCD activities and regional priorities, akin to NRHM flexi-pool.

No cadre of diabetescounselors

A diabetes educators cadre to provide specialized counselling services at ter� ary level

Diabetes educators or counsellors should be available on a toll free helpline for increasing compliance

High out of pocketexpenses due to lackof reimbursementmechanisms

An OPD based Insurance scheme for Non-communicable diseases like Diabetes.

The exis� ng reimbursement systems like Rashtriya Swashthya Bima Yojana (RSBY) cover only the hospitalization and not chronic illnesses like diabetes. There is a need to extend this to the out-patient care for DM, Hypertension to prevent subsequent expenditure on treating complications.

Drugs should be available, accessible and affordable at all levels of health system - the PHCs, CHCs, DHs and teaching centres. The free supply of medicines in the government medical college hospitals and tertiary care general hospitals needs to be streamlined.


Limited compliance to standard treatment guidelines

Doctors need to be provided with a protocol based guide for reference, appropriate training and CMEs

to become confi dent and work away the fear of prescribing insulin.

Weak referral linkages nReferral systems are weak at the peripheral level and there is a need for JSY-like referral transportation system for emergencies arising out of NCDs

Supply chain management issues

Glucometers, Insulin and other supplies procurement and logistics management should be adequately budgeted and timely procurement initiated, keeping in view the lag time.

The industry stakeholders could provide better packaging for anti-diabetic drugs with clear indications, treatment modalities and compliance printed on the packaging

Strategy 4) Capacity building of human resources (healthcare providers)

Training needs unknown Training needs assessment during and after the recruitment of manpower, on NCDs.

Budgeting related to training to be in line with the training needs assessment of each state.

Limited integration of training

Integration of NCDs prevention and treatment in pre-service and in-service training

The training on NCDs should be made mandatory or; linked to career development opportunities.

Annual training calendars for each state should be developed in advance in consultation with the NCD cell and shared with all potential training institutes to ensure timely engagement.

Limited diagnosticfacilities

Facility survey and facility needs assessment should be conducted regularly to know the exact status of existing equipment in various institutions, for diagnosis and treatment of DM

Glycosylated Hemoglobin tests and Microalbuminuria should also be added to the list of free investigations

Advanced tests should be conducted at DH and Medical College levels to screen for complications especially those related to kidney, eyes, feet and nervous system. At teaching institutions in addition to other tests, the Insulin sensitivity test should also be performed.


LSI COVER STORY


Limited orientation regarding NCDs

Standardized orientation programs for NCD program management team, including Simple operational guidelines on fund utilization.

Orientation training of policymakers on various prevention, treatment and complications management strategies for DM.

Training of nursing staff as Diabetic educators and in using innovative tools like Diabetes Conversation Maps

Chemists and pharmacists should be trained and sensitized about the need for providing literature, explaining the effects, side effects, importance of compliance and complications related to DM.

Few opportunities of continuing medical education around DM

DM should be included regularly in the CME programs for doctors and nurses

CMEs should focus on special indications like juvenile diabetes, gestational diabetes and complications management, with involvement of both public and private healthcare providers at primary, secondary and tertiary levels.

To avoid treatment related complications and enhance patient outcomes, have uniformity in the treatment modalities throughout the country. This could be achieved through standard treatment guidelines for DM.

nLimited capacity of State/ National training institutes

Government could source-in or source-out trainings on NCD through partnerships with multitude of leading training institutes (public and private) like SIHFW, NIHFW, Medical Colleges, Regional institutes and other autonomous public health bodies.


nVirtual (online) lectures for medical and paramedical staff for training on DM updating and enhancing technical expertise and confidence in managing a case of DM.

nMultiple training institutes working in isolation – no uniformity or accreditation of curriculum

A nodal agency at the national level capacitated to provide accreditation to training courses for healthcare providers to be followed uniformly by all states

Standard training modules or manuals on NCDs to be used uniformly by all training institutes

Regular up-gradation (maybe once a year) of training course curriculum across all training institutes

Strategy 5) Surveillance, Monitoring & Evaluation Recommendations

Multiple MIS formats There are several stand-alone MIS in the health system which need to be standardized and integrated.

The MIS for NPCDCS should be mainstreamed with other cross-sectoral initiatives being carried out by Government and other development partners (like World Bank, USAID, FAO, WFP, UNICEF, WHO etc)

Engaging PRI (Panchayati Raj Institutions) members in community-based monitoring. The Village Health Committee (VHC) should form the link between the Healthcare providers and the community.

Limited disease surveillance systems

A clinical registry of the people suffering from DM should be prepared. All the individuals seeking services from NPCDCS should be given health card with unique identity number to track treatment. Duplication of diagnostic tests leads to wastage. To avoid this medical history of the patient can be linked to the Aadhaar card (UID) on a medical record system.


A program surveillance unit to conduct performance audit and allocation of funds

Ensuring quality control by conducting frequent prescription audits to help in standardizing treatment practices and ensuring quality control towards ensuring patient satisfaction.


LSI COVER STORY

LEARNING FROM CII NCD STATE ROUNDTABLES


LSI COVER STORY


LSI COVER STORY


LSI COVER STORY

Q Chhattisgarh is implementing the NPCDS program since when and in what all districts? In 2010 the state received the offi cial communication from Government of India that 3 districts have been selected for Government’s national program on prevention and control of cancers, diabetes, cardiovascular diseases and stroke (NPCDCS). These programs were initiated initially in Bi-laspur (pilot district), while in and 2011 and 2012 two more districts Raipur and Jashpur were selected. Since 2010, not much progress had been made in the programme. In 2012-13, I was appointed as the state nodal offi cer for prop-er structuring and implementation of the program at the state level. NCD Cell set out to increase the visibility of the program in the fi eld in terms of structure, proper human resources and guidelines that could percolate down in the districts. At present, three NCD (Non Communicable Dis-ease) clinics have been established called the Healthy Life Style Centre one per district in district hospitals. 15 NCD clinics will be established in community health centers and a total of about 38 NCD clinics will be established in the entire three districts.

The current status is that the State NCD cell has been es-tablished as per the mandate of the program. Finance and logistics offi cers have been appointed. Program Associates are working in the districts along with 14 health counselors and 26 Data Entry Operators.

Dr. Kamlesh Jain, State Nodal of� cer, NCD,

Chhattisgarh in conversation with Deepti

Nirwal


LSI COVER STORY

Q What all constraints have been faced by the state in implementa-tion of the program?The mandate of the program is that state’s share of the budget is 15% and rest is provided by the centre. Here comes a challenge for implementation i.e. the funds are allocated activity wise. This needed to be streamlined as sometimes the available funds can’t be utilized properly. If the funds are provided as a complete grant for the programme it could be utilized as per activity. Another constraint is that NCDs are taken as a parallel program. The health system is more tuned to handle communicable dis-

eases like malaria and tuberculosis. NCDs should be made a comprehen-sive part of integrated health care. Refresher training is required for the existing human cadre as NCDs are not a parallel program. To begin with, already available specialist doctors should be mobilized. Further down the line when OPD strength increas-es the manpower strength can also be increased.

A major constraint in the NCD na-tional program that I faced was hir-ing of doctors and management staff. Chhattisgarh is a tribal dominant state so we had problem to get trained qualifi ed specialists. At times, quali-fi cations were high so there was mis-match with the remuneration.

Q What all initiatives have been taken by the state for the diabetes program and what is the way for-ward?In sub-health centers at grass root levels diabetes screening programs have been successfully implemented. Till date 9,70,028 people have been screened for diabetes with glucostrips. Amongst these 57,444 are diabetes

suspects with >140 mg/dl glucose lev-els. Although diabetes is an emerg-ing problem, its visibility is lacking in public. Even public health systems are not inclined to screen for NCDs. We have to break the myth that diabetes can be treated only by private provid-ers.

In 2012, I have carried out orienta-tion of doctors and health providers. Community vibrations were brought about by healthy life style abhiyans. Community mobilization was done using TV, audio video systems, health camps, counselor meetings, paint-ing competition at schools. The fi rst

week of November is every year cel-ebrated as Chhattisgarh establish-ment week “Rajyotsava”. During the 2012 celebrations, NCDs were given prominence through exhibitions and the message was clearly given that the health department is interested in managing NCDs. On 14th No-vember 2012, World diabetes Day, we ran a “Blue Light Campaign”. Major government buildings of the state were lighted with symbolic blue light to spread awareness about Diabetes. This innovative initiative of the state NCD cell received a wide media cov-erage and lot of print. TV channels covered the news with great impor-tance. This helped to sensitize the general public about World Diabetes Day and the campaign.

State NCD cell has succeeded to reach 10 lakh population of the state through media campaign in associa-tion with prestigious news and FM channels. Jingles on FM on diabetes and lifestyle diseases and awareness messages of Honorable Chief Minister of state resonated the message across the state. State of Chhattisgarh’s ef-forts in spreading awareness on Dia-

betes has become one of the unique initiatives across the country. Nearly 700 prominent personalities across the state were presented a symbolic blue ring (meaning uniting for Diabetes) and briefed about diabetes and their support was sought for the campaign. Campaign also made efforts to reach to the general population and more than 300 persons have been present-ed with the symbolic blue ring.

To bring more visibility, I have planned to identify parallel support from Pub-lic Private Partners (PPP) to establish Diabetic Day Care, Lifestyle Centre in Raipur and Bilaspur and also for school heath based program in PPP mode. I have roped in funds from European Union (European Union State Partnership Program) as well to establish Diabetic Clinics. At present we are looking for NGOs or company CSR to run these clinics for NCDs. Ex-pression of Interest (EOI) was issued and we have received about 35 EOIs. Currently, I have put up a proposal to CII to help in fi nding an implement-ing partner.

Under NCDs program, recruitment of doctors was diffi cult. So we gave good remunerations and empanelled part-time doctors for 3-4 hrs to conduct camps. State’s 2013 Essential Drug List has included the drugs for NCD program to provide free drugs. I had also initiated a proposal for juvenile diabetes mellitus to track young pa-tients and give them free insulin till 23 years of age. But due to free drug policy, the drugs for juvenile diabetes mellitus patients will now be given free anyways.

New innovative devices especially non-invasive technologies have been added in state’s project implementa-tion plan. Efforts have to be done to endorse new devices within the pub-lic health system. We have even con-stituted a committee to judge the util-ity of novel devices in public health system.

Under NCDs program, recruitment of doctors was di� cult.

So we gave good remunerations and empanelled part-

time doctors for 3-4 hrs to conduct camps


LSI SPOTLIGHT

HERBAL NEEM FORMULATION: Miracle cure for wound healing

-Poorva Shrivastava

Since time immemorial, herbal medicines have been popular as remedies for diseases worldwide. These are safe since they are natural products. Herbal formulations which have reached widespread acceptability as therapeutic agents in India include nootropics, antidiabetics, hepatoprotective agents and lipid lowering agents. The use of herbs is often more affordable than purchasing expensive modern pharmaceuticals.

Infected wounds in legs, foot and other parts of the body are very common clinical prob-lems that require intensive care in a wound clinic. These wounds are caused by trauma

or complicated surgical operations on infected or-gans. Patients suffering from diabetes, arterial or venous disease of lower limbs have a high risk of developing infected wounds. Any wound or ulcer that does not heal in 6 weeks is said to be a chronic wound.

There is more than one reason why a wound does not heal, infection being just one. Lack of blood supply, venous or arterial insuffi ciency, radiation, foreign bodies, nutritional defi ciency, diabetes, jaundice, alcoholism, toxins, cancer, steroids and chemotherapeutic agents, hereditary healing dis-


LSI SPOTLIGHT

Applications and bene�t of making Novel Oil

Soak Neem in water for 12 hrs

Boil the waterNeem

Decoction

Drink Neem decoction to

enhance immunity, activate metabolism,

purify blood

Steam isgenerated

Take neem bath and in-hale steam

Wash your bodyNeem Decoction

Mix in 4 oils and 17 herbs to get Novel Oil which would cure any kind of wound, any kind of skin

disease and Allopecia

order, old age etc., can be cited as other reasons. Among these the most common reason being diabetes, where the only solution at times is amputation. These wounds are treated with various antiseptics and dressing materials. Most of these are provided by multinational companies at a very high cost. Moreover the antiseptics used are harmful to the healing process and are expensive too.

The high cost makes these unaffordable to the common man. These antiseptics have been actually shown to be cytotoxic and damage the delicate granulation tissue and epithelial cell.

By efforts of Mr. Manish Saxena, a neem based herbal for-mulation has shown tremendous improvements in diabetic foot ulcers and healing in other wounds. A staunch devotee of Lord Krishan, he calls his oil as “Hare Krishna Oil.” The oil for-mulation can easily heal diabetic ulcers, bed sores, venous ulcers, arterial ulcers, varicose ulcers, knee replacement wounds etc.

In 1998 Mr. Manish Saxena was a research associate in Department of Surgery, AI-IMS and was associated with a clinical trial for wound care. He saw that there is rising number of amputations in non healing ul-cer cases among diabetic wounds (one lakh amputations per year). While trying to fi nd out a solution to this problem he met Dr. T. V Rao of Maharishi Ayurved Ltd who intro-

duced the benefi ts of neem based formu-lations to him. One of the major formu-lation created was a novel neem oil that was a miracle cure for healing wounds. In 1999 his innovation was recognized by Department of Science and Technol-ogy (DST) and they provided him with a grant under TePP (Techno-Entrepreneur Promotion Programme). With the avail-able funds from DST, a multi-centric randomised trail was conducted at the wound care clinic, Department of Sur-gery, AIIMS and Central Council for Re-search in Ayurveda & Siddha (CCRAS) with Principal Investigators Dr. Anurag Shrivastava and Dr. K.D Sharma respec-tively. All the laboratory experiments for pre-clinical toxicity studies were carried out at SGS India based in New Delhi. The oil formulation was completely safe and had no side-effects: obviously as the ingredients are all natural products and we have used them in one form or an-other.

The standardization of the innovation was done at Na-tional Institute for Pharmaceutical Education and Research (NIPER) with Dr. Parikshit Bansal as the principal inves-tigator. The formulation was also tested on eye wounds in rabbits at Rajendra Prasad eye centre at AIIMS under Pro-fessor S.C. Ghosh. The formulation has been commercial-ized by M/s Venus Remedies Ltd.

Among several neem based formulations that were re-searched and tested at various clinics and hospitals, anoth-er neem based formulation with more capabilities to heal wounds such as venous/arterial wounds, diabetic wounds, wounds due to MRSA (Methicillin-resistant Staphylococ-cus aureus causing several diffi cult-to-treat infections in

NEEM SPA


LSI SPOTLIGHT

humans), traumatic wounds, gunshot wounds, burns, wounds caused by chemotherapy/radiotherapy and all types of chronic skin infections like psoriasis, alopecia (stops hair fall), any pain or infl ammation, ear /nose infections, crack heels and aids skin rejuvenation have been developed by Mr. Manish Saxena. For complete healing, he recommends a holistic ap-proach as outlined in his neem spa.

Miracles of neem based oil formulation

A man driver by passion, Mr. Manish Saxena has been himself making the neem based formulation for the last 15 years utilizing herbs and oils of the highest quality to maintain quality and purity of the product. As a wound care expert, he is working with Dr. Amar Pal Singh Suri at Diabetes Foot-Care and Wound-Care Clinic, New

Delhi where more than 1000 patients have been success-fully treated for the last 15 years. According to Dr. Amar Pal Singh Suri, “We have not observed any side effect till date. Our success rate has been more than 95%. We wish to spread awareness about this center so that maximum dia-

betic wounds patients could get benefi tted and the ampu-tation rate can be decreased which is now two limbs per 30 seconds according to a WHO survey”. An NGO, Sri Ram Seva Trust, New Delhi helps Mr. Manish Saxena to dis-tribute the neem based oil formulation to poor and needy patients. Extensive research on this formulation has been taken up by Prof. Ameena Gurib Fakim at CEPHYR (Cen-tre de Phytothérapie et de Recherche, www.cephyr-recher-che.com) a limited company incorporated under Mauritian Law to promote the formulation worldwide.

Many miraculous healings have been observed with the oil. Orthopedic wounds caused due to knee replacement surgery where foreign body is inserted and likewise any surgical wound where some foreign body is put in the body like proline mesh have healed in record time with applica-tion of this oil. Three MRSA wounds have been healed till date while the oil has benefi tted leprosy patients as well. Several bomb blast cases of BSF, CRPF and army with splinters wounds and even bedsores have been success-fully treated and cured by Mr. Manish Saxena. His vision is to open neem clinics in every country and every city.

Manish Saxena can be contacted at [email protected]


LSI ACADEMIC SHOWCASE

What are the unique subjects and methodologies our course of-fers to the Biotechnology students?The Students of B.Tech biotechnology at KCT study a blend of courses from various related disciplines. These courses are relatively unique com-pared to most syllabi across India. For examples, courses related to Chemical engineering, Biopharma,Food tech-nology, IPR, biosafety and bioethics. These courses are in addition to the core biotech curriculum comprising

of fundamental biosciences, genetic engineering, bioprocess, downstream processing, Bioinformatics, Immunol-ogy In addition a unique blend of in-house and inter-departmental elec-tives is also offered to the students interested in other related topics like Immunotechnology, Biomedical en-gineering, Programming for bio-informatics, Environmental biotech-nology, Nanotechnology Medical textiles, Bioenergy, Clinical research and Management .

Which are the institutions that have recruited from KCT?The Kumaraguru College of Technol-ogy has over 200 students who have successfully passed out and pursuing their higher studies in various coun-tries including USA, UK, Canada, Australia, New Zealand, Germany, Sweden, Denmark, Belgium, Finland, Austria, Malaysia etc. Many of our graduates have completed their high-er studies in premier Indian institutes like IITs, IIMs, NITs, BITS, IISER and the list is growing.

It is our privilege to share that our graduates are working in many MNCs- Genentech Inc., Baylor Col-lege of Medicine, and Novartis, USA, Anglo Arabian Healthcare, Dubai, United Arab Emirates, Indian Immu-nological Limited, Hyderabad, Biocon, Bangalore, Ramky Group, India, No-vartis, OTC, India, GLR Laboratories Pte. Ltd., Chennai, Orchid Pharma-ceuticals Pte, Ltd., Chennai and many more..

Please enlist the Innovation-ini-tiative of the InstitutionThe Kumaraguru College of Biotech-nology Department has fi led a provi-sional patent registration for the se-lective extraction of dyes from textile dyeing unit wastewater.

We are pursuing research on nano-technology for the synthesis of nano-particles for antimicrobial activity. We are Investigating the plant resources for valuable biomolecules as pharma-ceutical for diseases such as cancer, diabetes, arthritis etc. We are de-veloping medical textiles with plant based enzymes for warts.

LSI Academic Showcase

Principal Kumaraguru College of Technology shares some of the unique Industry Academia

initiatives of the college. KCT is one of the premier institutions in the country .

Inspiring Innovation

The Confederation of Indian Industry (CII) works to create and sustain an environment conducive to the development of India, partnering industry, Government, and civil society, through advisory and consultative processes.

CII is a non-government, not-for-profi t, industry-led and industry-managed organization, playing a proactive role in India's development process. Founded over 118 years ago, India's premier business association has over 7100 members, from the private as well as public sectors, including SMEs and MNCs, and an indirect membership of over 90,000 enterprises from around 257 national and regional sectoral industry bodies.

CII charts change by working closely with Government on policy issues, interfacing with thought leaders, and enhancing effi ciency, competitiveness and business opportunities for industry through a range of specialized services and strategic global linkages. It also provides a platform for consensus building and networking on key issues.

Extending its agenda beyond business, CII assists industry to identify and execute corporate citizenship programmes. Partnerships with civil society organizations carry forward corporate initiatives for integrated and inclusive development across diverse domains including affi rmative action, healthcare, education, livelihood, diversity management, skill development, empowerment of women, and water, to name a few.

The CII Theme for 2013-14 is Accelerating Economic Growth through Innovation, Transformation, Inclusion and Governance. Towards this, CII advocacy will accord top priority to stepping up the growth trajectory of the nation, while retaining a strong focus on accountability, transparency and measurement in the corporate and social eco-system, building a knowledge economy, and broadbasing development to help deliver the fruits of progress to all.

With 63 offi ces, including 10 Centres of Excellence, in India, and 7 overseas offi ces in Australia, China, France, Singapore, South Africa, UK, and USA, as well as institutional partnerships with 224 counterpart organizations in 90 countries, CII serves as a reference point for Indian industry and the international business community.

For more detail please contact:

Confederation of Indian Industry

The Mantosh Sondhi Centre

23, Institutional Area, Lodi Road, New Delhi - 110 003 (India)

T: 91 11 45771000 / 24629994-7 F: 91 11 24626149

E: [email protected] W: www.cii.in

Reach us via our Membership Helpline: 00-91-11-435 46244 / 00-91-99104 46244

CII Helpline Toll free No: 1800-103-1244


LSI INTERVIEW

Dr Vijaraghavan, Secretary, Deparment of Biotechnology (DBT), government of India, shares his insights on the policy regulatory issues of the industry in conversation with Hareeni Mageswaran

As a policy maker, what is hindering the LifeScience Industry?In one word: Connectivity. All of us need to connect as partners for a shared purpose. This shared purpose helps bring a meaningful transformation . Sci-ence is but one component here but it is an important one. For this connectivity to happen we in the government must constantly keep in mind that the pur-pose of policy is to enable transformation through the responsible and correct use of public resources. If we worry only about using public resources in a pro-cedurally correct manner while forgetting our purpose, policy will be hollow. Connectivity ensures creativity with responsibility on all sides.

What are your views on the Clinical Trials industry? What is the fate of this industry in India? First, the term ‘Clinical trials industry’ sends a mixed message. This is not an industry in the sense the term is usually used. We are working with people here, we are working in a country of nearly a billion and half people. If we are to address our problems and fi nd solutions, clinical trials are a must. A country our size cannot rely on altruistic Scandinavians as participants who will test out the effi cacy of the drugs we use. A country of our size cannot expect the best research and consequent new drugs and vaccines to come from California or Switzerland.

India has a unique opportunity not only to take the lead in world-class research in biomedical sciences but also to lead in addressing the problems of the South.

Prof Vijayaraghavan in an exclusive interview with LifeScience India shares his views

on the Industry's key issues


LSI INTERVIEW

The present clinical trials imbroglio is an opportunity. It is an opportunity to set our house in order. It is an oppor-tunity to communicate to our people that we will do so in a manner that is exemplary from which others can learn. It is an opportunity to commu-nicate that we must research, discover and innovate solutions, take them through well-formulated and ethical trials and when our products pass, take them to our people and around the world.

To absolve ourselves of this responsi-bility is to be a vassal state where the rich can buy their expensive medi-cines and vaccines tested abroad while the poor are denied access to these medicines because we are gridlocked in our processes. Such a situation is simply immoral and unethical. Ethi-cal, well-laid out and correct clinical trials must be put in place and India will have to be a major site for such trials: our size, diversity and problems leave us no choice.

What do you think is the fu-ture of the clinical trials indus-try in our country with the cur-rent policy landscape? What is the outlook for this sector?The future is bright. Simply because we have to do this correctly and do it well. The Health Ministry is going through an extraordinarily diligent process in putting processes in place. This will happen soon and we must work together to ensure that we all participate in this process, keeping our higher-goals of being correct and rigorous in all what we do to further research and application of biomedi-cal sciences in the service of human-ity. There is a great future for the sec-tor as long as ‘industry’ and all of us keep in mind that our shared purpose is the service of humanity.

What are the plans of the De-partment to promote awareness on the various potential sub-sec-tors and their prospects? Also, could you outline the academic,

research and industry initia-tives?The applications of today come from investigator inspired basic- research of yesterday. If India is to be a knowledge power, we must either defi ne world-class basic research problems from our contexts or excel in problems that the West has defi ned. Being an excel-lent training ground for high-quality science is necessary but not suffi cient. So, we must and will expand and deepen our foundations. From this, we will move to team-driven research to solve complex problems.

We are doing both of these as well as speeding up the collaborative en-vironment between institutions and industry. Check out the BIRAC web-site for details on the latter.

As a policy maker which coun-try inspires you?Strangely, right now it is India. We have problems, we have a mess and we are searching for solutions. Yet, we have debates and a crisis brings out the best in us. We have every problem in the world and we have all the solu-tions within. Our solutions in afford-able health, energy, and sustainable development will have lessons for the world. Every impediment is a chal-lenge to us, a challenge to admit and correct errors, a challenge to convince detractors that we will change where wrong but we will be fi rm where we are right, particularly when we are saving lives by being active and being callous by waffl ing.

What is your vision for the in-dustry? Where do you want India to be ten years from now?Ten years is too long. Here is my chal-lenge for this industry. Many regard the rupee as falling or fallen. Can we make this into an opportunity to transform India, in fi ve years, into a manufacturing hub for biotech by partnering within and abroad? Our generics and vaccine industry is world famous. My vision is to make India a world-class hub for innovative biotech

in the coming years.The government is yet to take a fi nal call on FDI in pharmaceutical com-panies with divergent views among various departments. While there is a concern of very high priced acquisi-tion of Indian government companies in the past, some in the government are not sure if FDI will lead to higher production of affordable drugs in the country.

In the last 20 years or so, India excelled in generics because of our strength in reverse chemistry and favourable pol-icies such as for ̀ Process Patent’ rather than a `Product Patent’. Currently, the Indian pharmaceutical industry is one of the world’s largest and most devel-oped, ranking 4th in volume terms and 13th in value terms. The country accounts for 8% of global produc-tion and 2% of the world’s market in pharmaceuticals. Most of the domes-tic pharmaceutical drug requirements are met by the domestic industry. In-dia has the largest number of US FDA inspected plants (119 plants) outside the USA. Many of these drug com-panies supply medicines to around 200 developing countries all over the world at affordable price.

The policy on 100% FDI on pharma via the automatic route was encour-aged based on the premise that for-eign companies would bring in newer technologies, invest in infrastructure and promote R & D. This would mean they would re-orient the Indian com-panies from doing mainly brownfi eld projects to greenfi eld projects.

Most M&As have taken place with companies which were best in gener-ics with a market share close to 40%.. Companies that were acquired have large manufacturing capacity and contributed tremendously in making the country self-reliant in lower cost and affordable public health drugs and vaccines. Their mergers through the automatic route those with a large premium has led to thinking about how to stimulate investment in green-


LSI INTERVIEW

fi eld projects over brownfi eld ones.

Being a signatory of the WTO, India will be driven to develop new mol-ecules which means spending on ap-propriate infrastructure for R&D and skilled manpower. How FDI can help here is a very important ongoing de-bate.

Many drug companies are asking for Compulsory Licensing to manufacture patented drugs. What should be the policy? The government’s policy as initiated by the Commerce Ministry is clear and I would refer you to it for details. Compulsory licensing is an impor-tant system to produce and market a patented product or process without the consent of the patent owner. This mechanism enables timely interven-tion by the government to achieve equilibrium between two objectives---rewarding inventions and in an emergency, making them available to the public during the term of the pat-ent.

Through such an intervention mech-anism, governments balance the rights of the patent holder with its obligations to ensure working of pat-ents, availability of the products at a reasonable price, promotion and dis-

semination of technological inven-tion and protection of public health and nutrition. Internationally, the United States of America, Canada, UK, Italy have issued CL in many sectors including the pharmaceu-tical. About 52 Developing and Least Developed Countries issued CL after the Doha Declaration on the TRIPS agreement and Public Health, in Brazil in 2007 for an anti-AIDS drug; Thailand in 2006 and 2007 for anti-AIDS drugs; Malaysia in 2003 for Anti-AIDS

drugs; South Africa for Anti-AIDS Drug; Kenya issued voluntary licenses in 2004 and Ecuador in April 2010 for an anti- AIDS drug.

Recently, some have called in favour of Compulsory Licensing even going be-yond it to obtain Obligatory License, or OL, which is a system where roy-alty is paid to the patent holder. This view refers to a system which allows country to copy any drug as long as it pays 4% royalty to the patent holder. The debate continues.

Our National Pharmaceutical Poli-cy recognizes the need to ensure an abundant availability of good qual-ity essential pharmaceuticals of mass consumption at reasonable prices. However, there are diseases where due to high cost, the demand is low, as people cannot afford the costs. Take the case of cancer drugs: if we ac-cept that there are about 20 to 25 lakh people suffering from various cancers in the country at any time, a conser-vative estimate of the average cost of anti-cancer medicines at Rs 25,000 per annum/patient would require drugs worth Rs 5,000 crore. However, the present turnover of cancer medicines in India is only about Rs 150 crore which refl ects non-accessibility of the medicines to a vast majority of the af-

fected population due to high cost. No matter what our views on CL, ac-cessibility cannot be ignored. This is a public health access issue that we must address while keeping our treaty obligations.

Though the government has announced a pricing policy for essential drugs, it is yet to an-nounce a pricing policy for pat-ented drugs, which always enjoy freedom due to the high cost of drug development. Which factors should the government consider for a pricing policy for patented drugs?Under the WTO, India respects prod-uct patents. It is a fact that each new drug development takes tremendous effort, time, skill and money. The argument is that a company which spends on all these requirements would like to recover costs and earn a profi t. While the greening of patents by minor changes is not supported, pricing for newer drugs is a complex issue which need to address the dual issues of affordable access and a legit-imate recovery of development costs and consequent profi ts.

Some recent changes made in the clinical trials rules by the DCGI were governed mainly by the fact that while India has been a participant in the global trials of most new drugs, such drugs are either not released in India initially or released at unafford-ably high prices. In times of emergen-cies, governments can take recourse to CL or OL to bring down the costs automatically or develop technolo-gies indigenously in a short time as in the case of the H1N1 vaccine. Pub-lic health needs and the demand in socially-driven health projects such as childhood immunisation, tubercu-losis-RNTCP, NACO-HIV-AIDS etc are areas where issues are likely to be addressed in a manner which serves public interest and is compliant to our treaty obligations. Pricing is not the only way of addressing this tangled issue!

My vision is to make India a world-class hub for

innovative biotech in the coming years


LSI POLICY

Realizing the opportunity from Pharmaceutical Patents in India –

an empathetic approach is the key

The skew between India’s disease burden and ac-cess to healthcare is remarkably stark. India con-stitutes 17% of the world’s population, but bears a disproportionately high share (21%) of the world’s

disease burden and accounts for a grossly insuffi cient 1% of the world’s healthcare expenditure. Less than 8% of In-dia’s population have an annual household income above $30,000 contrasting to 70% of US population (on a purchas-ing power parity basis). To further aggravate the affordabil-ity issue, 61% of India’s healthcare expenditure is out-of-

pocket. Even though coverage of government-sponsored and private insurance is growing and is expect-ed to cover 500 to 600mn (50% of the population) by 2015, much of it will be state sponsored health in-surance with very limited fi nancial resources given the volume of pop-ulation that needs sponsoring.

The urgency of India’s need for ac-cess to advanced medical interven-tions including innovative phar-maceutical products cannot be overstated. Given this pressing need and the enshrined vision statements of MNC pharma that place patients’ need at the core, addressing India’s health needs should invariably be high on the agenda of most MNC pharma companies. However in re-ality, India has not benefi tted much from latest innovations of the phar-maceutical MNCs despite adopting product patent regime in 2005 af-ter signing the TRIPS agreement. There are three major reasons cited for this viz.

1. Pricing- Readiness of the mar-ket to afford the expected pricing of patented products as defi ned by global fl oor price

2. Patentability- Perceived inconsistency in the adminis-tration of patent laws according to the TRIPS agreement leading to anxiety regarding grant of patent

3. Patent protection- Employing the provision of Com-pulsory Licensing in the event of emergency or market failure.

PricingWe believe pricing of patented products for emerging mar-kets like India has to be very different and should not fol-low the philosophy and methodology followed in devel-oped markets.


LSI POLICY

(It is also important to note that there is an increasing scru-tiny on the fairness of patented products pricing even in developed economies driven by a belief that the current pricing is exorbitant and untenable and is a result of inef-fi cient R&D management and over provisioning for the cost of risk).

A comparative analysis of prices in India vis-à-vis prices in US, calibrated for income levels in India (per capita GNI at PPP) demonstrates that current prices in India are higher by 3 to 10 times for a few patented drugs.

India US % by which price in India is higher

Per capita GNI, PPP ($) 3,840 50,610

Per capita GNI PPP factor 1 13

Brand A (Cancer therapy) Price in Rs. 38,781 123,567

Adjusted for per capita GNI PPP 38,781 9,376 414%

Brand B (Immuno suppressant) Price in Rs. 41,039 56,705


Brand C (Smoking cessa� on) Price in Rs. 1,638 6,518

Adjusted for per capita GNI PPP 1,638 495 331%

Brand D (An� -rheuma� c) Price in Rs. 20,274 53,295


Source – World Bank, CIMS, RxUSA pharmacy

An interesting example is that of the most successful pat-ented product in India which is a leader in its category and has achieved sales in excess of Rs.200 crore in a fi fth of the time taken by some other brands to reach similar scale, on the back of “India friendly pricing” (i.e. India price is nearly equivalent to the per capita GNI PPP adjusted US retail price).Determination of patented product pricing is complex and a crucial aspect with far reaching implications. It is thus im-perative that the framework for a robust and effective pat-

ented medicine pricing balances the multiple and contrarian objec-tives of ensuring patient access, economic sus-tainability for the payor (private and public) and the commercial interest of innovation driven companies. Given In-dia’s dual challenge of a disproportionately high disease burden and scarce fi nancial re-sources, coupled with the stated objective of MNC pharma of put-

ting “patient fi rst”, an innate sense of social solidarity and compassionate pricing is expected from MNC pharma com-panies. However, their participation in the Indian market must be value-accretive and not loss-making for MNC in-terest to sustain. Given this context, we suggest the follow-ing principles for defi ning a robust framework for patented drug pricing for India –

Notes1. GNI (Gross National Income) PPP methodology can

be followed by adjusting the international reference

prices of patented medicines by the ratio of per capita income of reference countries to India and considering the lowest of these GNI (PPP) adjusted prices as the fl oor price.

2. Marginal cost to consider cost of production, variable costs of distribution and sales/marketing. It is assumed that expenses on R&D and overheads are a fi xed sunk cost incurred without considering India as a market and thus should not be reimbursed.


LSI POLICY

While this framework can be used for patented drug price fi xation for the pharmaceutical retail market, in case of pub-lic procurement of patented drugs, the Government could use these prices as reference for further negotiations.

Patentability and ProtectionIn the recent past, MNC global leadership have expressed their concerns around India's commitment for establishing a robust and effective patent regime. Much of it is based on the judgement where the highest judicial authority of India, the Supreme Court, has taken a position denying patent to a product on the basis of insuffi cient innovation or invok-ing of compulsory license on the basis of market failure by patent appellate authority.

While we are not experts in patent laws, our discussions with legal experts have revealed that the judgements have been robust and well-rounded in their assessment and completely within the limits of provisions entitled under the TRIPS agreement.

It is pertinent to note that WTO has not been supportive of this criticism by MNC pharma companies. WTO Direc-tor-General Pascal Lamy said the following on this subject "Recent decisions by the courts in India have led to a lot of protest by pharmaceutical companies. Decisions made by an independent judiciary have to be respected as such.” He also mentioned “TRIPs provides fl exibilities that allow countries to issue compulsory licences for patented medi-cines to address health urgencies.”

We do not subscribe to the view that denying a patent for something that has been awarded patent in developed economies is any indication of India's capability or commit-ment towards building a robust IP regime in India. There are several studies that have analysed and concluded that

much of the innovations that have won patents in pharma-ceutical ingredient may not stand a stringent test of sig-nifi cant incremental therapeutic effectiveness. Given that we have the highest burden of diseases and substantially less fi nancial resources both privately and at Government level, India needs to be very judicious in matters of patent-ability to ensure that only true innovation is respected and rewarded.

A robust and effective patentability and patented drug pricing can also mitigate the apprehensions caused among MNC pharma companies by the provision of Compulsory Licensing. A pricing mechanism aligned to the paying pro-pensity of India’s population would reduce the need and frequency of invoking this provision thus promoting its ju-dicious use. However, the provision of Compulsory Licens-ing must be retained so that the same can be invoked by the Government in case of national emergency or for a specifi c list of essential medicines aligned to India’s epidemiologi-cal requirements.

In conclusion, we believe there is a need to have an em-pathetic approach between the Government and MNC pharma to arrive at a workable model for realising the in-tended benefi ts of TRIPS agreement. Government cannot expect Companies to make loss in serving India market at the same time pharmaceutical companies have to realise that their pricing cannot be seen from the lens of global fl oor price. Policy of any country should always focus on larger interest of its population and Companies must fi nd a way to develop business models that are relevant for the population at large rather than expect policy that suits their global business model.

‘Intensity’ of need i.e. alignment to India’s epidemiological context

‘Improvement’ i.e. eff ec� ve

compared to therapeu� c

equivalence

Mass market Niche

No therapeu� c equivalent

in India i.e. substan� al

improvement

Lowest interna� onal reference price adjusted for per

capita GNI (at PPP)1 or Marginal cost2 whichever is

higher, given volume advantage off ered by the high

disease burden

Lowest interna� onal reference price adjusted

for per capita GNI (at PPP)1 or Marginal cost2

+ reasonable margin whichever is higher

Therapeu� c equivalent

exists in India i.e. marginal

improvement

Cost of treatment using therapeu� c equivalent drug

in India should be used as reference with add-

on premium based on Compara� ve Eff ec� veness

Research (add-on compensa� on per addi� onal unit of

health outcome e.g. per addi� onal Quality Adjusted

Life Year or QALY saved)

‘Indigeniza� on’ of business

model (i.e. level of localiza� on

of produc� on)

Addi� onal incen� ves over and above the base price

for encouraging localized produc� on (especially for

mass market drugs)

The writers are Ajit Mahadevan and Murali NairPartners- Performance Improvement Ernst & Young LLP


LSI POLICY

FDI in pharma in India the need for a clear policy regime

-Hareeni Mageswaran

FDI in pharmaceutical sector had only begun to see activity after Prime Minister Manmohan Singh himself endorsed policy changes to ensure that big acquisitions of domestic drug companies by mul-

tinationals did not deny cheap drugs to Indians. Pharma is one of the select sector that has managed to attract FDI fl ows even as over all FDI into the country declined. The DIPP's move for a review of the policy comes when the gov-ernment has liberalised the FDI regime to attract dollars into the country and Singh himself has promised a more liberal regime to foreign investors. India had opened phar-maceutical sector to 100% FDI via the automatic approval route in 2002, but last year was when it made a distinction between greenfi eld projects and brownfi eld ones following fears that Indians will be denied cheap medicines if MNCs

continued to buy big domestic companies. Stringent condi-tions were introduced into the policy along with a manda-tory FIPB nod. With complications in this policy decision the Indian pharmaceuticals sector has attracted $11.3 bil-lion in FDI, but the buyout of some big Indian companies by MNC drug makers raised public healthcare concerns, which led to one round of policy tightening.

The government had earlier this year put FDI in pharma companies on the approval route, but had not lowered the 100% limit. Stringent conditions, such as mandatory man-ufacturing, and research and development, were imposed. Over the past fi ve years, foreigners have acquired Ranbaxy Laboratories, Dabur Pharma, Matrix Lab, Shanta Biotech, Orchid Chemicals and Piramal Health Care. The government recently decided to take stock of the de-cade-old FDI policy for the pharma sector. This decision was in response to the potential threat of dominance from foreign players and a general rise in overall drug prices in the country, arising from a spate of acquisitions of Indian companies by MNCs starting in 2006. The most notable ones are the acquisition of Matrix Labs by Mylan, followed by Daichii Sankyo’s acquisition of Ranbaxy, Sanofi Aven-tis’s acquisition of Shanta Biotech and Abbott Labs’ acqui-sition of Piramal Healthcare.

As a direct reaction to the takeovers, the government through the Ministry of Commerce and Industry (Depart-ment of Industrial Policy and Promotion) amended the FDI policy in November 2011 by permitting FDI up to 100% for investments in existing companies in the pharma sector through the Foreign Investment Promotion Board (FIPB) approval route. At the same time, FDI up to 100% under the automatic route was continued for greenfi eld investments in the pharma sector.

The FIPB has laid out conditions for approving future pro-posals. MNC fi rm looking at buying a stake higher than 49% in an Indian pharma company will have to maintain the same level of investment in research activities and pro-duction of NLEM drugs for next fi ve years.

Facts to ponder • The government had kept decision on Mylan's takeover

of Agila Specialties, the injectables division of Banga-


LSI POLICY

lore-headquartered Strides Arcolab, in abeyance till the department of industrial policy and promotion (DIPP) fi nalises its policy on FDI in brownfi eld pharma. My-lan's proposal, which would be the largest FDI induc-tion so far this fi scal, has already received Competition Commission of India's endorsement.

• FIPB's decision on Symbiotec Pharmalab Limited's pro-posal has also been put on hold following DIPP's reser-vations.

Key Stakeholder’s Speak

Sujay Shetty –Director Leader Pharma LifeSciences PWC “Worldwide economies are bending backwards to attract FDI in pharma sector, the Indian environment leaves the investor in a no certainty climate that has set a gloomy tone. As a result of the added regulatory oversight FIPB and CCI, it is expected that these developments will add signifi cant time to the process of Mergers and acquisitions in India and as a result will create further uncertainty in M&A ‘s. The increasing number of stakeholders in this case like the De-partment of Pharma, Ministry of Health and all stakehold-ers further casts the gloom web. The Indian market is a very price-sensitive market. For companies active in the area of branded generics, this is defi nitely one particularity that needs to be taken into account. The second aspect worth mentioning is the labour attrition. With attrition rates as high as the IT sector, it is very diffi cult for pharmaceutical companies to keep hold of their people. A third aspect some MNC clients have been concerned about in the past has been the discussion of a cap on FDI. For some of the MNCs, counterfeiting has also been a concern, although the gov-ernment has recently run a study that minimized this prob-lem. Overall, it is a highly competitive market.” He says “having summed the industry my plea to the policy makers is carve a unilateral pattern of working ,and work closely with the Industry and clear the muddled negative signalled landscape for the Investor .

Dr Vijay Raghavan – Secretary DBT In the last 20 years or so, India had excelled in gener-ics because of our strength in reverse chemistry and very favourable Government policies such as for "Process Pat-ent" rather than "Product Patent”. Currently, the Indian pharmaceutical industry is one of the world’s largest and most developed, ranking 4th in volume terms and 13th in value terms. The country accounts for 8% of global produc-tion and 2% of world markets in pharmaceuticals. Most of the domestic pharmaceutical drug requirements are met by the domestic industry. India has the largest number of US FDA inspected plants (119 plants), outside the USA. Many of these drug companies supply medicines to around 200 developing countries all over the world at affordable price. The policy on 100% FDI on pharma through automatic

route by the GOI was encouraged with the premise that foreign companies would bring-in newer technologies, in-vest on infrastructure and promote R & D which means, they would re-orient the Indian companies from doing mainly brownfi eld projects to greenfi eld projects. Most M & A have taken place with the companies which were best in generics and holding close to 40 % of the market. Companies that have been acquired have large manufac-turing capacity and contributed tremendously making the country self-reliant in public-health drugs, cheaper costs and affordable vaccines. Their mergers through the auto-matic route that too with large premium has led to thinking about how to stimulate investment in greenfi eld projects over brownfi eld ones.

Foreign Investment Promotion Board – “The Govern-ment allows 100 per cent FDI in pharmaceuticals, but while investments in new projects are allowed automati-cally, investments in brownfi eld or existing pharmaceutical

companies are required to be routed through the Foreign Investment Promotion Board (FIPB) since late last year. Investment up to 49% will be on the automatic route but investment above that will be permitted only with prior FIPB approval. Moreover, investors will have to ensure that if foreign direct investment exceeds 49%, one-fourth of the total investment will go towards enhancing production of the existing facility or to set up greenfi eld operations. No change is proposed in the policy with regard to foreign di-rect investment in greenfi eld facilities, where 100% invest-ment will be allowed under the automatic route.”

DIPP- The DIPP, which is the nodal body for FDI policy, has circulated a draft Cabinet note that seeks to bring down the FDI limit in such companies to 49% and calls for put-ting foreign investment in drug facilities defi ned "critical" on the approval route. The current policy allows up to 100% FDI in Indian drug makers following government nod. The DIPP spokesperson shared “The DIPP is keen on placing a check on the acquisition of existing pharmaceutical projects, as it is concerned that it could seriously affect the country’s capacity to produce low-cost generic drugs. It wants to im-pose restrictions on at least three categories of pharmaceu-ticals —vaccines, injectibles and oncology medicines — in addition to bulk drugs.”

FDI in pharmaceutical sector had only

begun to see activity after Prime Minister

Manmohan Singh himself endorsed policy

changes to ensure that big acquisitions of

domestic drug companies by multinationals

did not deny cheap drugs to Indians


LSI OPINION

Future of healthcare IT outsourcing

Dr. Saji Salam MD, MBA

Gartner forecasts that spend-ing by global healthcare providers for IT services will grow by 6% to reach

$30.4 billion in 2013. Consulting, with 9% growth in 2013, will be the fast-est-growing sub segment within the global healthcare provider market for IT services.

U.S. healthcare delivery systems face unprecedented transformational de-cisions driven by the combination of healthcare reform and regulation.

As the future of outsourcing changes, the healthcare industry in the devel-oping world is bound to adapt to those changes. There are fundamental forc-es at work that go beyond the tradi-

tional spin on outsourcing we hear from the IT trade bodies. Some of the key factors that drive outsourcing in the future would center around de-mographics, education, labor mobility, and healthcare and immigration re-form in developed economies. One of the challenges that US, Europe Japan and China face today is the changing demographics, especially the increase in the graying population. To maintain an aging population these economies need a critical mass of young educated work force. The critical question then becomes, where is this educated tal-ent pool?

IT demand and supply: a hard look at the numbers

In 1999, with the rise of e-commerce, enrollments in computer science in the US hit new highs; the average computer science department had an enrollment of about 400 students. But with the dot-com crash, enrollments started to fall and hit bottom around 2007, at 200 per department.The aver-age enrollment per department today is just over 300 students at PhD grant-ing institutions. Estimates today range from 100,000 - 125,000 computer sci-ence enrollments per year in the US.

Per NASSCOM (National Association of Software and Services Companies) India produces about 550,000 engi-neers annually. Despite debates on quality of the education in India, and the percentage of these engineers that are really employable, the sheer num-bers do point to the magnitude of the talent gap.

The professional services sector in US is expected to create 5 million jobs by 2016 a growth of 16.7 percenatge.Com-puter and mathematical science occu-pations are projected to add 822,000 jobs by 2016 —at 24.8 percent growth, the fastest growing segment among professional subgroups. Though IT services in US have been hit by the re-cession, the impact has been lesser (so far) compared to other sectors.

Talent war: create vs im-port talent?

To keep the US/European economies afl oat, it is imperative to fi nd em-ployees in the productive age group to work and contribute towards taxes and social programs such as Social Security and Medicare. Of course the economy has to create jobs; however a critical mass of educated workforce is


LSI OPINION

also required to take on those jobs. In the US alone, there is a shortage of 40,000 healthcare IT professionals and a projected shortage of 75,000 physicians and 500,000 nurses by 2020. Making college education affordable is a basic fi rst step towards creating this talent pool. If generating home-grown talent is not working well, then the immigration policy has to be streamlined to facilitate smoother fl ow of labor to the US.

Immigration and Healthcare reform:To address labor shortages in the future, a comprehensive immigration reform that addresses the talent shortage in the country is needed. Studies by National Foundation for American Policy state that each H1B visa provided actually creates 5 additional jobs in the US economy. There could be counter arguments as well in the immigration debate, es-pecially in the wake of unemployment numbers in the US.

Europe, UK and Australia and the Middle East are attempt-ing to attract Indian talent with various immigration pro-grams to fast track growth in their economies. The shape and form of immigration system in the US/Europe will have to change dramatically to attract talent. Though the US continues to be the destination of choice for most im-migrants, several fi rst and second generation immigrants from emerging economies are making a beeline to return to their home countries to be part of the exciting growth stories there.

Healthcare provider IT pie: MNCs vs Indian Vendors

The US provider IT market is set to grow drastically, with a $ 19 billion investment into the sector as part of the US recovery plan signed by the President. However the Indi-an IT vendors may not be a good position to leverage the growth in this market as most vendors have not made the right preparations/investments to address this market. The global healthcare provider IT market is cornered by IBM, CSC, Accenture and Deloitte. In the last few years these MNC fi rms have made very good progress in ramping up their offshore capabilities in India.

On the other hand Indian vendors have made very little progress moving up the value chain or cutting into the in-tegrated service offerings that their global peers are able to provide. Indian vendors may lose out if they do not make the investments necessary to move to the next level. The

major challenge that Indian vendors face is the lack of in-vestment to acquire domain knowledge. Indian vendors have to move beyond downloading and rehashing content of the Net and throwing in a few key phrases from the in-dustries they service to really building deep industry knowl-edge. Some of the outsourcing companies present revenue generated by business analysts as consulting revenue, and the Indian media gobbles up the numbers. While one can manage to impress the media with such stories, the clients in the markets they service have more stringent criteria to evaluate industry knowledge. Though a handful of Indian outsourcing companies have a mild to medium presence in the health insurance sector, it is a different story all togeth-er in the provider (hospital) market. While growth in the health insurance sector has slowed, Indian vendors have not been able to make a dent in the provider market, which is growing rapidly. The established players make $ 50- 60 million from each large EMR implementations in the pro-vider segment.

ChallengesThough the IT industry grew in India despite the political system, India Inc has come to an infl ection point, where the political will to address a host of infrastructure, security and social challenges is critical for the industry’s move to the next level.Adding to the challenges is the fact that the cost arbitrage may be impacted by the vagaries of foreign exchange fl uctuations. The risk of a falling dollar, in the context of high infl ation in the US that may follow the injec-tion of trillions of dollars into the US economy via quantita-tive easing needs to be considered. Corporate governance will continue to play a role in the future of outsourcing as the recent scam at a top fi ve Indian outsourcer reminds us.

The emergence of several large and small players across the world that are able to provide cheaper labor needs to be watched as well. Though these players may not be able to build scale, they could develop niche skills that eat into the total outsourcing pie.

India Inc vs the Indian professionalIrrespective of the fate of Indian IT vendors, or India as an offshore IT destination, Indian professionals will continue to be in demand as they continue to fi ll up the jobs vacated by graying population across the world. Indian profession-als may travel to where the jobs are, or the jobs may travel to where the Indian professional is located. In the future of outsourcing, demographic stars seem to be aligned in favor of the ubiquitous Indian professional, a sort of micro-outsourcing shall we say?

Dr. Saji Salam is a healthcare management consultant based out of Minneapolis and serves as Director of Clinical Informa� cs at

a mul� na� onal informa� on services fi rm. He can be reached at

[email protected]

One of the challenges that US, Europe

Japan and China face today is the changing

demographics, especially the increase in

the graying population


LSI SPOTLIGHT

V.VIJAYA KUMAR, Manager(Biotech),

Core Green Sugar & Fuels Pvt. Ltd., Karnataka

Biopesticides or Biological Pesticides have been defined as a form of pesticides based on microorganisms or natural products. They include naturally occurring substances that control pests (biochemical pesticides), microorganisms that control pests (microbial pesticides), and pesticidal substances produced by plants containing added genetic material (plant-incorporated protectants) or PIPs.

Biopesticides-Ecofriendly Pesticides


LSI SPOTLIGHT

Advantages of Biopesticides1. They are less harmful than chemical pesticides.2. They are often effective in small quantities.3. Biopesticides give protection throughout the crop pe-

riod.4. They multiply easily in soil and leave no residual prob-

lem, eliminate the pathogens/pests from the site of in-fection.

5. Highly effective against specifi c diseases/ pests, can be used in combination with Biofertilizers.

6. They do not cause toxicity to plants and are eco friendly. They are safe to the environment and the person who applies them.

7. Along with controlling the plant diseases and pests, they can be used as a component in IPM (Integrated pest Management) and greatly reduce the use of con-ventional pesticides, while the crop yields remain high. They are easy to handle.

Mode of action of Biopesticides is not similar for all the Bi-opesticides. It differs based on the organism used as a Bi-opesticide and pest that is to be controlled.

The following are the categories of Biopesticides that are being widely used:1) Microbial Biopesticidesa) Bioinsecticides: Bacillus thuringiensis is the classical

example of microbial pesticide, which controls the Lepi-dopteron insects in cotton by secreting a crystal protein. After ingestion of the crystal protein by the insect, it stops feeding and dies. The genes from Bacillus thur-ingiensis are introduced through genetic engineering technique into the cotton genome and the protection against insects through out the life cycle of the crop period, became a reality. Beauveria bassiana, Metar-rhizium anisopliae, Verticillium lecanii are the other commonly used bioinsecticides for controlling various insects.

b) Biofungicides: Trichoderma viride and Pseudomonas species are the commonly used fungal & bacterial Bio-fungicides that controls various soil borne fungi that causes wilt, rots, damping off etc. diseases in various crops. They control fungal pathogens by various mech-anisms such as competition, mycoparasitism, antibio-sis & lysis and induced systemic resistance. When the spores of the fungus come into contact with the body of an insect host, they germinate, penetrate the cuticle, and grow inside, killing the insect within a matter of days. Afterwards, a white mold emerges from the ca-daver and produces new spores.

2) Botanical Biopesticides: The natural extracts from dif-ferent parts of the plant that are used to control insect

pests are called as Botanical Biopesticides. Azadirachtin extracted from the neem seeds is a classical example of Botanical pesticide. It acts as anti feedant and kills the various insects. Sqamocin, extracted from the seeds of Annona squamosa is another useful biopesticide for control of insects.

3) Viral Biopesticides: Granulosis virus and Nuclear Poly-hedrosis Virus (NPV) controls many caterpillar pests. NPV affects alfalfa looper, corn earworm, imported cabbageworm, cabbage looper, cotton bollworm, cotton leafworm, tobacco budworm, armyworms, European corn borer, almond moth, spruce budworm, Douglas fi r tussock moth, pine sawfl y and gypsy moth. The vial biopesticides invade an insect's body via the gut. They replicate in many tissues and can disrupt components of an insect's physiology, interfering with feeding, egg laying and movement.

4) Plant Incorporated Protectants: The genes from Bacillus thuringiensis (Bt) are introduced through Genetic Engi-neering into the cotton genome and protects against in-sects throughout the life cycle of the crop. The Bt genes are introduced successfully in potato, maize, soya bean to kill insects pests. Research is underway to introduce Bt genes in egg plant, okra, cabbage, caulifl ower, toma-to, wheat and rice in India.


LSI SPOTLIGHT

Other Biopesticides:1) Predators: Chrysopa carnea and Chrysopa rufi labris are found abundantly in the fi elds. They lay eggs on foliage. After hatching in a day or two they feed on aphids, larvae, eggs, small worms, mites, thrips and immature whitefl y.

2) Parasitoids: Trichogramma is an exclusive egg parasi-toid. It lays eggs in the eggs of various Lepidopteron pests (Moths, Butter fl ies etc.). After hatching the larvae feed on the host egg and destroy it. Being an egg para-sitoid, it destroys the pest population before it causes any damage to the crops. It is used against sugarcane, paddy, fruits and vegetable pests.

3) Entamopathogenic nematodes: Heterorhabditis is an entomopathogenic nematode used for control of dif-ferent beetle larvae in soil. It searches the host in the soil and after active penetration into the larval body through the cuticle, the nematode releases a symbiont pathogenic bacterium (Photorhabdus), that multiplies rapidly and kills the host, within 24 to 72 hours. Het-erorhabditis and Photorhabdus then feed upon the in-sect. Spawned juvenile nematodes then search for new hosts.

4) Pheromones: These are the Biochemical Biopesticides. Pheromones are chemical signals that trigger a natu-ral response in another member of the same species. Insects release pheromones to serve many functions.

Pheromones are secreted to indicate the location of food sources, to warn others around about po-tential dangers, or locate a potential mate for re-production.

Female moths release a sex pheromone into the air to attract male moths. Male moths detect the pheromone "scent" and then follow it to locate and mate with the fe-male.

Synthetic pheromones can be used to disrupt pest ecology and reduce crop damage. Small amounts of synthetic fe-male pheromone is used to attract males into traps, by measuring trap counts, the data can be used to predict the insect

population and a decision on appropriate pest control mea-sures can be initiated.

Status of Biopesticides in IndiaThe consumption of Biopesticides in the year 2011-12 is 5170.69 Mts. Bt accounts for around 15 % of total con-sumption of biopesticides in India and its consumption is increasing at a rate of about 10% per year. Neem based pesticides, NPV and Trichoderma are the other major bi-opesticides produced and used in India. Central Insecticide Board Registration Committee (CIBRC) has registered 21 Biopesiticides (18 Microbial Biopesticides and 3 Botanical Biopesticides) for use in the country under section 9(3) and 9(3B) of Insecticide Act, 1968.

For quality control of bio-pesticides, Government of India has notifi ed, vide Gazette notifi cation G.S.R. 756 (E) dated 15th December 2006, the 7 Laboratories in different States (New Delhi, Uttaranchal, Jammu, Assam, Maharashtra, Karnataka, Tamil Nadu) to function as Central Insecticides Laboratory in respect of bio-pesticides. A total 834 pesti-cides have been included in the Schedule to the Insecticides Act, as on 15-01-2013 by the Government of India by issu-ing the Gazette Notifi cations from time to time and listed on the website (www.cibrc.nic.in).

Some success stories about successful utilization of biopes-ticides and bio-control agents in Indian agriculture include


LSI SPOTLIGHT

control of diamondback moths by Bacillus thuringien-sis, control of mango hoppers and mealy bugs and coffee pod borer by Beauveria, control of Helicoverpa on cotton, pigeon-pea, and tomato by Bacillus thuringiensis, control of white fl y on cotton by neem products, control of Heli-coverpa on gram by N.P.V., control of sugarcane borers by Trichogramma, control of rots and wilts in various crops by Trichoderma-based products and control of wilts in differ-ent crops by Pseudomonas fl uorescens.

Constraints in Biopesticides productionThe major constraint in Biopesticides production is their slow activity, target specifi city and limited availability. Other constraints include limited shelf life and requirement of skilled man power to produce good quality Biopesticides without contamination.

Availability of Biopesticide CulturesGood quality Biopesticides cultures (Fungal and Bacterial) are available at • Indian Type Culture Collection (ITCC) at IARI, New

Delhi • Tamil Nadu Agriculture University, Coimbatore• Microbial Type Culture collection (MTCC) at IMTECH,

Chandigarh• National Collection of Industcial Microorganisms

(NCIM) at NCL, Pune

Regulations Governing BiopesticidesThe Central Insecticide Board under Department of Agri-culture was established by Government of India, which is a regulatory authority for registering Insecticides. The In-secticides were covered under Insecticides Act 1968, whose names were included in the Insecticides Schedule from time to time by publishing in the Gazette of India, by the Government of India.

Biopesticides are also governed by the Insecticide Act 1968, included in the Schedule. For any Biopesticide to be manu-factured, which are included in the Insecticides in Sched-

ule, it should be mandatory to register at Central Insecticide Board (CIB), Faridabad. After obtaining the registration from CIB, then only the State Agriculture Departments of respective states will issue the license for manufacturing of Biopesticides and Principle certifi cates for Marketing of Biopesticides.

Registration of Biopesticides at CIB:The Biopesticides are to be registered with Central Insec-ticide Board, (Department of Agriculture, Govt. of India), Faridabad, provisionally under section 9(3)b of Insecticides Act 1968. The provisional Registration will be given for 2 years and extendable further, on yearly basis depending on the progress of data generation and submission of the same to CIB. During the period of provisional registration, the products can be manufactured and marketed in accordance with the specifi cations and the shelf life given in the provi-sional registrations.

After obtaining the provisional registration, the data per-taining to Toxicology, Bioeffi cacy, shelf life and container content compatibility of product is to be submitted. After all the conditions of provisional registration are fulfi lled, then only the Biopesticide is allowed for permanent regis-tration.

Role of Biopesticides in Economic Devel-opment

The Biopesticides can be used very effectively in Integrated Pest Management Programme (IPM). By using Biopesti-cides reduction in chemical pesticides consumption can be achieved. Pesticides residue problems can also be avoided, which is a boon for Agricultural exports, where pesticidal residues are the major problem. Biopesticides in combina-tion with Biofertilizers play a key role in Organic farming where the food crops, vegetables, fruits crops are grown organically without using synthetic fertilizers/ pesticides. The produce from these crops fetch higher income to the farmers.

S.No Names of Biopes� cides Category

1 Bacillus species, Gliocladium Species, Pseudomonas spp, Agrobacterium radiobacter strain 84, Agrobactarium tumefaciens Alcaligenes spp., Serra� a marcescens GPS 5

Bacterial

2 Trichoderma Species , Beauveria bassiana, Metarrhizium anisopliae, Ver� cillium lecanii, Nomuraea

rileyi,Hirsutella species, Streptomyces griseoviridis, Streptomyces lydicus, Candida oleophila, Fusarium

oxysporum (non pathogenic), Pythium oligandrum, Erwinia amylovora (Hairpin protein), Ampelomyces

quisqualis, Phlebia gigantean, Plaecilomyces lilacinus, Penicillium islanidicum (for groundnut), Aspergillus niger-

strain AN27, VAM , Chaetomium globosum, Piriformospora indica

Fungal

3 Grannulosis Viruses (GV), Nuclear Polyhedrosis Viruses (NPV) Viral

4 Neem products (Neem leaves, Neem oil, Neem seed kernel, Neem cake), Squamocin Botanical

Biopes� cides included in the Insec� cides schedule (Source: www.cibrc.nic.in)


LSI TECHNOLOGY

Virus quantifi cation represents a rate-limiting step at many stages of vaccine development and pro-duction, for both egg and cell culture. Currently, one of the most widely used tools for the deter-

mination of virus concentration is the viral plaque assay, or variations such as tissue/egg culture infectious dose (TCID50/EID50). The viral plaque assay is a cumbersome, subjective and traditional biological technique that was originally applied to the quantifi cation of animal viruses in 1952. This assay requires signifi cant hands-on time by a trained technician, and has a time to result of several days or weeks depending on the virus. Other methods for vi-rus quantifi cation exist, including a variety of ELISA-type protein assays, transmission electron microscopy (TEM), and quantitative PCR (qPCR). However, each of these ap-proaches has its own drawbacks, perhaps the most impor-tant being that they require well-trained technicians and have a signifi cant time to result. The table below summa-rizes the primary methods of quantifying virus.

The ViroCyt Virus Counter 2100 was developed in response to needed improvements in virus quantifi cation. The instru-ment is a personal fl ow cytometer optimized for rapid virus enumeration (less than 5 min analysis time) at a per sample cost below $5. As illustrated in Figure 1, the Virus Counter assay utilizes a dual fl uorescence staining approach. Viral genomes (and nucleic acids in general) are stained with a dye that emits in the yellow region of the visible spectrum and proteins in viral capsids (and other background pro-

teins) are stained with a dye that emits in the red region of the spectrum. This “universal” approach to staining allows for the detection of a wide variety of viruses using a simple assay.In the instrument, stained viral particles are hydro-dynamically focused through a laser probe region and sub-sequently detected via fl uorescence on two separate optical channels. Fluorescence bursts on each channel are counted as a function of time. However, when fl uorescence bursts are simultaneously observed on both the nucleic acid and protein emission channels the “simultaneous event” is counted as an intact virus particle. The dual stain approach provides some degree of discrimination from free protein aggregates (counted only on the protein channel) or free nucleic acids (counted only on the nucleic acid channel) in solution. The number of simultaneous events counted dur-ing the analysis time is used in combination with sample

TECHNIQUE ASSESSMENT REPRODUCIBILITY TIME LABOR COST/SAMPLE

Plaque assay Infec! ve units Poor Days High Inexpensive

FFA Infec! ve units Poor Days High High

TCID50 Infec! ve units Poor Days High Inexpensive

HPLC Viral an! gen Excellent Days High, experienced High

HA Viral an! gen Good Hours Low Inexpensive

SRID Viral an! gen Good Days Moderate High

ELISA Viral an! gen Good Hours Moderate Moderate-High

qPCR Viral gene expression Excellent Hours High, experienced High

TEM Viral par! cles Good Days-weeks High, very experienced Very High

Virus Counter Viral par! cles Excellent 10 minutes Low Inexpensive

Improving Vaccine Development and Production Using Rapid Virus Quantification


LSI TECHNOLOGY

fl ow rate to calculate the volumetric concentration of virus particles (Fig-ure 2). Because the sample fl ow rate is accurately and precisely measured in real-time, there is no need for an internal calibrant bead such as those used in typical fl ow cytometric cell counting assays.

Comparing Infec-tious and Total Particle Counts

To compare infectious titers with total particle count, samples of in-fl uenza H1N1, Cytomegalovirus (CMV), Respiratory Syncytial Virus (RSV) and Rubella were measured by TCID50 assay or plaque titer, Vi-rus Counter 2100 instrument and quantitative TEM. As shown in Fig-ure 3, total particle counts deter-mined by either TEM or the Virus Counter were statistically identical, while titer by TCID50 measured a fraction of the total particles, with counts ranging from 2-3.5 orders of magnitude lower than TEM or Virus Counter 2100 values. These results highlight the relative abun-dance of non-infective particles as a percentage of the total population across multiple virus types.

Why Infectivity Assays Are Increasingly Irrel-evant

There are a variety of approaches for determining viral titer, many of which rely on measuring infectivity or the amount of antigen, but do not enu-merate viral particles. There is grow-

ing evidence, however, that the num-ber of non-infectious viral particles is of signifi cant biological importance and can impact both in vitro and in vivo studies. This mounting data sug-gests a need for rapid quantifi cation of the total number of viral particles in a virus containing sample, which is only possible using the Virus Counter

2100.

Background: The Biolo-gy and Biological Conse-quences of Non-Infective Viral ParticlesAlthough viral particles may be non-infective for a number of biological reasons, defective viral replication is often the cause. For example, vi-ral capsids which lack genomes may be produced during the packaging phase, leading to empty particles. Mutations or defects in viral ge-nomes also result in the production of viral particles which are incapable of supporting full replicative cycles. These include relatively minor mu-tations in key genes controlling the viral life cycle or much larger-scale defects.

In the case of so-called “defective interfering particles” (DIPs) discov-


LSI TECHNOLOGY

ered in infl uenza, very large portions of the viral genome are often missing. A full replicative cycle is possible only if the DIP particles are in the presence of replication-competent, co-infecting viral particles. In such a case, DIPs may “piggyback” competent particle replication offsetting their defects, and as a result, DIPs compete for re-sources against replicative-competent particles and have even been shown to protect against lethal infections. In addition to providing potential com-petition for critical resources, it has been more recently documented that DIPs affect the severity of infection through modulation of host immune response.

As a result of increasing amount of research into non-infectious infl u-enza particles, other classes of these particles have been discovered. Noninfectious cell-killing particles (niCKP) found in infl uenza cultures, interferon-inducing particles (IFPs), and interferon induction-suppressing particles (ISPs) all play signifi cant biological roles without causing viral infection. The observation that these non-infectious particle types actu-ally make up the majority of particles in active infl uenza infections, raises the question of whether these par-ticles should be ignored. DIPS have also been documented in other virus types. In Dengue viral infections, they appear to play a role in natural biolog-ical attenuation. In HIV, genome rep-lication errors due to the reverse tran-

scription process cause the formation of DIPs which actively contribute to infection through “priming” of CD4+ T lymphocytes.

In addition to their effect on biological systems, monitoring non-infectious particle numbers can be important for other applications as well. During production of the seasonal fl u vaccine, infl uenza is grown then purifi ed from chicken eggs. Following purifi cation, the virus particles are split apart using a specialized reagent and the immu-nogenic HA proteins are harvested from this solution. Non-infectious particles that are known to have a pro-tein capsid and a partial genome will also contribute the immunogenic HA protein after being split. It is therefore essential during this process to have a rapid method for accurately measur-ing total particle concentrations.

Other types of vaccine production can also benefi t from total particle quantifi cation. Attenuated vaccines use a replication defi cient version of a

virus to cause an immune response, but with little to no viral infection. Since these attenuated viruses do not replicate, they will not cause the cytopathic effect that most infectiv-ity assays base their detection on. In a sense, all attenuated vaccines con-sist of non-infectious virus particles, and thus, the only methods to reliably quantify them are total particle quan-tifi cation methods. Virus-Like Parti-cles or VLPs are an emerging vaccine platform, and because of the require-ment that they be devoid of genetic material, are also non-infective. The primary means of quantifi cation are currently antigen-based or depend on analysis using electron microscopy. Given the extensive biological role of these non-infective particles, as well as their impact on the development and manufacture of viral vaccines, vi-ral particle quantifi cation is essential.

APPLICATION EXAM-PLES

Rapid Quanti� cation of Egg-Grown In� uenzaEmbryonated chicken eggs have been the primary means of producing in-fl uenza vaccines for many decades. Although there has been signifi cant effort to move away from this system, it will continue to provide the bulk of the global vaccine supply during the current decade and possibly well into the next. Until newer cell-based ap-proaches are validated and scaled-up, there remains ample opportunity to


LSI TECHNOLOGY

improve egg-based methods. A nota-ble bottleneck is the quantifi cation of virus along the entire vaccine devel-opment and manufacturing process. Current approaches often require days or weeks to obtain a result, lim-iting their utility or potentially delay-ing the time-critical process of getting vaccines for seasonal and emerging pandemic strains to the public. Con-sequently, there is an urgent need for faster, more accurate methods of de-termining the amount of virus pres-ent during the creation of these life-saving products.

An Overview of In� uenza Virus Growth in EggsVaccination against harmful infec-

tious diseases has been one of the most important global public health advances of the past 100 years. Due to surging demand for a wider range of vaccines, the industry is facing the challenge to updating from tradi-tional, time-consuming methods to new, more effi cient technology. An example of anticipated changes in the vaccine industry is the drive to tran-sition away from egg-based produc-tion of infl uenza vaccine toward more nimble methods such as cell-culture, recombinant protein expression and virus-like particles. While there has been signifi cant progress, top global producers of fl u vaccine still rely heav-ily on eggs to grow the virus.

Egg-based production has a long timeline and requires close coordi-nation between government agen-cies and vaccine producers to deliver safe and effective vaccines before the onset of fl u season.Since the Vi-rus Counter provides a direct, physi-cal measurement of total intact virus

concentration within minutes, it can have a signifi cant impact at multiple stages during vaccine research, devel-opment and production, such as those indicated by a star in Figure 4 below.These include:

• The selection of high-growth re-assortants that have the appropri-ate antigenic properties for each type and strain to be used in the multivalent vaccine would sig-nifi cantly reduce the time to seed stock selection.

• Faster elucidation of virus yield as a function of various parameters during culture would speed time to scale up for production.

• Tracking virus concentration dur-ing subsequent purifi cation steps

is also essential in that identify-ing points where virus is lost will enable process improvements and lead to greater effi ciencies in cal-culated in both time and money.

• The ability to track virus levels in real-time, which is not possible with traditional methods, will ensure optimal harvest time with maximal yields.

Using Eggs to Produce Flu Vaccine: Primary Unmet NeedsChicken eggs have been utilized since the mid-20th century to grow a vari-

ety of viruses (Figure 5), which are then inactivated and injected into the individual to provide protective immunity. Although the bulk of the seasonal fl u vaccine is still produced in this manner, there are a number of issues associated with egg-based systems. Chief of these are the vari-ability in growth characteristics of each viral strain and batch to batch differences between eggs. In addition, even seemingly minor inconsistences in incubation times can have a signifi -cant impact. Consequently, providing as close to “real time” quantifi cation of total viral particle count during the growth cycle is a primary unmet need in the vaccine industry. Of utmost im-portance is the ability to take samples

from a large representative number of eggs, and rapidly prepare and analyze the samples to allow for adjustments in incubation conditions or immedi-ately harvest.

Same Day Determination of Virus Concentration in Allantoic Fluid Now that we’ve defi ned the unmet need for a method that provides rapid, quan-tifi able and reproducible results, what is the proof that the Virus Counter is the solution, specifi cally with regards to egg-grown infl uenza? The follow-


LSI TECHNOLOGY

ing are just a small sample of results obtained by the Virus Counter in this setting.

Serial dilution curve. An es-sential fi rst step in validating any quantifi cation method is to perform a serial dilution analysis, whereby a concen-trated sample is diluted by known fractions and ana-lyzed. In this example, sam-ples of three different infl u-enza strains were obtained from allantoic fl uid and di-luted. The expected result is to see a linear relationship between the logarithm of the dilution and the logarithm of the result.

The results in Figure 6 show good linearity across the dilution series, with slopes near 1. Data from the nega-tive control do not show this same pattern, as they are at or below the stated limit of detection of the Virus Coun-ter of 1x106 vp/ml.

Comparison of Virus Coun-ter with TCID50. Traditional approaches to virus quanti-fi cation fall into two catego-ries: Those that determine infectivity, and those that do not. Examples of the former include plaque titer assay and tissue culture infectious dose 50 (TCID50), and trans-mission electron microsco-py (TEM) and quantitative polymerase chain reaction (qPCR) for the later.

Four different infl uenza strains were quantifi ed using both the Virus Counter and TCID50. As is typically the case for infl uenza (and many other vi-ruses), the number of intact virus par-ticles per unit volume (vp/ml) is 1-2.5 logs higher than the number of infec-tious particles (Figure 7), due primar-

ily to the abundance of the previously discussed Defective Interfering Par-ticles. Since DIPs are known to play a role in immunity, these results can provide information about subsequent

use of a given stock. It is worth noting that the TCID50 assay typically takes between 3-8 days to perform, and is often subject to signifi cant variability.

Comparison of Virus Counter with qPCR. Quantitative PCR (qPCR, also known as real time PCR) utilizes primers specifi c to the viral genome to amplify and simultaneously quantify a target-ed DNA molecule. The quantity can be either an absolute num-ber of copies or a relative amount when normalized to DNA input or additional normalizing genes. Figure 8 illustrates a close cor-relation between the two quan-tifi cation techniques. Notice the much larger error bars for the qPCR results relative to those for the Virus Counter.

CONCLUSIONThere are many points during the process of developing, opti-mizing and producing vaccines that would benefi t from rapid enumeration of viral particles. One of the most signifi cant is tracking effi ciency following harvest from egg- and cell-based systems. More often than not, the long and complex steps of taking crude material and trans-forming it into a product ready for patients results in substantial loss of material.

The ability to track essentially in real time the quantity of virus at beginning and end of each dis-tinct stage will identify where losses are occurring, and allow improvements to be made. Even small gains in effi ciency at each step would lead to considerable fi nancial benefi ts.

Michael Ar� nger, Michael Moeller

and Kevin Kohlmeier

The writers work at ViroCyt LLC,

Denver, CO, USA

mar� [email protected]


LSI TECHNOLOGY

NMR spectroscopy:

Creating waves in life sciences-Neel Sarovar Bhavesh

ICGEB, New Delhi

http://www.neelsb.com

World is visible to us through a fi ne interplay between the matter, it is composed of, and the light, that shines on it. Our limitations as human beings allow us to see only a small

part of light, the visible part, which along with some of its well-known cousins - X-rays, microwaves and radiowaves, is part of a large family called the electromagnetic spec-trum. This spectrum, similar to a rainbow, is made up of a nearly infi nite number of ‘colors’ that cannot be perceived directly by us. The way that matter interacts with the elec-tromagnetic spectrum forms the underlying principle of spectroscopy. Many of our scientifi c advances of the mod-ern era, right from determining how fast the universe is expanding to looking at the incredibly tiny atoms and mol-ecules that make up our body, owe their success directly or indirectly to spectroscopy. To put this in perspective, we now know that a piece of our skin as small as the point of a needle contains more than a thousand skin cells, each

of which contains thousands of proteins, carbohydrates, fats, nucleic acids, and small compounds. These ‘biological macromolecules’ and ‘metabolites’ in turn, are composed of six basic elements – carbon, nitrogen, hydrogen, oxygen, phosphorus and sulphur which, when arranged in an ex-tremely ordered fashion, ultimately make us what we are.

Nuclear magnetic resonance or NMR spectroscopy is a modern day tool that is used to delve deep into the intricate machinery that operates within each cell. Initially devel-oped by physicists to gain insight into the magnetic prop-erties of atom, NMR spectroscopy has evolved very rapidly and become an essential tool for physicists, chemists, ge-ologists, biologists, and clinicians. Technical advances in NMR spectroscopy and its applications have earned twelve Nobel prizes in the fi eld of physics, chemistry and physi-ology/medicine confi rming its importance and ubiquitous nature. In recent years, NMR has provided many signifi -cant breakthroughs, which were earlier thought to be near impossible, like atomic-resolution structure of protein in-side a living cell, functional imaging of brain, biomarker identifi cation using bio-fl uids (urine, serum, saliva etc), oil exploration, detection of explosives, quality control of wine to name a few.


LSI TECHNOLOGY

NMR spectroscopy makes use of the fact that atomic nu-clei, which usually spin randomly, sometimes tend to be-have themselves in the presence of a powerful magnetic fi eld (about million times as powerful as that of the Earth!) and get aligned in the same direction as this fi eld. These magnetized atoms can then be irradiated with a concen-trated blast of radio waves (similar to those used in mo-bile communication) to see how they react. Their reaction (called free induction decay) gives us vital knowledge about how these atomic nuclei are affected by their environment and vice. For instance, a carbon nucleus bound to hydrogen will react differently as compared to one bound to oxygen. Changes in atomic environments as a result of interactions with other entities also result in unique NMR signals. Just as each FM radio station has its own frequency band (98.3 megahertz (MHz), 93.5 MHz, to quote a few); every type of atomic nuclei has its own unique radio frequency called resonance frequency. In a magnetic fi eld around 200,000 times that of the Earth, hydrogen atoms have a resonance frequency of 500 MHz, carbon-13 (an isotope of carbon) at-oms resonates the most at 125 MHz and nitrogen-15 (an isotope of Nitrogen) resonates at 50 MHz. However, in the presence of external infl uences, resonance frequencies un-dergo very minute changes. While the frequencies are in the order of MHz (106 hertz), these minute changes are in hertz (Hz) – very small, but detectable. These tiny changes in frequency are called ‘chemical shifts’ (The phenomenon of chemical shift was fi rst observed by Prof. S. S. Dhar-matti who later initiated NMR research at TIFR, Bombay). As long as the environment of an atom remains constant, its chemical shift value also stays unchanged. A slight per-turbation however, is suffi cient to cause a perturbation in chemical shift. Atomic nuclei give different reactions to a radiofrequency pulse when placed in different environ-ments and they start cross-talking with neighboring atomic nuclei. This cross-talk with other atoms closer in space is crucial for determining what any organic molecule, be it a

protein, nucleic acid or a small carbohydrate, looks like in 3D (The NMR technique to calculate 3D structure is called nuclear Overhausser enhanced spectroscopy (NOESY) was fi rst performed by Prof. Anil Kumar who currently works at IISc, Bangalore). This development helped scientists not only to visualize the atomic-resolution three-dimensional structure of macromolecules in solution mimicking their natural environment inside the cell but also study the dy-namics and interactions. Though almost half a century younger to X-ray crystallography, NMR spectroscopy has contributed to about 40% of nucleic acid and 12% of protein structures deposited in the protein data bank (PDB, http://www.rcsb.org).

One might wonder what use might these have at a tangi-ble level. NMR spectroscopy can tell you for instance, if a particular protein can be a potential therapeutic target for an anti-malarial or anti-tuberculosis drug, if the abnormal level of a carbohydrate in blood marks the presence of a potentially life-threatening tumor, or if an unexplainable illness is caused just because one protein out of thousands decided not to perform its intended role. NMR spectros-copy has proven to be indispensable in the design and screening of such compounds. Moreover, the modes of ac-tion of many drugs have also been discovered using NMR and other forms of spectroscopy. For instance, in 2010, a group of scientists in Singapore found that a drug called Tacrolimus or FK506, usually given to people who have had organ transplants, also kills the malaria parasite by binding specifi cally to a receptor called PfFKBP35 on its cell surface. This discovery was possible largely by determining the mo-lecular structure of PfFKBP35 before and after it bound to Tacrolimus, using NMR spectroscopy.

The use of NMR in drug discovery is best highlighted in case of the human survivin protein. This protein is an at-tractive target for anti-cancer therapy because survivin in its inactive form makes immortal cancer cells to die in a natural manner. Abbott laboratories have recently screened a large number of peptides (small fragments of proteins) to determine which would best fi t onto the surface of the sur-vivin protein to render it completely inactive. This was done by fi rst determining the 3D structure of survivin protein by NMR spectroscopy. The structure of the protein provided clues to where possible drugs (peptide fragments) could bind. The binding site would contain amino acids whose atoms would undergo a large change in chemical shift when bound tightly to a peptide and remain unperturbed if no binding occurred, thus helping in selecting those frag-ments, which could potentially act as anti-cancer drugs. This approach has been used for designing several drugs in the recent past and comes under the banner of Fragment Based Drug Discovery (FBDD).

The survivin case is also an interesting example of how the


LSI TECHNOLOGY

study of biological interactions provides insight into possi-ble modes of drug binding. The NMR derived 3D structure of survivin protein showed that in its functional form, it exists as a pair of two survivin molecules, together form-ing the shape of a bow and a tie. Under normal conditions inside a cell, survivin binds to a peptide called Smac. The exact amino acids of survivin that are engaged in this bind-ing could be accurately determined using NMR, by check-ing the changes in chemical shifts of atoms inside survivin after the addition of Smac. It could then be concluded that these amino acids constituted the binding site on the sur-vivin protein.

Just as NMR has proven to be a crucial implement for drug discovery, it has also recently proven its mettle in the fi eld of metabolomics. Metabolomics involves the fast and accu-rate detection of small molecules that fl oat around in bodily fl uids such as urine, blood (serum or plasma), cell or tissue extracts. Such small molecules are usually not more than 1500 times the weight of a single hydrogen atom, the small-est atom in the universe. In contrast, the average protein is

more than 30,000-100,000 times heavier than hydrogen! It can be used to quantitatively measure dynamic biochemi-cal responses of living organisms to physiological or patho-logical stimuli. Metabolomics has diverse range of applica-tion areas including investigation of disease mechanisms, diagnosis/prognosis of pathologies, nutritional interven-tions and drug toxicity. Profi ling of metabolites has become increasingly important in identifying biomarkers of disease progression and drug intervention, and can provide addi-tional information to support or aid the interpretation of genomic and proteomic data.

Among the techniques used for study of metabolites high-resolution NMR spectroscopy has advantages over others, as it is a quantitative nondestructive, noninvasive, non-equilibrium perturbing technique that provides detailed information on solution-state molecular structures, based on atom-centered nuclear interactions and properties. It can also used to explore metabolite molecular dynamics and mobility (such as ligand–protein binding). It is a ro-bust and reliable technique for metabolomics applications in which high reproducibility is paramount. It allows the detection of a wide range of structurally diverse metabo-

lites simultaneously, providing a metabolic ‘snapshot’ at a particular time point. Metabolite concentrations down to the few micromolar range are readily detectable.

A study carried out in 2006, for example, used NMR to show that in patients with cancer of the pancreas (the organ that makes insulin), a type of fat called phosphatidyl inosi-tol was much lower than normal in blood. This was dis-covered using blood sample of patients for metabolomics. When compared to the blood of a normal, healthy person, it was found that the hydrogen signals that belonged to phos-phatidyl inositol were of a far lower strength, though their chemical shift values were unchanged. The signifi cance of this fi nding is that doctors can monitor the level of this compound in the blood of those who have a family history of pancreatic cancer or those who work with cancer causing chemicals. A rapid treatment is thus, now possible before the cancer progresses to a more dangerous state. Thanks to NMR, phosphatidyl inositol is now an important ‘bio-marker’ for pancreatic cancer.

Besides the usual biofl uids, cerebrospinal fl uid or CSF is also being tested for biomarkers nowadays. CSF is the nu-tritious liquid in which our brain and spinal cord fl oat. In some cases of tuberculosis, the outer covering of the brain (called meninges) gets swollen in a condition called men-ingitis. This condition is potentially fatal unless detected early. NMR based biomarker discovery showed that a mol-ecule called cyclopropane (consists of three carbon atoms forming a triangle) is present in CSF when this disease strikes. Similarly, other biomarkers have been discovered for other diseases affecting the nervous system. These in-clude Alzheimer’s disease, Huntington disease, bacterial and viral meningitis. Given that 89% of known drugs are small molecules, one can appreciate the therapeutic poten-tial of discovering such biomarkers. These biomarkers hold tremendous promise as weapons against many of the un-beatable diseases that exist today. Even if a small percent-age of these pass through clinical trials and fi nally come into the market as prescription drugs, it will still be a big leap forward for medicine.

NMR spectroscopy, along with other methods, has shed light in the last few decades on the way macromolecules behave inside a cell and outside. The fi nely tuned harmony that exists between the parts of a cell has been made vis-ible to us thanks to these techniques. Advances in basic sciences have provided a clearer picture of the role of ev-ery cellular component, be it a lowly amino acid or a huge ribosome. This knowledge is a stepping-stone to the next era of medicine, giving us the capability to make extremely targeted approaches to combating illnesses. Be it miracle drugs, diagnostic kits, vaccines or therapies, we now have the formidable arsenal that we lacked a decade or more ago, thus paving the way for a more secure future.

The use of NMR in drug discovery is best

highlighted in case of the human survivin

protein. This protein is an attractive target

for anti-cancer therapy because survivin

in its inactive form makes immortal cancer

cells to die in a natural manner

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