CHAPTER 1 RESEARCH METHODOLOGY

RESEARCH PROPOSAL

Macro Objective
To study & analyze overall domestic market for OVARIAN & CERVICAL CANCER DRUGS.

Micro Objective
1. To analyze price incorporation strategy of drugs in pharmaceutical industry 2. To study & analyze overall domestic market for generic version of PEGYLATED LIPOSOMES OF DOXORUBICINE & compare it with other existing brands of OVARIAN CANCER DRUGS in terms of available dosage forms, efficacy & price 3. To suggest an appropriate launch strategy to launch a new generic version of the DOXORUBICINE

Motivation for the research

Pharmaceutical is one of the most intense Knowledge Driven industries. It is a life line industry, which plays a very crucial role in building a strong human capital of a country, and is very essential for economic growth and development. In 2008, global spending on prescription drugs topped $700 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for almost half of the global pharmaceutical market, with $300 billion in annual sales followed by the EU and Japan. Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.

The pharmaceutical industry is one of the fastest growing sectors in Indian economy. The size of the Indian pharmaceutical industry is estimated at US $ 7.76 billion. It is growing at an average rate of 14.1 %. The pharmaceutical industry has shown a robust growth of 13% in 2007 and has grown by 12% in 2008. It is expected to continue growing at the rate of 12% in 2009. (Source: ORG IMS SSA May 2008).

Medicines in the cancer therapeutic area account for the third largest source of revenue within the pharma industry. The cancer market has experienced significant innovative change in recent years, creating attractive opportunities for a range of new and established biotechnology players as well as established pharma companies. Although new product development continues to involve substantial levels of risk, innovation is the key driving force in the market, and has led to the competitive exclusion of several of the industrys traditional competitors. With successful launches now being applied to multiple indications faster than ever before, subsequent increases in product sales volumes are rapidly changing the competitive landscape of the cancer market.

The cancer market expanded by 19.9% during 2009 and is forecast to reach $40.9b by 2012. The highest growth will occur in the antineoplastic class of drugs, which is expected to become the primary growth driver of the cancer market over the next four years.

Research Objective
To study & analyze overall domestic market for OVARIAN & CERVICAL CANCER DRUGS.

Introduction Market research process is the process used to obtain information regarding market opportunity & problem and there by making strategies for the business. Our purpose is to launch a new brand of PEGYLATED LIPOSOMES OF DOXORUBICINE .Therefore; we need to do market analysis of the current payers of the same & their strategies. Thus, it will help us making strategies for launching a new brand of DOXORUBICINE Detailed process for research methodology is discussed below

Our research will answer the following questions: What is ovarian & cervical cancer? Epidemiology of ovarian & cervical cancer. What are the different dosage forms available of ovarian & cervical cancer drugs? What are the existing brands of ovarian & cervical cancer drugs? Which are the generic players of ovarian & cervical cancer drugs? Who are the top players of ovarian & cervical cancer drugs & what about their markets? Statistical analysis of price comparison for ovarian & cervical cancer drugs. Indian market share for doxorubicin in Cancer drugs and its expansion capacity How we will launch our brand & its positioning? What will be the promotional, communication & operational strategies for our brand? Analysis and Finding Recommendation and Suggestions

Research Methodology
Research Type: Exploratory followed by Descriptive The Researchers will use exploratory followed by descriptive research design to define the opportunity & to develop an approach for international market for generic drugs. The researcher will use both qualitative & quantitative data for the research work. The researcher will use secondary as well as primary data for marketing research. The reason for choosing this type of data is, qualitative research provides insights & understanding of problem setting, while quantitative research seeks to quantify the data & typically applies some form of statistical analysis.

Figure 1.1

Data Sources
Secondary Data This data will be collected from journals, internet, reports, industry publications and dissertations. Primary Data This data include both qualitative and quantitative data. Data are generated through interaction with various doctors who has handle cancer cases. Data for the price strategy and distribution related data are generated by interaction with druggist, stockiest and carrying and forwarding agent.

a) Research Approach:
Survey Method: Primary data are collected through survey of doctors, stockiest, carrying and forwarding agent and stockiest b) Research Instrument: Questionnaire: It includes both open ended and closed ended questions. Close ended includes different scaling technique.

c) Types of Questionnaire:
Structured

d) Type of Questions:
Open-ended and Close-ended questions e) Sampling Plan: Sampling Unit: For price analysis C & F agents, stockiest & retailers. Drug related information through doctors who have handled cancer cases Sample Size: 30 doctors (20 Oncologists & 10 Consultant Physiologists) 05 Carrying & Forwarding agents 30 stockiest & 30 retailers Sampling Procedure:
Nonprobabilityconvenience Contact Method: Personal

f)

Mode of collecting data: The respondents will be chosen randomly and requested to. The questions will then be

asked in a predetermined sequence. g)

Data Processing:
A number of tables and charts to be prepared to bring out the main characteristic

of the collected data. Inferences to be drawn from the data collected.

Analysis and Finding

Method of data analysis Data analysis is done through the primary data gathered from the survey of doctors, stockiest, c & f Agent and retailer. It includes presentation through table and chart preparation.

CHAPTER 2 INTRODUCTION TO PHARMACEUTICAL INDUSTRY

PHARMACEUTICAL INDUSTRY-OVERVIEW:
Pharmaceutical is one of the most intense Knowledge Driven industries, which is continuously in a state of dynamic transition. Defined as a complex matrix of processes, operations and organizations involved in the discovery, development and manufacture of drugs and medications, the pharmaceutical industry is a life line industry, which plays a very crucial role in building a strong human capital of a country, and is very essential for economic growth and development.

2.1 Origins and Evolution: The modern pharmaceutical industry is a highly competitive non-assembled1 global industry. Its origins can be traced back to the nascent chemical industry of the late nineteenth century in the Upper Rhine Valley near Basel, Switzerland when dyestuffs were found to have antiseptic properties. A host of modern pharmaceutical companies all started out as Rhine-based family dyestuff and chemical companies e.g. Hoffman-La Roche, Sandoz, Ciba-Geigy (the product of a merger between Ciba and Geigy), Novartis etc. Most are still going strong today.

Over time many of these chemical companies moved into the production of pharmaceuticals and other synthetic chemicals and they gradually evolved into global players. The introduction and success of penicillin in the early forties and the relative success of other innovative drugs, institutionalized research and development (R&D) efforts in the industry. The industry expanded rapidly in the sixties, benefiting from new discoveries and a lax regulatory environment. During this period healthcare spending boomed as global economies prospered.

These included the first oral contraceptive, "The Pill", Cortisone, blood-pressure drugs and other heart medications. MAO Inhibitors, chlorpromazine (Thorazine), Haldol (Haloperidol) and the tranquilizers ushered in the age of psychiatric medication. Valium (diazepam), discovered in 1960, was marketed from 1963 and rapidly became the most prescribed drug in history, prior to controversy over dependency and habituation.

2.2 Research and development: Drug discovery is the process by which potential drugs are discovered or designed. In the past most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. Modern biotechnology often focuses on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using molecular biology or Biochemistry.

Drug development refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate Formulation and Dosing, as well as to establish safety. Research in these areas generally includes a combination of in vitro studies, in vivo studies, and clinical trials. The amount of capital required for late stage development has made it a historical strength of the larger pharmaceutical companies.

2.3 Industry revenues: In 2009, global spending on prescription drugs topped $680 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for almost half of the global pharmaceutical market, with $290 billion in annual sales followed by the EU and Japan. Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.

2.4 Marketing: Pharmaceutical companies commonly spend a large amount on advertising, marketing and lobbying. Pharmaceutical companies generally employ sales people (often called 'med. reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers.

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INDIAN PHARMACEUTICAL INDUSTRY

Indian pharmaceutical industry is mounting up the value chain. From being a pure reverse engineering industry focused on the domestic market, the industry is moving towards basic research-driven, export-oriented global presence, providing wide range of value added quality products and services.

The first Indian pharmaceutical company, Bengal Chemicals and Pharmaceutical Works, which still exists today as one of 5 government-owned drug manufacturers, appeared in Calcutta in 1930. The government started to encourage the growth of drug manufacturing by Indian companies in the early 1960s, and with the Patents Act in 1970, enabled the industry to become what it is today.

This patent act removed composition patents from food and drugs, and though it kept process patents, these were shortened to a period of five to seven years. The lack of patent protection made the Indian market undesirable to the multinational companies that had dominated the market, and while they streamed out, Indian companies started to take their places. They carved a niche in both the Indian and world markets with their expertise in reverseengineering new processes for manufacturing drugs at low costs.

As in the present scenario, only a few people can afford costly drugs, which have increased price sensitivity in the pharmaceutical market. Now the companies are trying to capture the market by introducing high quality and low price medicines and drugs. With the Product Patent Act, which came into action in January 2005, this industry is able to attract big MNCs to India. Earlier these big firms had apprehensions in launching new drugs in the Indian market.

Approvals given by Foods and Drugs Administration (FDA) and ANDA (Abbreviated New Drug Application)/DMF (Drug Master File) have played an important role in making India a cost-effective and high quality product manufacturer. Furthermore, the changes that took place in the patent law, change of process patent to product patent, have helped in reducing the risk of loss for intellectual property.

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2.1 Market Overview: The size of the Indian pharmaceutical industry is estimated at US $ 7.76 billion. It is growing at an average rate of 14.1 %. The pharmaceutical industry has shown a robust growth of 13% in 2007 and has grown by 12% in 2008. It is expected to continue growing at the rate of 12% in 2009. (Source: ORG IMS SSA May 2008) Despite the economic slowdown the Indian Pharmaceutical sector will be worth US $ 20 billion by 2015. The revenues from the Indian healthcare sector account for 5.2% of the GDP, making it the third largest growth segment in India. Consumer spending on healthcare increased from 4% of the GDP in 1995 to 7% in 2007.

The Indian pharmaceutical industry contributes 8 percent in volume but less than 2 percent in value terms to the global pharmaceutical sales as drug prices in India are one of the lowest in the world. Indian Pharmaceutical Industry is worlds 4th largest producer in terms of volume and 11th in value terms globally. (Source: www.prlog.org)

The Indian pharmaceutical industry has 300 medium and large size researches and development (R&D) based pharmaceutical companies including multinationals, government owned and Indian private companies. In addition to these large companies, it is estimated that there are 10,000 smaller licensed generic manufacturers. There are 74 US FDA approved manufacturing facilities and 5 central public sector unit.

This highly fragmented industry has resulted in with no players controlling more than 7 percent of the retail formulation market. However, similar to the global trends, mergers and acquisitions in the Indian pharmaceutical industry has resulted in the 10 top formulation firms accounting for 37 percent of the retail formulation market. The industry manufactures about 400 bulk drugs and almost the entire range of formulations. (Source: www.export.gov.il/2351 the Indian Pharmaceutical Market.docm)

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2.2 Market Trends: The industry has enormous growth potential. Factors listed below determine the rising demand for pharmaceuticals. The growing population of over of a billion Increasing income Aggressive market penetration Health insurance penetration Medical infrastructure build up Demand for quality healthcare service Changing lifestyle has led to change in disease patterns, and increased

demand for new medicines to combat lifestyle related diseases (Source:www.export.gov.il/2351 the Indian Pharmaceutical Market.docm)

2.3 Important Developments after Liberalization Process in 2006: Following are some of the important developments that have taken place in pharmaceutical sector after the process of liberalization of the Indian economy was initiated by the Government in the year 1991.

Industrial Licensing: Industrial licensing for all kinds of drugs has been abolished. However the need for obtaining manufacturing licence under Drugs and Cosmetics Act,1940 continues for all units whether organized or small scale. The State Drug Controllers are authorized to issue such licences in most cases.

Foreign Direct Investment: FDI up to 100% is permitted, subject to stipulations laid down from time to time in the Industrial Policy.

Foreign Technology Agreement: Automatic approval for Foreign Technology Agreement (FTA) is already available in the case of all the bulk drugs cleared by Drug Controller General (India) . Imports: Imports of drugs and pharmaceuticals are regulated through EXIM Policy in force and presently all items except those requiring clearance under The Narcotics and

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Psychotropic Substances Act , 1985 are allowed under OGL. Further, a centralized system of registration has been introduced under the Drugs & Cosmetics Act and Rules made there under, administered by Ministry of Health and Family Welfare. Exports: Exports are permitted in accordance with the EXIM Policy and relevant procedures/rules formulated for the purpose by the Directorate General of Foreign Trade. Exports are also subject to laws prevalent in importing countries. Also, the exporters are allowed imports of inputs on duty-free basis for export production. The industry has shown commendable export performance, the trade balance being positive. Over the last few years the compounded annual growth rate in exports has been 22.7 percent.

2.4 Government Support: Export Promotion Cell: An Export Promotion cell in this sector has been incorporated with the objective of Boosting Pharmaceutical exports Function as a nodal centre Promotional Activities aiming at accelerating pharma exports. Suggestions for modifications in the EXIM Policy. Seminars / Workshops on standards, quality control requirements etc

Pharma Export Promotion Council (Pharmexcil): The Pharma Export Promotion Council (Pharmexcil) has been constituted with the objective of Facilitation of exports of Drugs, Pharmaceuticals, Biotechnology products, Herbal Medicines, Diagnostics Export thrust to various products through workshops, conferences and seminars and delegate visits.

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Foreign Direct Investment (FDI) in Drugs and Pharmaceuticals: FDI upto 74% in the case of bulk drugs, their intermediate Pharmaceuticals and formulations (except those produced by the use of recombinant DNA technology) would be covered under automatic route. FDI above 74% for manufacture of bulk drugs will be considered by the Government on case to case basis for manufacture of bulk drugs from basic stages and their intermediates and bulk drugs produced by the use of recombinant DNA technology as well as the specific cell/tissue targeted formulations provided it involves manufacturing from basic stage.

2.5 Pharma Parks/SEZs for Pharma Industry: In order to enable India to achieve a leading position as the Drug Maker of the World it is essential that a World class infrastructure is provided for the accelerated growth of the industry. In order to provide the required infrastructure it is essential to have a scheme where Central Government, State Governments and industry are participants. A special scheme for setting up pharmaceutical parks in the country (separate for bulk and for formulations) in the next 5 years is proposed. This would be broadly on the lines of Scheme for Integrated Textile Parks.

Each park would be set up in a minimum area of 250 acres for bulk and 100 acres for formulations. It would be expected to have about 50 to 100 units, investment of Rs 1000 crs to Rs 2000 crs and likely employment of about 20,000 persons.

Where an SEZ is to be set up the minimum size criterion for pharma SEZs would be 50 hectares for the next 3 years. This would encourage quick setting up of such parks and for demonstration effect. After a successful take-off of the scheme minimum size may be increased suitably all environmental approvals in the case of pharma parks would be granted at the State level only.

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2.6 Strengths of Indian Pharmaceutical Industry & its Players: Capital Investment in Technology: Owing to the availability of advanced technology at low costs, the companies can produce drugs at lower costs. Cost Effective: The filing cost of ANDAs (Abbreviated New Drug Application) and DMFs (Drug Master File) is comparatively low for the Indian companies. Manpower: There is a large pool of technical experts available at modest salaries. Contract Research & Contract Manufacturing: There is a good scope for contract research and contract manufacturing. Infrastructure: There is a well-developed infrastructure for the pharmaceutical industry. Generic Drugs: In the last few years, the generic drug-manufacturing segment has received huge investments, in the process making it more competitive and efficient.

2.7 Challenges: All of these changes are ultimately good for the Indian pharmaceutical industry, which suffered in the past from inadequate regulation and large quantities of spurious drugs. They force the industry to reach a level necessary for global competitiveness.

However, they have also exposed some of the inadequacies in the industry today. Its main weakness is an underdeveloped new molecule discovery program. Even after the increased investment, market leaders such as Ranbaxy and Dr. Reddys Laboratories spent only 5-10% of their revenues on R&D, lagging behind Western pharmaceuticals like Pfizer, whose research budget last year was greater than the combined revenues of the entire Indian pharmaceutical industry.

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This disparity is too great to be explained by cost differentials, and it comes when advances in genomics have made research equipment more expensive than ever. The drug discovery process is further hindered by a dearth of qualified molecular biologists.

Due to the disconnect between curriculum and industry, Pharma in India also lack the academic collaboration that is crucial to drug development in the West.

2.8 Major Players in India: Aurobindo Pharma: Aurobindo Pharma manufactures generics and APIs in the antibiotic, antiretroviral, cardiovascular, central nervous system, gastroenterological and anti-allergy fields, and markets them in over 100 countries.

Aventis Pharma: 50.1 percent of Aventis Pharma is held by European drug major Sanofi-Aventis and, in early April 2006, it was reported that UB Holdings had sold its 10 percent holding in the firm to Variegate Trading, a UB subsidiary. The firm's major products are in the anti-infective, antiinflammatory, cancer, diabetes and allergy market segments

Cipla: India's second-largest drug manufacturer was originally established in 1935 as The Chemical, Industrial and Pharmaceutical Laboratories. Until 2000 its business was primarily domestic, but exports, to more than 150 countries.

Dr Reddy's Laboratories: Dr Reddy's Laboratories is an emerging global pharmaceutical and biotechnology company, which was founded by Chairman Anji Reddy in 1984. It operates in over 60 countries, although India and the USA each accounts for around a third of the firm's total sales.

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Lupin: Lupin is one of the world's largest manufacturers of APIs and finished formulations for TB, bacterial infections and cardiovascular disease. Its products are sold in more than 50 countries.

Nicholas Piramal: Nicholas Piramal is the flagship company of Piramal Enterprises (PEL), one of India's largest diversified business houses. It was formed in 1988 when PEL acquired Nicholas Laboratories (NPIL) a small formulations company, from Sara Lee.

Ranbaxy Laboratories: India's largest pharmaceutical company is ranked among the top 10 generics manufacturers worldwide and aiming to be in the top five with sales of $5 billion by 2012.

Sun Pharma: Sun Pharma, established in 1983, makes specialty pharmaceuticals and APIs for use in chronic therapy areas such as cardiology, ovarian, cervical cancer, gastroenterology, diabetes and respiratory conditions, sold in 26 markets worldwide.

Wockhardt: The overseas ambitions of this Mumbai-based pharmaceutical and biotechnologybased company have already been covered elsewhere in this report, but in mid-March 2006

Zydus Cadila: Zydus Cadila is India's fifth largest pharmaceutical company. Cadila was founded in 1952 and, following restructuring, the Zydus Cadila Group was established in 1995. The operating environment for medium-sized generic drug manufacturers is changing rapidly as the industry matures and growth focuses on new market opportunities. Consolidation continues to affect companies, as acquisition becomes the instrument of choice in the drive for market share.

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Ranbaxy Ranbaxy is number one player in India, both in terms of market capitalization and in terms of sales. Other major players are Cipla, DRL, Glaxo etc. Though Pfizer is worlds number one company with a market share of approximately 11% and sales almost 10 times of the whole of Indian pharma industry, it has not done so well in India so far. But this can be attributed to poor intellectual property protection provisions in India which prevented MNCs like Pfizer, Novartis and Eli Lilly from introducing their blockbuster drugs in India, but now with the arrival of patent regime things can be very different.

Intas Pharmaceutical Ltd. Intas pharmaceutical Ltd. is located near ahmedabad. Its turnover is 1200 cr. The company has is involved in various diseases with some of the top brands. It has diverse portfolio of pharmaceutical products. It is involved in cardio. Diabeto & CNS segments.

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CHAPTER 3 ASSIGNED PROJECT SCOPE

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Background The project involved analyzing the market potential of OVARIAN & CERVICAL CANCER DRUGS. It also includes the statistics of various players of brands of DOXORUBICINE & its effectiveness for particular disease thereby promoting it into that segment. It also includes analyzing competitors strategy. Product DOXORUBICINE Objective Evaluating the Market Potential for DOXORUBICINE and Surveying doctors for promotion of the drug into particular segments. Suggesting brand launching strategies and promotional strategies after evaluating the competing brands and target market.. Answers sought for following questions What type of price incorporation strategy is there in pharmaceutical industry? Statistics of Ovarian & Cervical Cancer in India What are the existing brands of OVARIAN & CERVICAL DRUGS? Which are the generic players of DOXORUBICINE? Who are the top players & what about their markets? How will we launch our brand & its positioning? What will be the promotional, communication & operational strategies for our brand?

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Benefits: It will help in knowing as the company desires to expand to newer markets, the data collected would be of supreme importance to the company to formulate strategies and plan out future action plans. Understanding competitors strategies, competing with them, building successful import export patterns with logistical success would also help the company to cut down costs and increase efficiency and productivity. Analysis would also help to gauge which products are most feasible and demanded in the desired markets, thereby enabling the company to focus on such products wholly

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CHAPTER 4 KEY FINDINGS & ANALYSIS

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PHARMACOLOGICAL REVIEW
What is Ovarian Cancer? Ovarian cancer is a disease in which malignant or cancerous cells are found in the ovaries. An ovary is one of two small, almond-shaped organs located on each side of the uterus that store eggs or germ cells and produce female hormones estrogen and progesterone.

Cancer Basics

Cancer develops when cells in a part of the body (in this case the ovary) begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells.

Normally, cells in your body divide, and form new cells to replace worn out or dying cells and to repair injuries. Because cancer cells continue to grow and divide, they are different from normal cells. Instead of dying, they outlive normal cells and continue to create new abnormal cells forming a tumor. Tumors can put pressure on other organs lying near the ovaries.

Cancer cells sometimes can travel to other parts of the body where they begin to grow and replace normal tissue. This process, called metastasis, occurs as the cancer cells move into the bloodstream or lymph vessels of our body. Cancer cells that spread from other organ sites (such as breast or colon) to the ovary are not considered ovarian cancer

There are many types of tumors that can start in the ovaries. Some are benign, or noncancerous, and the patient can be cured by surgically removing one ovary or the part of the ovary containing the tumor. Some are malignant or cancerous. The treatment options and the outcome for the patient depend on the type of ovarian cancer and how far it has spread before it is diagnosed.

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What is the general outlook for women diagnosed with ovarian cancer? In women age 35-74, ovarian cancer is the fifth leading cause of cancer-related deaths. An estimated one woman in 58 will develop ovarian cancer during her lifetime. The American Cancer Society estimates that in 2008, there will be 21,650 new cases of ovarian cancer and 15,520 women will die from ovarian cancer. Because each woman diagnosed with ovarian cancer has a different profile, it is impossible to give a general prognosis. If diagnosed and treated early, when the cancer is confined to the ovary, the 5-year survival rate is over 90%.9 out of 10 women are cured. Unfortunately, due to ovarian cancer's non-specific symptoms and lack of early detection tests, the only 19% of all cases are found at this early stage. If caught in stage III or higher, the survival rate can be as low as 29%.(Source: American Cancer Society) Types of Ovarian Cancer There are more than 30 different types of ovarian cancer which are classified according to the type of cell from which they start. Cancerous ovarian tumors can start from three common cell types:

Surface Epithelium - cells covering the lining of the ovaries Germ Cells - cells that are destined to form eggs Stromal Cells - Cells that release hormones and connect the different structures of the ovaries Common Epithelial Tumors - Epithelial ovarian tumors develop from the cells that cover

the outer surface of the ovary. Most epithelial ovarian tumors are benign (noncancerous). There are several types of benign epithelial tumors, including serous adenomas, mucinous adenomas, and Brenner tumors.

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Cancerous epithelial tumors are carcinomas - meaning they begin in the tissue that lines the ovaries. These are the most common and most dangerous of all types of ovarian cancers. Unfortunately, almost 70 percent of women with the common epithelial ovarian cancer are not diagnosed until the disease is advanced in stage. There are some ovarian epithelial tumors whose appearance under the microscope does not clearly identify them as cancerous. These are called borderline tumors or tumors of low malignant potential (LMP tumors). Epithelial ovarian carcinomas (EOCs) account for 85 to 90 percent of all cancers of the ovaries. We must continue research and expand our knowledge about this group of cancers in order to improve treatment and save lives. Germ Cell Tumors - Ovarian germ cell tumors develop from the cells that produce the ova or eggs. Most germ cell tumors are benign (non-cancerous), although some are cancerous and may be life threatening. The most common germ cell malignancies are maturing teratomas, dysgerminomas, and endodermal sinus tumors. Germ cell malignancies occur most often in teenagers and women in their twenties. Today, 90 percent of patients with ovarian germ cell malignancies can be cured and their fertility preserved. Stromal Tumors - Ovarian stromal tumors are a rare class of tumors that develop from connective tissue cells that hold the ovary together and those that produce the female hormones, estrogen and progesterone. The most common types are granulosa-theca tumors and SertoliLeydig cell tumors. These tumors are quite rare and are usually considered low-grade cancers, with approximately 70 percent presenting as Stage I disease (cancer is limited to one or both ovaries).

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Primary Peritoneal Carcinoma The removal of one's ovaries eliminates the risk for ovarian cancer, but not the risk for a less common cancer called Primary Peritoneal Carcinoma. Primary Peritoneal Carcinoma is closely rated to epithelial ovarian cancer (most common type). It develops in cells from the peritoneum (abdominal lining) and looks the same under a microscope. It is similar in symptoms, spread and treatment. Stages of Ovarian Cancer Once diagnosed with ovarian cancer, the stage of a tumor can be determined during surgery, when the doctor can tell if the cancer has spread outside the ovaries. There are four stages of ovarian cancer - Stage I (early disease) to Stage IV (advanced disease). Your treatment plan and prognosis (the probable course and outcome of your disease) will be determined by the stage of cancer you have. Stage I - Growth of the cancer is limited to the ovary or ovaries. Stage IA - Growth is limited to one ovary and the tumor is confined to the inside of the ovary. There is no cancer on the outer surface of the ovary. There are no ascites present containing malignant cells. The capsule is intact. Stage IB - Growth is limited to both ovaries without any tumor on their outer surfaces. There are no ascites present containing malignant cells. The capsule is intact. Stage IC - The tumor is classified as either Stage IA or IB and one or more of the following are present: (1) tumor is present on the outer surface of one or both ovaries; (2) the capsule has ruptured; and (3) there are ascites containing malignant cells or with positive peritoneal washings.

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Stage II - Growth of the cancer involves one or both ovaries with pelvic extension. Stage IIA - The cancer has extended to and/or involves the uterus or the fallopian tubes, or both. Stage IIB - The cancer has extended to other pelvic organs. Stage IIC - The tumor is classified as either Stage IIA or IIB and one or more of the following are present: (1) tumor is present on the outer surface of one or both ovaries; (2) the capsule has ruptured; and (3) there are ascites containing malignant cells or with positive peritoneal washings. Stage III - Growth of the cancer involves one or both ovaries, and one or both of the following are present: (1) the cancer has spread beyond the pelvis to the lining of the abdomen; and (2) the cancer has spread to lymph nodes. The tumor is limited to the true pelvis but with histologically proven malignant extension to the small bowel or omentum. Stage IIIA - During the staging operation, the practitioner can see cancer involving one or both of the ovaries, but no cancer is grossly visible in the abdomen and it has not spread to lymph nodes. However, when biopsies are checked under a microscope, very small deposits of cancer are found in the abdominal peritoneal surfaces. Stage IIIB - The tumor is in one or both ovaries, and deposits of cancer are present in the abdomen that are large enough for the surgeon to see but not exceeding 2 cm in diameter. The cancer has not spread to the lymph nodes. Stage IIIC - The tumor is in one or both ovaries, and one or both of the following is present: (1) the cancer has spread to lymph nodes; and/or (2) the deposits of cancer exceed 2 cm in diameter and are found in the abdomen. Stage IV - This is the most advanced stage of ovarian cancer. Growth of the cancer involves one or both ovaries and distant metastases (spread of the cancer to organs located outside of the peritoneal cavity) have occurred. Finding ovarian cancer cells in pleural fluid (from the cavity which surrounds the lungs) is also evidence of stage IV disease.

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These statistics, and the information regarding tumor stage and grade, demonstrate that there is a critical need to establish an agenda for more research into the areas of basic and translational research, genetic susceptibility and prevention, diagnostic imaging, screening and diagnosis, and therapy. These could hold the most promise for future discoveries that will lead to improved prevention, detection, and treatment of ovarian cancer, particularly the common epithelial. Symptoms of Ovarian Cancer Ovarian cancer is difficult to detect, especially, in the early stages. This is partly due to the fact that these two small, almond shaped organs are deep within the abdominal cavity, one on each side of the uterus. These are some of the potential signs and symptoms of ovarian cancer:

Bloating Pelvic or abdominal pain Trouble eating or feeling full quickly Feeling the need to urinate urgently or often

Other symptoms of ovarian cancer can include:

Fatigue Upset stomach or heartburn Back pain Pain during sex Constipation or menstrual changes

If symptoms persist for more than two weeks, one should consult physician.

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Persistence of Symptoms When the symptoms are persistent, when they do not resolve with normal interventions (like diet change, exercise, laxatives, rest) it is imperative for a woman to see her doctor. Persistence of symptoms is key. Because these signs and symptoms of ovarian cancer have been described as vague or silent, only around 19% of ovarian cancer is found in the early stages. Symptoms typically occur in advanced stages when tumor growth creates pressure on the bladder and rectum, and fluid begins to form.

A rectovaginal pelvic examination is when the doctor simultaneously inserts one finger in the rectum and one in the vagina.

It is helpful to take a mild laxative or enema before the pelvic exam. Have a comprehensive family history taken by a physician knowledgeable in the risks associated with ovarian cancer. 5% to 10% of ovarian cancer has a familial link. Every woman should undergo a regular rectal and vaginal pelvic examination. If an

irregularity of the ovary is found, alternatives to evaluation include transvaginal sonography and/or tumor markers. The most common tumor marker is a blood test called the CA-125. Research New Blood Tests New blood tests (serum and plasma tumor markers) are being developed that can identify early stage ovarian cancer by the presence of newly identified tumor markers that circulate in the blood of women with advanced stage ovarian cancer. Therefore, the presence of these tumor markers in apparently healthy women could lead to the diagnosis of early stage rather than late stage ovarian cancer.

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The following are examples tumors markers that may play a role in the early detection of ovarian cancer:

Lysophospholipids (such as LPA) Growth factor (such as EGFRs) Soluble urinary-type plasminogen activator (such as suPAR) Matrix metalloproteinases (such as MMPs) Hypermenthylated gene products Extra cellular matrix proteins.

Ovarian Pap test The "Ovarian Pap Test" is a new diagnostic test performed to detect pre-cancerous or early cancerous changes on the ovaries. Using minimally invasive office laparoscopy, the "Ovarian Pap Test" directly visualizes the ovaries and collects cells from the surface of the ovary and from the surface of the abdomen, similar to the cervical Pap test that collects surface epithelium from the cervix.

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CERVICAL CANCER
The outlook for preventing one of the world's top female cancer killers is better than it has ever been. Cervical cancer kills one woman in the world every two minutes. The good news is that there is now a way to stop cervical cancer before it starts - with vaccination against the challenging virus which causes the cancer, the human papillomavirus. Cervical Cancer Today Cervical cancer is a major cause of death in women around the world. In the UK there are around 2,800 new cases and 1,100 cervical cancer deaths a year. While in the US there are 10,000 new cases and 3,700 deaths per year. Around the world, every two minutes a woman is dying of cervical cancer. Looking at cervical cancer across the globe, over 80 per cent of the deaths from cervical cancer occur in the developing world. Sub-Saharan Africa is the worst-affected region. In Zambia, for example, cervical cancer strikes 63 women in 100,000, which is almost ten times Australia's rate of 7 per 100,000 women. Relatively high rates are also seen in some of the former Eastern block states notably Romania and Bulgaria. It has been found that increased cases of cervical cancer are apparent in countries where either no or poorly maintained screening programs exist. Cervical cancer commonly strikes women early, often in their mid-thirties, at an age when they are in the prime of their lives. Many affected women will be caring for young children and extended families, so one death from cervical cancer can devastate the lives of many people. Worldwide cervical cancer affects over 1.4 million women, is the second most common cancer in women aged 15-45 and the third leading cause of cancer death among women, after breast and lung cancer.

32

Most of the deaths occur in the developing world. In women who do not undergo regular screening, cervical cancer can be a silent killer as it can take many years to develop and women may not experience symptoms for a long time. By the time symptoms appear the disease is often Symptoms and prognosis of cervical cancer

The pre-cancerous stages and earlier stages of cervical cancer are usually symptom-less, which is why it is important for women to have regular pap smear tests, also known as cervical screening. In the absence of screening, the most common sign of invasive cervical cancer is bleeding from the vagina at times other than during menstruation. Between 1975 and1995, average five-year survival rates for women diagnosed with cervical cancer in the UK rose from around 50 per cent to 65 per cent but for those diagnosed with more advanced stages of the disease in which the cancer has spread, the outlook is even worse. VIRUS Cervical cancer is caused by a virus called human papillomavirus (HPV) which is caught through sexual activity. Unfortunately condoms do not fully protect women from HPV infection since the spread of the virus does not depend on full intercourse only but may also occur simply through skin-to-skin contact in the genital area. There are about 100 known types of HPV but only about 15 can cause cervical cancer. Together four cancer-causing virus types (16, 18, 45 and 31) are the most common, accounting for more than 80 percent of all cervical cancer cases worldwide. HPV 16, 18 and 45 are particularly concerning since these three are associated with nearly 90 per cent of cases of adenocarcinoma, a particularly aggressive form of cervical cancer.

33

Figure 4.1 HPV is very common: it is estimated that up to 80 per cent of women will acquire an HPV infection in their lifetime and up to 50 per cent of these will be with a cancer-causing virus type. Luckily most infections resolve spontaneously but when the infection persists the risk of developing cervical cancer rises sharply. A persistent infection with a cancer-causing virus type may cause the development of abnormal and pre-cancerous cervical cell changes which over time can develop into cancer. HPV is a challenging virus because the natural immune response, following infection with a cancer-causing virus type, may not be strong enough to protect against subsequent infection. What is more, as immune function gets weaker with age, infections are more likely to persist and hence progress to cancer as a woman gets older. Screening- Cervical cancer The strongest weapon in the fight against cervical cancer is prevention. Where it is available, regular screening using smear testing provides an early warning system, detecting evidence of abnormal or pre-cancerous cells and allowing in some instances to remove the diseased tissue. While screening helps detect abnormalities, around 20 percent of abnormal cases remain undetected. It is also significant that receiving an abnormal smear test result can be a traumatic and unsettling experience for women, as can the surgical procedures used to eliminate the affected cells.

34

In the developed world, potentially dangerous changes in the cervix are usually spotted before cancer emerges which is predominantly attributed to national screening programs. The British system is a good example of a successful screening program. It prevents around 4,500 deaths each year in the UK, by detecting cervical disease when it is still at the easily treatable, pre-cancerous stage. Similar programs in North America, Western Europe and Australasia have also seen the number of cervical cancer cases fall dramatically. In the UK, women are supposed to be called by their General Practitioner to be screened every three years from the age of 25 onwards for pap smear tests. Cervical cancer experts warn, however, that in recent years attendance for cervical smears has fallen. Between 2000 and 2005, the coverage of the screening program among the women aged 25-29, fell from 77 per cent to 71.6 per cent. Smear tests may seem straightforward to health professionals but there is evidence that some women do not know the importance of a smear test, find them embarrassing or even traumatic, and in part this may explain why screening fails to reach everyone who is at risk. However, in many poorer countries screening is less consistent and in most developing countries, screening is virtually non-existent. This is why the death rates from cervical cancer may be ten times higher in East Africa than in some countries in Western Europe. This lack of screening makes the need for a vaccine against cervical cancer even more pressing. Vaccination against cervical cancer Because HPV is no ordinary virus and poses particular challenges by managing to hide from the natural immune system, it is important to ensure that the immune response induced by vaccination is consistently strong and long-lasting that it protects against the most common and aggressive cancer-causing virus types.

35

To stop infections with cancer-causing human papillomavirus types from occurring, vaccination before a first sexual encounter is recommended, but, since a woman can come across the virus at any point in her life, nearly all women could benefit from vaccination. Worldwide, cervical cancer affects more women under 45 than any other malignancy apart from breast cancer. So its surprising that the disease, known also as cancer of the cervix, is in most cases unknown by women. On the whole, most women do not know that cervical cancer is caused by a virus but there is a definite eagerness to know more about this preventable disease within the female community. Despite the positive impact cervical cancer screening has had in managing this disease, cervical cancer continues to have a high prevalence. However, a feeling of optimism is emerging as for the first time, revolutionary vaccines will make it possible to prevent most cases of this disease. Treatment Options After your diagnosis, your doctor will develop your customized treatment plan. Women should always discuss their treatment options with a physician, because the best and most appropriate treatment will be different based on the stage of disease, the woman's age and the overall condition of her health. 1) Surgery - Surgery to remove the cancerous growth is the most common method of diagnosis and therapy for ovarian cancer. It is best performed by a qualified gynecologic oncologist. 2) Chemotherapy - Chemotherapy is the treatment of cancer using chemicals (medications) that travel through the bloodstream to destroy cancer cells or stop them from growing both in and outside the ovaries. Chemotherapy is used in the majority of cases as a follow-up therapy to surgery.

36

3) Radiation Therapy - Radiation therapy uses high-energy X-rays to kill cancer cells and shrink tumors (only rarely used in the treatment of ovarian cancer in the United States). Complementary Therapies Some women with ovarian cancer turn toward the whole-body approach of complementary therapy to enhance their fight against the disease, as well as to relieve stress and minimize side effects such as fatigue, pain and nausea. Complementary therapies are diverse practices and products that are used in conjunction with conventional medicine. Many women have tried and benefited from the following complementary therapies. You might want to speak with other women with cancer or your healthcare team to see which therapies they found most helpful or might work best for you and your lifestyle. Acupuncture - An ancient Chinese method of healing in which small sterilized needles are inserted into the body's energy centers to promote healing.

Aromatherapy - The use of essential oils from flowers, herbs and trees to promote health and wellbeing. Herbal Medicine - Use of remedies using plant parts to treat symptoms and illnesses. (Consult your healthcare professional prior to using herbal medicine).

Massage - Manipulating the body's muscle and connective tissue through rubbing, kneading and patting to promote relaxation and well being. Massage - Manipulating the body's muscle and connective tissue through rubbing, kneading and patting to promote relaxation and well being. Meditation - Conscious relaxation and focused breathing to relax the mind and body.

37

Qi Gong (chee-GUNG) - A type of Chinese medicine that combines movement, meditation and breathing to enhance the flow of qi (an ancient term given to what is believed to be vital energy) in the body, improve blood circulation and enhance immunefunction. Stress Reduction - Use of stress reduction methods such as exercise, meditation, etc. which have been found to be beneficial in reducing cancer progression and recurrence. Yoga, Tai Chi - Postures, movements and breathing exercises to strengthen and heal the body, mind and spirit. Safe Use of Complementary Therapy There are questions about most complementary therapies that have not yet been answered through well-designed scientific studies, such as clinical trials. Before beginning any complementary therapy, it is important to discuss the approach with your healthcare team and complementary therapy practitioner.

38

CANCER STATISTIC IN INDIA

Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer and there is growing evidence of HPV being a relevant factor in other anogenital cancers (anus, vulva, vagina and penis) and head and neck cancers. HPV types 16 and 18 are responsible for about 70% of all cervical cancer cases worldwide. HPV vaccines that prevent against HPV 16 and 18 infection are now available and have the potential to reduce the incidence of cervical and other anogenital cancers.

India has a population of 366.58 millions women ages 15 years and older who are at risk of developing cervical cancer. Current estimates indicate that every year 132082 women are diagnosed with cervical cancer and 74118 die from the disease. Cervical cancer ranks as the 1st most frequent cancer among women in India, and the 1st most frequent cancer among women between 15 and 44 years of age. About 7.9% of women in the general population are estimated to harbour cervical HPV infection at a given time, and 82.5% of invasive cervical cancers are attributed to HPVs 16 or 18.

Cancer of the cervix uteri is the second most common cancer among women worldwide, with an estimated 493,000 new cases and 274,000 deaths in 2002. About 83% of the cases occur in developing countries, representing 15% of female cancers. Worldwide, mortality rates of cervical cancer are substantially lower than incidence with a ratio of mortality to incidence to 55%. The majority of cases are squamous cell carcinoma and adenocarcinomas are less common.

39

Table 4.1

From the above table, it can be inferred that dearth rate because of cervical cancer is more than 50%. Same way, by 2025, cervical cancer patients would more than 90 % than current cases. Oral contraceptives are major factor responsible for cervical cancer followed by smoking & total fertility rate.

40

Table 4.2

India is more prone to cervical cancer as we can see from the above data. Around of the cases are from India alone of the total cases from the world. This only shows increasing growth of dangerous cervical cancer.

41

CHART 4.1

Crude Incidence ratio is found out by finding the probability of a new case occurring during a stated time interval. India is also in a dangerous state as can be observed from the graph

CHART 4.2

Standardized incidence ratio is a using direct method & world population as reference. Rates are per 100,000 populations. India is highest in this aspect also.

42

Table 4.3

CHART 4.3

As we can see New Delhi & Mumbai are having more cases compared to other cities of India. These are metro cities. So, changing life style (like late marriages, working women, smoking etc) is responsible for cervical cancer.

43

CHART 4.4

Incidence of cervical cancer in india among other cancer in women

44

CHART 4.5

Age-specific cervical cancer incidence compared to age-specific incidence of other cancers among women 15-44 years of age in India

45

CHART 4.6

46

CHART 4.7

Annual number of new cases of cervical cancer by age group in India and Southern Asia

47

CHART 4.8

48

CHART 4.9

Estimated number of deaths of cervical cancer in India by age group, in 2002 and projected in 2025

49

CHART 4.10

50

Factors contributing to cervical cancer

HPV is a necessary cause of cervical cancer, but it is not a sufficient cause. Other cofactors are necessary for progression from cervical HPV infection to cancer. Tobacco smoking, high parity, long-term hormonal contraceptive use, and co-infection with HIV have been identified as established cofactors. Co-infection with Chlamydia trachomatis and herpes simplex virus type-2, immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified. Table 4.5

Factors contributing to cervical carcinogenesis (cofactors) in India

Table 4.6

Estimated coverage of cervical cancer screening in India

51

Available drugs for the treatment of ovarian & cervical drugs Table 4.7 GENERIC NAME Cisplatin STRENGTH (MG) 10/50 0.5/1 30/100/250 30/100 250/500 DOSAGE FORM Injection Injection Injection Injection Injection Injection, Capsule Tablet Tablet Injection Injection Injection Injection

BRAND NAME

COMPANY

Cytoplatin Platin

Cipla Cadila Cipla Intas Biological E

Peclitaxel

Paclitax Cytax

5-Fluorouracil

Fludin

Fluracil

BIOCHEM

250/500

Tamoxifane

Temofane Cytutam

Dabur Cipla Cipla Biochem Cadila Nicholas Piramal

10 10/20 15 15 10/50 10/50

Bleomycin

Bleocip Bleochem

Doxorubicine

Cadria Levadox

(Source: Indian Drug Review, Oct-Nov, 2009 & Survey of Doctors, Retailers & Stockiest)

52

EXISTING BRANDS OF DOXORUBICINE Table 4.8 SR. NO. 1 2 3 4 5 6 7 8 9 10 11 12 14 16 17 18 19 20 21 23 BRAND Oncodox Adrim Adriamycin Cadria, Doxomed Doxolem Dxocare Tevadox Oncodria Dobixin Dobicin Doxobin Doxorex Duxocin, Doxorubicin Inj. Rubinat Lyphidox Doxil Rubex Zodox Tumodox Adrosol-RD COMPANY Cipla Dabur Upjohn Cadila Elder Pharma Citricare Nicholas Piramal Sun Pharma German Remedies Chandra Bhagat Pharma Biological E Samarth Biochem Natco Alkem Alza Bristol Intas Max VHB Life Sciences PRICE (RS), (10/50 MG PER 5/25 ML PER VIAL RESPECTIVELY) 289/1274 192/910 (2 mg/ml) 310/1540 250/1085, 250/1025 240/1190 251.63/1157.47 250/950 205/950 265/1188 (2 mg/ml) 250/950 234/1062 270/975 278/1008, 234/1062 254/1103.34 292/954 198/887 375/1278 190/925 284.70/1186.25 210/895

(Source: Indian Drug Review, Oct-Nov, 2009 & Survey Of Doctors, Retailers & Stockiest) 53

PEGYLATED LIPOSOMAL DOXORUBICIN

Pegylated liposomal doxorubicin (PLD) is doxorubicin HCl encapsulated in longcirculating STEALTH liposomes (Doxil). PLD achieves good response rates and many patients maintain long-lasting stable disease (SD), which is one of the advantages. In addition, the clinical benefit is high in platinum-resistant disease, and PLD is thus considered to be the first option.

PLD is associated with a number of adverse events, but these events are mild to moderate. PLD is safer for heavily pretreated patients than topotecan and gemcitabine due to mild bone-marrow toxicity, but that nonhematotoxity, such as PPE, stomatitis, mucositis, and other cutaneous reactions were the most common side effects attributable to PLD. Based on a review of previous studies, there are no differences in efficacy between 50 and 40 mg/m2 of PLD, therefore, a dose of 40 mg/m2 is preferable in patients with platinum resistant disease to reduce adverse events.

The 1-hour infusion schedule every 4 weeks makes PLD easy to administer. A rational approach to combine PLD with other drugs should take the slow accumulation and delayed peak of PLD in tumors into consideration. When combined with other useful agents, the lower dose of PLD (30 to 35 mg/m2) with a 3-week schedule may reduce severe PPE and stomatitis with negligible effects on the level of DI and the therapeutic efficacy.

Epithelial ovarian cancer is sensitive to chemotherapy and approximately 75% of patients achieve complete clinical remission after the initial treatment. However, most patients have a recurrence, which results in death after a chronic course.

The progression-free survival (PFS) for advanced ovarian cancer patients with optimal residual disease range from 18 to 24 months, while PFS for patients with suboptimal residual disease is 18 months.15 The PFS of dose-dense paclitaxel/carboplatin therapy improved to 28 months for patients with both optimal and suboptimal disease in our study (JGOG3016).

54

In the treatment of recurrent cancer, the issues to consider are the treatment-free interval (TFI), toxicity continuously observed from the initial treatment, recurrent tumor diameter and increased CA125.

The TFI is the most important for selecting drugs or regimens, and the longer the TFI, the higher the response rate.7,8 When the TFI is 6 months or longer, the tumor is considered to be sensitive to chemotherapy, but when the TFI is less than 6 months, the tumor is considered resistant to chemotherapy. However, 6 to 12 months of TFI is considered to be a gray zone, and such tumors require more careful consideration when selecting drugs or regimens.

Recommended therapies for tumors sensitive to drugs, based on the results of randomized controlled trials (RCT) and meta-analyses, are carboplatin-combination therapy such as carboplatin/ paclitaxel, carboplatin/gemcitabine, and carboplatin/ pegylated liposomal doxorubicin (PLD).911 For patients with TFI of 6 to 12 months, a non-platinum drug is one option for prolonging the platinum-free interval and reducing toxicity. However, patients must therefore be carefully observed to determine when the switch from non-platinum chemotherapy to platinum combination therapy should be made.

A phase III trial has been recently launched comparing carboplatin/paclitaxel versus PLD in the above cited clinical setting (NCT00657878). On the other hand, for patients with a drugresistant tumor, a drug without cross-resistance to paclitaxel and carboplatin must be selected. The goal of therapy is to delay progression, relieve symptoms and improve the QOL, and monotherapy is generally chosen for the most favorable toxicity profile. PLD, topotecan, and weekly paclitaxel are drugs that have been approved by the Food and Drug Administration (FDA), and gemcitabine (GEM), oral etoposide, and docetaxel can also be used. In Japan, weekly irinotecan (CPT-11) is widely used.

When selecting drugs, the differences in toxicity must be fully understood. It is usually difficult to completely cure recurrent disease with one drug or one regimen with high efficacy and low toxicity, and the drugs must therefore be changed as required while assessing the effect and toxicity.

55

Topotecan and GEM are highly hemotoxic, and patients should be monitored for nonhemotoxic events that reduce the QOL when PLD and irinotecan are used. There is concern about palmar-plantar erythrodysesthesia (PPE) and stomatitis, both of which can occur with PLD treatment, diarrhea due to irinotecan, and peripheral neuropathy and arthralgia during weekly paclitaxel therapy.

PLD was approved in 1999 by the FDA and in 2000 by the European Medicines Evaluation Agency as a treatment for chemorefractory and chemoresistant epithelial ovarian cancer, and has been used worldwide as the first option for patients with chemorefractory and chemoresistant epithelial ovarian cancer.

Mechanism of Action, Metabolism and Pharmacokinetic Profile PLD consists of doxorubicin encapsulated in N-(carbonyl- methoxypolyethylene glycol 2000)-1, 2- distearoyl-sn-glycero-3- phosphoethanolamine sodium salt (MPEG-DSPE) coated liposome (STEALTH liposome). Liposomes have the advantage of biocompatibility and versatility of formulation for intravenous use.

However, the disadvantages of liposomes are rapid uptake by the reticuloendothelial system (RES) and removal from the circulatory system, thus reducing the amount of drug that reaches the tumor. MPEG-DSPE is a hydrophilic material and characteristically decreases RES uptake.

Therefore, the STEALTH liposome achieves prolonged circulation time without rapid uptake by RES, and PLD has made prolonged delivery of doxorubicin and prolonged circulation time possible. Gabzon et al undertook a pilot clinical study about the pharmacokinetics compared with PLD and free (unencapsulated) doxorubicin (DOX), and reported that the AUC of PLD in plasma was approximately 250-fold higher than that of DOX.12 Furthermore, the diameter of PLD of approximately 100 mm makes it generally difficult are involved in doxorubicin metabolism are NADPHdependent aldo-keto reductase and microsomal glycosidase.

56

Figure 4.2

57

Price incorporation strategy in pharmaceutical industry:

Generally, in pharma industry, after complete process of manufacturing and packaging, various drugs go to market through following chain: Carry & forwarding agents (C & F Agents) Stockiest (Wholesalers) Retailers

By surveying above channels we found out following information about them & their price incorporation strategy:

(1) Carry & forwarding agents (C & F Agents) They are appointed by companies in a particular state. Every company has their own C & F agents. They supply drugs to wholesalers. Their margin is around 1.5-2%.

(2) Stockiest (Wholesalers) As the name suggest, they keep drugs of various companies & supply them to retailers. Their margin is around 8-9 %.

(3) Retailers They are the one who supply drugs to patients. Their margin is around 20-22%.

From, the above information, we can say that price of various drugs includes approximately 20-22% mark up cost which includes cost & profit. Incase of branded drugs, margin is very less compared to local drugs..Incase of ovarian & cervical cancer drugs, they are more costly & their side effects are very high. So, mostly they are given in combinations. So, overall therapy (which is called chemotherapy treatment) is vey costly.

58

We also checked the feasibility of E-PROCUREMENT & DIGITAL DISPLAY by surveying above channels.

90% of the retailers denied for E-PROCUREMENT as it does not provide medicines on time & without middle channels it is not possible to procure drugs directly from the company.

60% of the retailers denied service to digital promotion t does not benefit them much.

59

MARKET ANLYSIS
GENERIC CANCER MARKET:

Tthe generic cancer market, defined to include cytotoxics, antihormonal therapies, immunostimulating agents, targeted therapies and supportive care products (growth factors), was worth $1.3 billion across the seven major pharmaceutical markets in 2004. Forecasts this market to reach $10.9 billion in value by 2014, achieving a CAGR of 23.5%.

This staggering level of growth is attributable to upcoming patent expiries on key products, as well as the imminent introduction of a regulatory pathway for biogenerics, which will open a previously untapped market that is currently worth billions; a large number of anticancer products were granted regulatory approvals in the 1990s and early 2000s, totaling 48 (FDA Oncology Tools). As a natural progression from this high volume of product approvals is an increase in the number of impending patent expiries in the coming years.

Several of these products currently achieve blockbuster sales, while others are forecast to break the $1 billion sales barrier in the forecast period of this report, thus representing a highly lucrative opportunity for generics manufacturers. Has identified 2009 as the year with the greatest potential for generics manufacturers, when nearly $15 billion worth of oncology product sales will be at risk from generic erosion. As a result of this, the impact of generics on the cancer market will become dramatically amplified in the next five years; upon entry to the market, generic drugs will generally rapidly cannibalize sales of the original branded product.

In addition, no delay in revenue growth will occur while clinical recognition is achieved, as efficacy and safety of the original product will already have been established by the time the generic enters the market.

60

Last four years trend

Table 4.8 BRAND APR-09 MAT (Rs Cr.) 73.02 APR-08 MAT (Rs Cr.) 60.7 APR-07 MAT (Rs Cr.) 48.5 APR-06 MAT (Rs Cr.) 40.24

DOXORUBICINE

ONCODOX

18.56

17.67

15.98

13.24

TEVADOX

12.28

11

9.6

8.41

ONCODRIA

10.5

8.74

7.89

CADRIA

9.45

7.24

6.56

5.98

ADRIM

7.9

6.86

5.65

4.67

(SOURCE: ORG SURVEY APRIL09)

61

CHART 4.11

Market of Doxorubicine molecule is growing at approximately 23% every year. Also, Overall market in April09 is more than 80% of April06. This indicates good market opportunity.

62

CHART 4.12

Generic market of the Doxorubicine is also strong. All the generic drugs have more than 80% market within 4 years from April06 to April09. Oncodox from Cipla is at the top.

63

Growth Projection of DOXORUBICINE:

Table 4.9 DOXORUBICINE MARKET (Rs. Crores) 2006-07 2007-08 2008-09 2009-10 2010-11 2011-12 40.24 48.5 60.7 73.02 90.17 114.51 22 23 22.5 23.5 27 27

YEAR

GROWTH (%)

64

CHART 4.13

Growth projection forecasts market to be Rs. 114.51 crore with a growth rate of 27% indicating great opportunity in generic cancer market by 2012.

65

Regional analysis

Table 4.10

VALUE %MS (Rs. Cr) ALL INDIA NORTH EAST SOUTH WEST 47.00 15.04 12.00 11.00 9.00 100 32 25.53 23.40 19.14 23 24 18 28 12 % GROWTH

(SOURCE: ORG SURVEY, DEC. 2009)

66

CHART 4.14

North is highest with 16% especially New Delhi & Mumbai with more affected

67

PRESCRIPTION ANALYSIS OF OVARIAN & CERVICAL CANCER DRUGS

Table 4.11
MOLECULES ANTI CANCER DRUGS DOXORUBICINE CYCLOPLATIN PACLITAXEL DECOTAXEL 5-FLUROURACIL MEGESTEROL ACETATE TAMOXIFEN BLEOMYCIN VINCRISTIN VINBLASTIN VACCINE (FOR CERVICAL CANCER)

ONCOLOGIST Rx Response share trend

NOV-FEB08 9,O02= 100 % 44.9 16.8 9.4 8.3 6.1 5.4 3.4 0.9 4.5 0.3 4.3 MAR-JUN08 9126 =100 % 44.5 16.9 9.7 8.3 7.9 5.5 2.4 2.5 1.3 1.0 2.3 JULY-OCT08 8898 =100 % 42.8 16.6 8.2 9.1 3.2 5.1 2.1 0.6 2.0 0.3 1.0

(C-MARC)
NOV-FEB09 8909=100 % 43.3 16.6 7.8 8.4 2.9 4.9 2.2 0.5 2.3 0.2 0.3

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Table 4.12
MOLECULES ANTI CANCER DRUGS DOXORUBICINE CYCLOPLATIN PACLITAXEL DECOTAXEL 5-FLUROURACIL MEGESTEROL ACETATE TAMOXIFEN BLEOMYCIN VINCRISTIN VINBLASTIN VACCINE (FOR CERVICAL CANCER)

CONS PHYSIO Rx Response share trend (C-MARC)

NOV-FEB 08 2318= 100 % 56.7 19.8 2.7 4.3 3.6 3.4 2.2 0.6 2.4 MACH-JUNE 08 2397 =100 % 56.2 20.0 4.8 4.8 3.3 2.9 2.6 0.7 2.0 0.6 2.3 1.2 JULY-OCT 08 2232 =100 % 56.5 19.4 3.3 4.5 2.6 1.8 1.9 0.9 2.3 1.2 0.6 NOV-FEB 09 2324=100 % 54.7 19.3 4.6 4.6 2.2 3.6 2.0 0.9 2.5 2.2

69

SWOT ANALYSIS
Strengths Well accepted formulation High demand Better perception in ovarian cancer Side effects are less Weaknesses Very High Cost Stiff competition from well known corporate brands

Opportunities Consolidate in every type of cancer

Threats Intense competition from cheap drugs

Untapped Gyneclology segment

70

SURVEY OF DOCTORS
SURVEY FINDINGS: Opinion of total of 20 expert oncologists doctors was taken with sample questionnaire for Doxorubicine.
Table 4.13 Oncologists survey
Parameters for Doxorubicin Doxorubicine is the proffered first drug of choice for particular disease (No. of response from doctors)

Ovarian Cancer (3)

Cervical cancer (3)

Breast cancer (2)

Lung cancer (2)

All of them (10)

Doxorubicine is preferred because of its

Efficacy (08)

Potency (04)

Better half life (02)

Lesser side effects (02)

Rapid onset of action (04)

Most preferred strength of Doxorubicine is

10 mg (10)

50 mg (07)

100 mg (02)

250 mg (01)

Doxorubicine is widely used as a

Plain drug (00)

In combination (20)

Doxorubicine is preferred most in dosage form

Injections (10)

Oral solid tab (06)

Capsule (04)

Any Other (00)

The criteria doctors keep in mind while writing a particular brand is

Efficacy (06)

Reputation of brand (04)

Broad spectrum of the drug (03)

Benefits to the patients (07)

71

SURVEY FINDINGS: Opinion of total of 10 expert Consultant Physiologists was taken with sample questionnaire for Doxorubicine.
Table 4.14 Consultant Physiologists survey
Parameters for Doxorubicin Doxorubicine is the proffered first drug of choice for particular disease (No. of response from doctors)

Ovarian Cancer (0)

Cervical cancer (0)

Breast cancer (0)

Lung cancer (0)

All of them (10)

Doxorubicine is preferred because of its

Efficacy (03)

Potency (03)

Better half life (00)

Lesser side effects (02)

Rapid onset of action (02)

Most preferred strength of Doxorubicine is

10 mg (05)

50 mg (03)

100 mg (01)

250 mg (01)

Doxorubicine is widely used as a

Plain drug (00)

In combination (10)

Doxorubicine is preferred most in dosage form

Injections (06)

Oral solid tab (03)

Capsule (01)

Any Other (00)

The criteria doctors keep in mind while writing a particular brand is

Efficacy (03)

Reputation of brand (02)

Broad spectrum of the drug (01)

Benefits to the patients (04)

72

CHART 4.15

Doxorubicine is the preffered choice of drug for all type of cancer. This is a good opportunity as it can be projected in all type of cancers.

73

CHART 4.16

Doxorubicine is most prefferd because of its efficacy & potency followed by rapid onset of action. However because of its liposomal form side effects are reduced,

74

CHART 4.17

Around 50% doctors said preferred strength is 10 mg/5 ml followed by 50 mg/25 ml for needed higher dose.

75

CHART 4.18

Not only Doxorubicine, almost all the cancer drugs are prescribed in combination therapy because of high side effects. However, Doxorubicine is having less side effects because of its liposomal form compared to traditional dosage forms

76

CHART 4.19

Injections are most preferred because of rapid onset of action followed by tablets & capsules. Most of the available anticancer drugs are in the Injecteble. (Ref: Table no. 4.7 & 4.8)

77

CHART 4.20

Doctors while writing a particular brand benefit to patients which also include economical benefits & efficacy for a particular brand followed brand reputation spectrumn & brand reputation

78

CHAPTER 5 CONCLUSION

79

Due to changing life style (especially for women who are working & marrying at older age), there has been rapid increase in ovarian & cervical cancer drugs. However, due rapid change & development in technology, it has been possible to get catch on cancer. Ovarian and cervical cancer are detected in first past and second stage which is too late in most of the cases, makes them life threatening disease.

Report of cancer statistics from WHO indicates there will be more than 226084 case of cervical cancer by 2025, indicate rising number of women more prone to cervical cancer

As we have seen, there has been increasing market of ovarian & cervical cancer drugs. Secondary data of generic cancer drugs shows forecast of $10.9 billion market by 2014 with CAGR OF 23.5%

Also data of C-MARC from Table 4.11 to 4.16 shows Doxorubicine is the preferred choice of drug for ovarian & cervical cancer drugs.

From the table 4.8, it can be observed increasing growth of Doxorubicine. There has been approximate 40% growth in april-09 from april-06. . This indicates good market opportunity Table 4.9, shows growth projection of 25% every year which will lead to Doxorubicine market to 115 crore in 2011-12. This shows Doxorubicine is at its peak of growth which favors launching a new brand for Doxorubicine. So, from the above references of market we can be optimistic for good growing market of Doxorubicine We can be optimistic about good market share.

Prescription analysis shows Doxorubicine is the drug of choice for ovarian & cervical cancer & also for other types of cancer. while there is also good scope in cons. physicians & Gynecology segment.

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CHAPTER 6 SUGGESTIONS & RECOMMENDATIONS

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BRAND LAUNCH & POSITIONING

4Ps of marketing which are product, place, price & promotion for new brand launch of Doxorubicine SHOULD BE as follows: (1) PRODUCT: Our product will be PEGYLATED LIPOSOMES OF DOXORUBICINE (10/50 mg) in the form injection. Preferred brand name will be DOXALITE. The product will be made available in VIAL of 5 & 10 ml. (2) PLACE: DOXALITE will be placed for ovarian ,cervical & other types of cancer disease as a monotherapy as well as adjunctive therapy. (3) PRICE: Following price is recommended for various strength of DOXALITE STRENGTH 10 mg/ 5ml 50 mg/ 25ml PRICE (RS) 300/ VIAL 1200/VIAL

(4) PROMOTION: DOXALITE should be promoted with positioning theme

NOW REMAIN IN LIGHT WITH DOXALITE NEW LIGHT IN LIFE WITH DOXALITE

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PROMOTIONAL STRATEGY
DOXALITE should be promoted in following 3 ways: (1) (2) (3) Brand promotion Advertising promotion Sales promotion

(1) Brand promotion: Promo plan for DOXALITE brand amongst doctors
should be as follows: Dr segmentation Oncologist Gynecologist Consultant physiologist

Positioning theme (with payoff line)

NOW REMAIN IN LIGHT WITH DOXALITE NEW LIGHT IN LIFE WITH DOXALITE
Action Plan In-clinic involvement of the DOCTOR Comparison with Cisplatin, Paclitaxel and highlighting the benefit of DOXALITE without addiction Aggressive brand conversion of the market leader-Oncodox,

Levidox,,Cadria, Oncodria & others Mailers Visual Aid Leave Behind Literature(LBL) Promotional input 83

Product monograph Abstract of journals References

Promotional inputs for doctors (1) Mailer: (As Brand Recall) 6 Pocket shape mailer representing convenience (Two in a month) Anxiety/Phobia-relating convenience Which facilitated use of DOXALITE Melt in Mouth Activity Small Size

(2) Visual Aid: (As Brand Energizer) (Communication theme for DOXALITE) Diseases like ovarian, cervical & other type of cancers shown as various heads of RAVAN (Character from RAMAYAN) & DOXALITE (DOXORUBICINE) as a killing soldier (showing having weapon in hand & body of tablet wearing cap on head) A woman shown in jovial mood because of DOXALITE molecule. ONCOLOGIST & CONSULTANT PHYSIOLOGIST Start early with DOXALITE A convenient formulation for all the type of cancers Effective drug of choice ovarian & cervical cancer Rapid onset of action Reduced side effects GYNECOLOGIST A Perfect Quick solution that rapidly stabilizes acute symptoms of cancer Effective drug of choice ovarian & cervical cancer Highly efficient Reduced side effects Immediate relief

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(3) Leave behind Literature (LBL): (As Brand Recall) (4) Promotional input: (As Brand Recall) Promotional inputs like calendars, chart etc highlighting packing of DOXALITE & its indications, benefits etc. (5) Product monograph: (As Brand Energizer) (6) Abstract of journals: (As Brand Energizer) (7) References: (As Brand Energizer) (8) Diagnosed the situation campaign for physician only: (As Brand Recall) (9) Prescription pads with brand name DOXALITE :(As Brand Recall)

(2) ADVERTISING PROMOTION:

DOXALITE should be promoted by advertising it in various pharmaceutical & medical publications like IPA, Indian Drug Review (IDR), Drug Today, MIMS. LANCET etc. DOXALITE should be promoted online in various pharmaceutical & medical websites

(3) SALES PROMOTION

Promo plan for stockiest/retailers (1) Promotional inputs (2) Promotional schemes like Order for 100 VIALS & get 2 VIAL free 300 VIALS & get 5VIAL free 500 VIALS & get 7VIAL free 2 % discount to patient on continuous therapy which will be added to fund for welfare of cancer patients. (3) Gifts like letter pads, diaries, ball pens

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OPERATIONAL PLAN
Modus operandi.. 1. 10 Doctor/Field sales officer 2. Can be done in first week of every month. 3. Will focus mainly on DOXALITE during the call 4. FSE need to send to send back a report of completion of the campaign by the second week of every month in the given format

Series Modus Operandi 1. 15 Dr/Field sales offocer (Mini.5 CPs) apart from AASHA- a new life campaign. 2. Regular visit after every 10 days to maintain the continuity in the campaign

Drug interaction Chart/LBLs/Mailer 1 .O (Their will be 2 type of chart one for Physician & other for oncologist)

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