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1.  Contribution of world health organization in the global acceptance of Ayurveda 
Amongst the mandates of United Nations, health of mankind is the thrust area of UN through World Health Organization (WHO). Planning and execution of policies for mainstreaming of traditional medicines (TRM) of respective countries along with conventional system of medicine (allopathy), first in the country of origin followed by the international arena, is the priority agenda of operations of WHO. Within Indian context, WHO accorded prime focus to Ayurveda in its activities related to TRM.Sponsorship and encouragement of studies substantiating parameters of standardization, safety and efficacy of herbal medicines of Ayurveda are under chief consideration of WHO. In this review, several guidelines of WHO are summarized. Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH), Central Council of Research in Ayurveda and Siddha and numerous other collaborative centers of WHO in India are assigned with several Appraisal Project Work (APW) and Direct Financial Cooperation (DFC) projects that will strengthen Ayurveda as evidence-based medicine for its global acceptance. Implementation of pharmacovigilance program in Ayurveda, publication of documents for rational use and initiatives to prepare consumer guidelines for appropriate use of Ayurvedic medicines are some other contributions of WHO toward advancement of Ayurveda at national as well as global level. Here, we suggest further exploration, interaction and interpretation of traditional knowledge in the light of contemporary core sciences and biomedical sciences that can pave the way for accreditation of Ayurveda worldwide as an established system of medicine.
doi:10.4103/0975-9476.90769
PMCID: PMC3255448  PMID: 22253507
Ayurveda; efficacy; standardization; safety; traditional medicine
2.  Global challenges of graduate level Ayurvedic education: A survey 
In the present day scenario, Ayurveda is globally being perceived in several contradictory ways. Poor quality of Ayurveda graduates produced as a result of poorly structured and poorly regulated education system is at least one of the important factors responsible for this scenario. The present study was carried out to evaluate the ‘Global challenges of graduate level Ayurvedic education’ and is based on the responses of Ayurvedic students and Ayurvedic teachers from various educational institutions of India to a methodically validated questionnaire. As the study indicates, the poor standard of Ayurvedic education in India is definitely a cause of concern. The curriculum of Bachelor of Ayurvedic Medicine and Surgery (BAMS) course of studies is required to be reviewed and restructured. The syllabi are required to be updated with certain relevant topics like laws governing the intellectual property rights, basic procedures of standardization of medicinal products, fundamental methods of evaluating the toxicity of the medicinal products, essentials of healthcare management and the basics of cultivation and marketing of medicinal plants. Furthermore, the study suggests that the Ayurvedic academicians are required to be trained in standard methods of research and documentation skills, and the educational institutions are required to be encouraged to contribute their share in building up the evidence base for Ayurveda in the form of quality education and research.
doi:10.4103/0974-7788.59945
PMCID: PMC2876920  PMID: 20532099
Ayurveda education; global challenges; India; mailed survey
3.  Patented Drug Extension Strategies on Healthcare Spending: A Cost-Evaluation Analysis 
PLoS Medicine  2013;10(6):e1001460.
In a cost-evaluation analysis of pharmacy invoice data in one Canton in Switzerland, Nathalie Vernaz and colleagues find that “evergreening” strategies pursued by drug manufacturers have been successful in maintaining market share and contribute to increased overall healthcare costs.
Please see later in the article for the Editors' Summary
Background
Drug manufacturers have developed “evergreening” strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole (“spillover effect”).
Methods and Findings
We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. “Extra costs” were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community.
Estimated “extra costs” over the study period were €15.9 (95% CI 15.5; 16.2) million for scenario 1, €14.4 (95% CI 14.1; 14.7) million for scenario 2, and €30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover “extra cost” of €330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of €7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in “extra costs” of €503,600 (95% CI 444,500; 563,100).
Conclusions
Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development of a new medical drug—from discovery of a new compound to regulatory approval for its use—can take many years and cost millions of dollars. In 1995 the World Trade Organization adopted an international law (Trade-Related Aspects of Intellectual Property Rights—TRIPS) by which pharmaceutical companies can protect their intellectual property through patents. Under TRIPS, pharmaceutical companies are granted exclusive manufacturing rights for up to 20 years for each new drug, generating large revenues that often exceed initial investments costs, thus providing an incentive for pharmaceutical companies to continue to invest in the research and development of new drugs. However, recent stricter regulatory procedures for drug approval, national price control policies, and increased competition from generic manufacturers (that produce drugs similar to the brand drug once the patent has expired) have meant that pharmaceutical company profits have increasingly come under pressure.
Why Was This Study Done?
One of the tactics that pharmaceutical companies currently use in response to this situation is to extend their market monopoly. This practice is known as “evergreening” and refers to the situation in which pharmaceutical companies slightly change the formulation of their brand drug into “follow on” drugs, for example, by combining formulations or producing slow-release forms, so that they can extend the patent. The impact of such follow-on drugs on overall healthcare costs in high-resource settings is unclear and has received little attention. In this study, the researchers assessed the overall costs associated with the prescribing of follow-on drugs in the Swiss canton of Geneva.
What Did the Researchers Do and Find?
The researchers identified prescriptions of eight follow-on drugs issued by hospital and community pharmacists in Geneva between 2000 and 2008. To analyze the impact of evergreening strategies on healthcare spending, they calculated the market share score (an indicator of market competitiveness) for all prescriptions of the originally patented (brand) drug, the follow-on drug, and generic versions of the drug. The researchers then used hospital and community databases to analyze the costs of replacing brand and/or follow-on drugs with a corresponding generic drug (when available) under three scenarios (1) replacing all brand drug prescriptions, (2) replacing all follow-on drug prescriptions, and (3) replacing both follow-on and brand prescriptions.
Using these methods, the researchers found that over the study period, the number of patients receiving either a brand or follow-on drug increased from 56,686 patients in 2001 to 131,193 patients in 2008. The total cost for all studied drugs was €171.5 million, of which €103.2 million was for brand drugs, €41.1 million was for follow-on drugs, and €27.2 million was for generic drugs. Based on scenario 1 (all brand drugs being replaced by generics) and scenario 2 (all follow-on drugs being replaced by generics), over the study period, the healthcare system could have saved €15.9 million and €14.4 million in extra costs, respectively. The researchers also found some evidence that hospital prescribing patterns (through a restrictive drug formulary) influenced prescribing in the community: over the study period, the influence of hospital prescription patterns on the community resulted in an extra cost of €503,600 (mainly attributable to two drugs, esomeprazole and escitalopram). However, this influence also resulted in some savings because of a generic drug listed in the hospital formulary: use of the generic version of the drug cetirizine resulted in savings of €7,700.
What Do These Findings Mean?
These findings show that in a high-income setting, evergreening strategies developed by pharmaceutical companies for follow-on drugs substantially contributed to an increase in overall healthcare costs. These findings also provide further evidence that policies encouraging prescribing of generic medicines could have substantial savings on healthcare expenditure and, if implemented in hospital formularies, could also influence prescribing outside of the hospital setting, resulting in further savings. However, in their analysis, the researchers assumed that the health outcomes of patients would be the same whatever type of drug they used (brand, generic, or follow-on), as they had no information on health outcomes. Nevertheless, this study provides useful information for healthcare providers and policy makers about the cost implications of the evergreening strategies used by the pharmaceutical industry, particularly for follow-on drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001460.
This study is further discussed in a PLOS Medicine Perspective by Aaron Kesselheim
Wikipedia provides an explanation of evergreening (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Trade Organization has detailed information on TRIPS
doi:10.1371/journal.pmed.1001460
PMCID: PMC3672218  PMID: 23750120
4.  Knowledge, attitude, and practices toward ayurvedic medicine use among allopathic resident doctors: A cross-sectional study at a tertiary care hospital in India 
Context:
Ayurveda is most commonly practiced form of complementary and alternative medicine (CAM) in India. There are very few studies showing the knowledge, attitude, and practices (KAP) of allopathic doctors about Ayurvedic drugs and its use.
Aims:
The study was initiated to assess KAP toward Ayurvedic medicine use among allopathic resident doctors.
Settings and Design:
Cross-sectional and prospective study.
Materials and Methods:
After obtaining permission from the Institutional Ethics Committee, allopathic resident doctors from clinical departments were approached personally. They were given pre-formed validated questionnaire to assess KAP toward Ayurvedic medicine use.
Statistical Analysis Used:
Descriptive statistics.
Results:
Allopathic residents had little knowledge about basic concepts of Ayurveda, that is, ‘panchakarma’ and ‘tridosha’. Majority residents (99%) had no opportunity to learn basics of Ayurveda, but 67% residents prescribed Ayurvedic medicines to patients. However, many residents (76%) mentioned that cross practice should not be allowed due to lack of knowledge. One resident knew that cross-practice was not allowed by law. The commonly prescribed proprietary Ayurvedic medicines were Liv-52 (39%), Shatavari (13%), Cystone (12%) and common ailments for which these medicines prescribed were liver disorders (34%), arthritis (18%), cough and cold (13%), kidney stones (11%), and piles (10%). Nearly 76% residents felt incorporation of Ayurveda with modern medicine would attract more patients and at the same time most residents (92%) agreed that Ayurvedic medicines need scientific testing before use. Though 50% of the residents agreed for voluntary training in Ayurveda, 80% denied compulsory training. Nearly 63% residents recommended Ayurveda among all CAMs. Most of residents heard of Ayurveda from their colleagues.
Conclusions:
This study reveals that allopathic resident doctors had little knowledge about Ayurveda and Ayurvedic medicine use but engaged in prescription of Ayurvedic medicines. So some interventions should be taken to increase the knowledge and awareness of allopathic resident doctors about Ayurvedic medicine use.
doi:10.4103/2229-3485.115380
PMCID: PMC3757582  PMID: 24010059
Allopathy; Ayurveda; cross-practice; knowledge; attitude; and practices study; residents
5.  Biological Diversity in the Patent System 
PLoS ONE  2013;8(11):e78737.
Biological diversity in the patent system is an enduring focus of controversy but empirical analysis of the presence of biodiversity in the patent system has been limited. To address this problem we text mined 11 million patent documents for 6 million Latin species names from the Global Names Index (GNI) established by the Global Biodiversity Information Facility (GBIF) and Encyclopedia of Life (EOL). We identified 76,274 full Latin species names from 23,882 genera in 767,955 patent documents. 25,595 species appeared in the claims section of 136,880 patent documents. This reveals that human innovative activity involving biodiversity in the patent system focuses on approximately 4% of taxonomically described species and between 0.8–1% of predicted global species. In this article we identify the major features of the patent landscape for biological diversity by focusing on key areas including pharmaceuticals, neglected diseases, traditional medicines, genetic engineering, foods, biocides, marine genetic resources and Antarctica. We conclude that the narrow focus of human innovative activity and ownership of genetic resources is unlikely to be in the long term interest of humanity. We argue that a broader spectrum of biodiversity needs to be opened up to research and development based on the principles of equitable benefit-sharing, respect for the objectives of the Convention on Biological Diversity, human rights and ethics. Finally, we argue that alternative models of innovation, such as open source and commons models, are required to open up biodiversity for research that addresses actual and neglected areas of human need. The research aims to inform the implementation of the 2010 Nagoya Protocol on Access to Genetic Resources and the Equitable Sharing of Benefits Arising from their Utilization and international debates directed to the governance of genetic resources. Our research also aims to inform debates under the Intergovernmental Committee on Intellectual Property and Genetic Resources, Traditional Knowledge and Folklore at the World Intellectual Property Organization.
doi:10.1371/journal.pone.0078737
PMCID: PMC3827099  PMID: 24265714
6.  PA01.47. Making ayurveda affordable and acceptable to all 
Ancient Science of Life  2012;32(Suppl 1):S97.
Purpose:
Ayurveda is eternal science of life because of its evolution is prior to human being itself. Ayurveda is part of our day to day life as a food & day routine. The study was performed as a survey in Delhi NCR (India) among the common men who use ayurveda or want ayurveda to be their system of medicine. The Aim of this study was to know their opinion that what are the ground realities and how ayurveda can be made more affordable and acceptable to them.
Method:
Sixty individuals were selected randomly comprising equally males and females. Age group was 18 to 70 yrs. All of them have undergone Ayurvedic treatment or have taken ayurvedic medicines as a part of their treatment. They were asked 31 questions about ayurveda under four categories as general questions, questions related to ayurvedic physicians, questions related to ayurvedic retailers and questions related to ayurvedic manufacturers. Their answers were taken on a printed questionnaire as a tick Yes, No and can’t say. Some questions were subjective to get suggestions of patients.
Result:
Result of the survey indicated some valuable points like 90% under study doesn’t know that BAMS are Ayurvedic Physicians. Pure Ayurvedic Retailers are rare; condition of ayurvedic medicines were not good at mixed ones. There was absolute majority for the expiry date on ayurvedic medicines & more research work on Ayurvedic preparations to make them tastier, easily differentiable & patient friendly.
Conclusion:
The results of the study should be addressed by the Ayurvedic Physicians, Ayurvedic manufacturers and retailers community on priority basis. The study also revealed the need of a broad based survey to get further insight of the present ayurvedic scenario in India & abroad and suggestions to make ayurveda more patients friendly and acceptable to all.
PMCID: PMC3800980
7.  Ayurveda–modern medicine interface: A critical appraisal of studies of Ayurvedic medicines to treat osteoarthritis and rheumatoid arthritis 
The potential of Ayurvedic philosophy and medicines needs to be recognized and converted into real life treatment paradigm. This article describes a comprehensive therapeutic approach used in Ayurveda and modern medicine to treat arthritis. We present concise summary of various controlled drug trials carried out by us to validate standardized Ayurvedic drugs using modern medicine protocol to treat Rheumatoid Arthritis and Osteoarthritis knees. Several of the latter are published. The trials consistently demonstrate excellent safety of Ayurvedic medicines but often fail to unequivocally show superior efficacy. Some key findings of a recently unpublished trial in OA knees are also presented to show equivalence between Ayurvedic medicine and celecoxib and glucosamine, and we speculate that equivalence trials may be a way forward. The data from the trials also supports the Ayurvedic ‘Rasayana’ concept of immune-modulation and healing. We need to interpret logic of Ayurveda when, adopting modern science tools in drug development and validation and much research is required. Validation of Ayurvedic medicines using the latter approach may lead to an evidence based Ayurveda – Modern Medicine interface. Also, in pursuit of finding better treatment solutions, we ought to step beyond the realm of only drugs and attempt validation of comprehensive specific treatment package as per classical Ayurveda. Finally, validation of a combined (Ayurveda and modern medicine) therapeutic approach with superior efficacy and safety is likely to be a major leap in overcoming some of the current frustrations to treat difficult disorders like arthritis using only modern medicines.
doi:10.4103/0975-9476.72620
PMCID: PMC3087360  PMID: 21547047
Ayurveda; rheumatoid arthritis; osteoarthritis; clinical trials; Rasayana
8.  Driving a decade of change: HIV/AIDS, patents and access to medicines for all 
Since 2000, access to antiretroviral drugs to treat HIV infection has dramatically increased to reach more than five million people in developing countries. Essential to this achievement was the dramatic reduction in antiretroviral prices, a result of global political mobilization that cleared the way for competitive production of generic versions of widely patented medicines.
Global trade rules agreed upon in 1994 required many developing countries to begin offering patents on medicines for the first time. Government and civil society reaction to expected increases in drug prices precipitated a series of events challenging these rules, culminating in the 2001 World Trade Organization's Doha Declaration on the Agreement on Trade-Related Aspects of Intellectual Property Rights and Public Health. The Declaration affirmed that patent rules should be interpreted and implemented to protect public health and to promote access to medicines for all. Since Doha, more than 60 low- and middle-income countries have procured generic versions of patented medicines on a large scale.
Despite these changes, however, a "treatment timebomb" awaits. First, increasing numbers of people need access to newer antiretrovirals, but treatment costs are rising since new ARVs are likely to be more widely patented in developing countries. Second, policy space to produce or import generic versions of patented medicines is shrinking in some developing countries. Third, funding for medicines is falling far short of needs. Expanded use of the existing flexibilities in patent law and new models to address the second wave of the access to medicines crisis are required.
One promising new mechanism is the UNITAID-supported Medicines Patent Pool, which seeks to facilitate access to patents to enable competitive generic medicines production and the development of improved products. Such innovative approaches are possible today due to the previous decade of AIDS activism. However, the Pool is just one of a broad set of policies needed to ensure access to medicines for all; other key measures include sufficient and reliable financing, research and development of new products targeted for use in resource-poor settings, and use of patent law flexibilities. Governments must live up to their obligations to protect access to medicines as a fundamental component of the human right to health.
doi:10.1186/1758-2652-14-15
PMCID: PMC3078828  PMID: 21439089
9.  Pharmacovigilance: Boon for the safety and efficacy of Ayuvedic formulations 
Pharmacovigilance is a corrective process originating in pharmaco-epidemiology. The 1997 Erice Declaration, presented at the World Health Organisation, became the basis on which the concept was implemented internationally for conventional systems of medicine. The increasing international acceptance of Ayurveda, led regulators to implement a similar program for Ayurveda, particularly as some medical professionals, scientists and members of the public reported adverse reactions after taking Ayurvedic formulations. The World Health Organisation therefore persuaded the Department of AYUSH, Ministry of Health and Family Welfare, Government of India, to implement a pharmacovigilance program for Ayurveda, as a means to ensuring the safety and efficacy of Ayurvedic medicines. After a year of due diligence, the pharmacovigilance program was launched nationally on 29 September 2008. Since that time, Ayurveda, Siddha and Unani medicines have been monitored according to the provisions of a protocol prepared by the National Pharmacovigilance Resource Centre, IPGTRA, Jamnagar, and approved by Department of AYUSH. The program was reviewed, first, on 21st January 2009 by the National Pharmaco-vigilance Consultative Committee for ASU drugs (NPCC-ASU), and again, on 15 Feburary, 2010, when an evaluation meeting effectively rubber stamped the program. Among the outcomes of these meetings were several suggestions of measures to improve the program’s efficiency. Recent developments include the constitution of pharmacovigilance centers at all Ayurveda Teaching institutes and research centers.
doi:10.4103/0975-9476.74427
PMCID: PMC3117316  PMID: 21731371
Adverse drug reaction; Awareness; Ayurvedic medicine; Pharmacovigilance; Safety
10.  Seekership, Spirituality and Self-Discovery: Ayurveda Trainees in Britain 
This paper examines the backgrounds and motivations of persons trained or training as Ayurvedic practitioners at two London-based institutions offering Ayurveda programmes at undergraduate and postgraduate levels. It draws upon in-depth interviews with individuals at various stages of their training and practice in order to examine the paths that bring them to Ayurveda, their motivations for undergoing training, and the ways in which they apply their knowledge of Ayurveda during and after their training period. The findings here corroborate what other scholars have demonstrated in the case of Asian traditions like Yoga and Ayurveda in the West; these traditions have inevitably undergone shifts in meaning by virtue of their assimilation into the Western, in this case British, holistic health milieu. Most significant in Ayurveda's case is the shift away from a preoccupation with remedial medicine (the bedrock of mainstream Ayurveda in modern South Asia), to a focus on self-knowledge and self-empowerment as a path to ‘holistic healing’ (understood to address mental and spiritual, not just physical, wellbeing). Even though the Ayurvedic curriculum transmitted at the educational institutions in London is based largely on that taught at Ayurveda colleges in India, the completely different orientations and dispositions of students in Britain (as compared to their South Asian counterparts) ensures that the Ayurveda they go on to apply and practise is radically different – this is ‘spiritualised’ Ayurveda, in radical contrast to the ‘biomedicalised’ version obtaining in modern mainstream South Asian contexts.
doi:10.1163/157342009X12526658783691
PMCID: PMC2898496  PMID: 20617123
Ayurveda; New Age; subjectivisation; spiritualisation; biomedicalisation; seekership; healing; holism; self-discovery; authenticity
11.  Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Declaration: A Database Analysis 
PLoS Medicine  2012;9(1):e1001154.
Reed Beall and Randall Kuhn describe their findings from an analysis of use of compulsory licenses for pharmaceutical products by World Trade Organization members since 1995.
Background
It is now a decade since the World Trade Organization (WTO) adopted the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha. Many anticipated that these actions would lead nations to claim compulsory licenses (CLs) for pharmaceutical products with greater regularity. A CL is the use of a patented innovation that has been licensed by a state without the permission of the patent title holder. Skeptics doubted that many CLs would occur, given political pressure against CL activity and continued health system weakness in poor countries. The subsequent decade has seen little systematic assessment of the Doha Declaration's impact.
Methods and Findings
We assembled a database of all episodes in which a CL was publically entertained or announced by a WTO member state since 1995. Broad searches of CL activity were conducted using media, academic, and legal databases, yielding 34 potential CL episodes in 26 countries. Country- and product-specific searches were used to verify government participation, resulting in a final database of 24 verified CLs in 17 nations. We coded CL episodes in terms of outcome, national income, and disease group over three distinct periods of CL activity. Most CL episodes occurred between 2003 and 2005, involved drugs for HIV/AIDS, and occurred in upper-middle-income countries (UMICs). Aside from HIV/AIDS, few CL episodes involved communicable disease, and none occurred in least-developed or low-income countries.
Conclusions
Given skepticism about the Doha Declaration's likely impact, we note the relatively high occurrence of CLs, yet CL activity has diminished markedly since 2006. While UMICs have high CL activity and strong incentives to use CLs compared to other countries, we note considerable countervailing pressures against CL use even in UMICs. We conclude that there is a low probability of continued CL activity. We highlight the need for further systematic evaluation of global health governance actions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development of a new drug is a time-consuming and expensive process. To stimulate investment in drug development, the creators of new drugs (including the pharmaceutical companies that undertake the development and testing that is needed before any drug can be used in patients) can apply for “intellectual property rights” (a patent). Intellectual property rights protect the investments made by companies during drug development by preventing other companies from making the new drug for a fixed period of time and by providing a means by which creators of new drugs can negotiate payment from other companies for the use of their creation. Until recently, the extent and enforcement of intellectual property rights varied widely around the world. Then, in 1995, the World Trade Organization (WTO) was established. By providing a set of ground rules for trade among nations, the WTO aims to ensure that trade flows as smoothly, predictably, and freely as possible around the world. One of the founding documents of the WTO is the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement), which attempts to bring the protection of intellectual property rights (including patents) under common international rules.
Why Was This Study Done?
Unfortunately, patent protection for drugs (pharmaceuticals) means that many medicines are too expensive for use in developing countries. While maintaining incentives for drug development, the TRIPS Agreement allows governments to license the use of patented inventions to someone else without the consent of the patent owner. Such “compulsory licensing” normally occurs only after negotiations for a voluntary license have failed, and the patent owner still receives an appropriate payment. It soon became clear that some governments were unsure of their right to use compulsory licensing and other flexibilities in the TRIPS Agreement, a situation likely to affect public health in poor countries by hindering universal access to medicines. Consequently, the WTO issued the “Declaration on the TRIPS Agreement and Public Health” at its 4th Ministerial Conference in Doha in November 2001. Reaction to the Doha Declaration, which reaffirms that the “TRIPS Agreement does not and should not prevent members from taking measures to protect public health,” has been mixed. Some experts predicted that it would increase compulsory licensing of pharmaceuticals, but others suggested that political pressure against compulsory licensing and health system weaknesses in poor countries would limit claims for compulsory licenses. In this database analysis, the researchers systematically assess the impact of the Doha Declaration on the compulsory licensing of pharmaceuticals.
What Did the Researchers Do and Find?
By systematically searching media archives for reports of WTO member states considering or announcing compulsory licensing of pharmaceuticals, the researchers identified 24 verified compulsory licensing episodes in 17 nations that occurred between January 1995 and June 2011. Half of these episodes ended with an announcement of a compulsory license, and the majority ended in a price reduction for a specific pharmaceutical product for the potential issuing nation through a compulsory license, a voluntary license, or a negotiated discount. Sixteen of the compulsory licensing episodes involved drugs for HIV/AIDS, four involved drugs for other communicable diseases, and four involved drugs for non-communicable diseases such as cancer. More than half the compulsory licensing episodes occurred in upper-middle-income countries (including Brazil and Thailand). Finally, most compulsory licensing episodes occurred between 2003 and 2005. There was a smaller peak of activity in the months leading up to the Doha conference, but after 2006 activity declined substantially.
What Do These Findings Mean?
Given these findings, the researchers suggest that the Doha Declaration is unlikely to have an important long-term impact on the use of compulsory licensing or on access to pharmaceuticals for communicable diseases other than HIV/AIDS in developing and low-income countries. Most notably, the researchers found no evidence of a spike in compulsory licensing episodes immediately after the Doha Declaration, and they note that the lagged spike that occurred between 2003 and 2005 could have resulted in large part from the global antiretroviral advocacy campaign. Moreover, compulsory licensing activity has diminished greatly since 2006. Thus, the researchers conclude, health advocates who pushed for the Doha Declaration reforms have had little success in engaging trade as a positive, proactive force for addressing health gaps.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001154.
The World Trade Organization provides information on intellectual property rights, on the TRIPS Agreement, on TRIPS and pharmaceutical patents, and on compulsory licensing of pharmaceuticals and TRIPS (in English, French, and Spanish); the Doha Declaration on the TRIPS Agreement and Public Health is also available
The World Health Organization provides information on the Doha Declaration on the TRIPS Agreement and Public Health and an analysis of the implications of the Doha Declaration
Wikipedia has pages on intellectual property rights, on the TRIPS Agreement, and on the Doha Declaration (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001154
PMCID: PMC3254665  PMID: 22253577
12.  Evaluating Drug Prices, Availability, Affordability, and Price Components: Implications for Access to Drugs in Malaysia 
PLoS Medicine  2007;4(3):e82.
Background
Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components.
Methods and Findings
The methodology developed by the World Health Organization (WHO) and Health Action International (HAI) was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs) to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB) prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%–76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high—25%–38% and 100%–140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector.
Conclusions
The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and affordability, promotion of generic medicines and improved availability of medicines in the public sector are required.
Drug price and availability data were collected from West Malaysian public sector facilities, private sector retail pharmacies, and dispensing doctors. Mark-ups were higher on generic drugs than on innovator brands.
Editors' Summary
Background.
The World Health Organization has said that one-third of the people of the world cannot access the medicines they need. An important reason for this problem is that prices are often too high for people or government-funded health systems to afford. In developing countries, most people who need medicines have to pay for them out of their own pockets. Where the cost of drugs is covered by health systems, spending on medicines is a major part of the total healthcare budget. Governments use a variety of approaches to try to control the cost of drugs and make sure that essential medicines are affordable and not overpriced. According to the theory of “free market economics,” the costs of goods and services are determined by interactions between buyers and sellers and not by government intervention. However, free market economics does not work well at containing the costs of medicines, particularly new medicines, because new medicines are protected by patent law, which legally prevents others from making, using, or selling the medicine for a particular period of time. Therefore, without government intervention, there is nothing to help to push down prices.
Why Was This Study Done?
Malaysia is a middle-income country with a relatively effective public health system, but it is facing a rapid rise in drug costs. In Malaysia, medicine prices are determined by free-market economics, without any control by government. Government hospitals are expected to provide drugs free, but a substantial proportion of medicines are paid for by patients who buy them directly from private pharmacies or prescribing doctors. There is evidence that Malaysian patients have difficulties accessing the drugs they need and that cost is an important factor. Therefore, the researchers who wrote this paper wanted to examine the cost of different medicines in Malaysia, and their availability and affordability from different sources.
What Did the Researchers Do and Find?
In this research project, 48 drugs were studied, of which 28 were part of a “core list” identified by the World Health Organization as “essential drugs” on the basis of the global burden of disease. The remaining 20 reflected health care needs in Malaysia itself. The costs of each medicine were collected from government hospitals, private pharmacies, and dispensing doctors in four different regions of Malaysia. Data were collected for the “innovator brand” (made by the original patent holder) and for “generic” brands (an equivalent drug to the innovator brand, produced by a different company once the innovator brand no longer has an exclusive patent). The medicine prices were compared against international reference prices (IRP), which are the average prices offered by not-for-profit drug companies to developing countries. Finally, the researchers also compared the cost of the drugs with daily wages, in order to work out their “affordability.”
The researchers found that, irrespective of the source of medicines, prices were on average very much higher than the international reference price, ranging from 2.4 times the IRP for innovator brands accessed through public hospitals, to 16 times the IRP for innovator brands accessed through private pharmacies. The availability of medicines was also very poor, with only 25% of generic medicines available on average through the public sector. The affordability of many of the medicines studied was again very poor. For example, one month's supply of ranitidine (a drug for stomach ulcers) was equivalent to around three days' wages for a low-paid government worker, and one month's supply of fluoxetine (an antidepressant) would cost around 26 days' wages.
What Do These Findings Mean?
These results show that essential drugs are very expensive in Malaysia and are not universally available. Many people would not be able to pay for essential medicines. The cost of medicines in Malaysia seems to be much higher than in areas of India and Sri Lanka, although the researchers did not attempt to collect data in order to carry out an international comparison. It is possible that the high cost and low availability in Malaysia are the result of a lack of government regulation. Overall, the findings suggest that the government should set up mechanisms to prevent drug manufacturers from increasing prices too much and thus ensure greater access to essential medicines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040082.
Read a related PLoS Medicine Perspective article by Suzanne Hill
Information is available from the World Health Organization on Improving Access to Medicines
Information on medicine prices is available from Health Action International
Wikipedia has an entry on Patent (a type of intellectual property that is normally used to prevent other companies from selling a newly invented medicine). (Wikipedia is an internet encyclopedia anyone can edit.)
The Drugs for Neglected Diseases Initiative is an international collaboration between public organizations that aims to develop drugs for people suffering from neglected diseases
doi:10.1371/journal.pmed.0040082
PMCID: PMC1831730  PMID: 17388660
13.  Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease 
PLoS ONE  2012;7(11):e51022.
Objective
The threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.
Methods
Using the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.
Materials
We examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.
Results
Of the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.
Conclusions
We find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.
doi:10.1371/journal.pone.0051022
PMCID: PMC3511406  PMID: 23226453
14.  'Linkage' pharmaceutical evergreening in Canada and Australia 
'Evergreening' is not a formal concept of patent law. It is best understood as a social idea used to refer to the myriad ways in which pharmaceutical patent owners utilise the law and related regulatory processes to extend their high rent-earning intellectual monopoly privileges, particularly over highly profitable (either in total sales volume or price per unit) 'blockbuster' drugs. Thus, while the courts are an instrument frequently used by pharmaceutical brand name manufacturers to prolong their patent royalties, 'evergreening' is rarely mentioned explicitly by judges in patent protection cases. The term usually refers to threats made to competitors about a brand-name manufacturer's tactical use of pharmaceutical patents (including over uses, delivery systems and even packaging), not to extension of any particular patent over an active product ingredient. This article focuses in particular on the 'evergreening' potential of so-called 'linkage' provisions, imposed on the regulatory (safety, quality and efficacy) approval systems for generic pharmaceuticals of Canada and Australia, by specific articles in trade agreements with the US. These 'linkage' provisions have also recently appeared in the Korea-US Free Trade Agreement (KORUSFTA). They require such drug regulators to facilitate notification of, or even prevent, any potential patent infringement by a generic pharmaceutical manufacturer. This article explores the regulatory lessons to be learnt from Canada's and Australia's shared experience in terms of minimizing potential adverse impacts of such 'linkage evergreening' provisions on drug costs and thereby potentially on citizen's access to affordable, essential medicines.
doi:10.1186/1743-8462-4-8
PMCID: PMC1894804  PMID: 17543113
15.  Evolution of Antiretroviral Drug Costs in Brazil in the Context of Free and Universal Access to AIDS Treatment  
PLoS Medicine  2007;4(11):e305.
Background
Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.
Methods and Findings
We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005.
Conclusions
Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally.
Amy Nunn and colleagues analyze the cost of antiretroviral drugs in Brazil between 2001 and 2005 and discuss the implications for HIV treatment in other developing countries.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed 29 million people since the first case occurred in 1981 and an estimated 40 million people live with HIV/AIDS today. AIDS is caused by the human immunodeficiency virus (HIV), which destroys the immune system. Infected individuals are consequently very susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within a few years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a cocktail of antiretroviral drugs (ARVs)—was developed. For people who could afford HAART (which holds HIV infections in check), AIDS became a chronic disease. People who start HAART must keep taking it or their illness will progress.
Unfortunately, few people in low- and middle-income countries could afford these expensive drugs. In 2001, ARV prices fell in developing countries as AIDS activists and developing country governments challenged pharmaceutical companies about ARV prices, pharmaceutical companies set tiered prices for the low- and middle-income countries and more generic (inexpensive copies of brand-named drugs) ARVs became available. In 2003, the lack of access to HIV/AIDS treatment was declared a global health emergency. Governments, international organizations, and funding bodies began to set targets and provide funds to increase access to HAART in developing countries. By 2007, over 2 million people in low- and middle-income countries had access to HAART, but another 5 million remain in urgent need of drugs for treatment.
Why Was This Study Done?
In 1995, many countries in the world signed the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property (TRIPS) agreement, which requires countries to acknowledge intellectual property rights for many products, including pharmaceuticals. In 1996, Brazil became the first developing country to commit to and implement policies to provide free and universal access to HAART. Since then, Brazil's successful AIDS treatment program has become a model for the developing world, and 180,000 Brazilians were receiving HAART at the end of 2006. However, as a WTO member that signed on to the TRIPS agreement, Brazil was required to recognize the intellectual property rights of pharmaceutical companies' patented ARVs. As Brazil scaled up treatment in the late 1990s, the cost of treating AIDS patients rose quickly and the country took controversial public policy steps to reduce the cost of providing HAART to people living with HIV/AIDS. Brazil produces several non-patented ARVs locally, and since 2001 has challenged multinational pharmaceutical companies about the prices of patented ARVs. To induce price reductions for patented ARVs, Brazil has threatened to issue compulsory licenses (which under WTO terms allow countries facing a health emergency to produce patented drugs without consent of the company holding the patent). Brazil also recently issued a compulsory license for one ARV.
Although world leaders have set a target of universal access to HAART by 2010, little is known about the long-term costs of AIDS treatment in developing countries. In this study, the researchers have investigated how and why the costs of ARVs changed in Brazil between 2001 and 2005 and discuss the relevance of the Brazilian model for AIDS treatment for other resource-limited settings.
What Did the Researchers Do and Find?
The researchers analyzed the prices for each ARV recommended in Brazil's therapeutic guidelines for adults and estimated the changes in purchase quantities for each between 2001 and 2005. These changes likely stem from the growing number of options in Brazil's treatment guidelines, the steadily rising number of patients commencing treatment, and patients' shifts to second- and third-line treatments when their HIV infection became resistant to first-line drugs or they developed side effects. The researchers report that the generic drugs produced in Brazil were generally more expensive than similar drugs made elsewhere, but Brazil's negotiated drug prices for many patented ARVs were lower than elsewhere. Overall, total annual drug expenditure on ARVs doubled between 2001 and 2005, reaching US$414 million in 2005. Because many drug prices fell sharply as a result of declining patented drug prices over the study period, this increase was mainly attributable to increases in drug quantities purchased. If these quantities had stayed constant, the total annual cost would have increased by only $7 million, to $211 million. Conversely, without the decrease in the price of patented drugs, Brazil would have spent $952 million annually by 2005. If Brazil had enjoyed the lowest global prices for generic medicines, the total costs per year in 2005 would have been $367 million, or nearly $50 million less than the costs Brazil actually realized.
What Do These Findings Mean?
These findings tease out the many factors—clinical, commercial, and political—that affected the total costs of the Brazilian AIDS treatment program between 2001 and 2005.
Brazil's ability to produce generic drugs facilitated Brazil's price negotiations for patented drugs. Although Brazil saved approximately US$1 billion over the study period as a result of declining prices for patented medicines, the cost of producing generic drugs locally has risen while the prices for generic drugs have fallen elsewhere. Brazil's recent decision to import a generic ARV using a compulsory license suggests that the Brazilian model for AIDS treatment continues to evolve.
Questions remain about the precise causes of year-to-year cost trends in Brazil because, for example, the researchers did not have full data on when patients switched from first-line to second- or third-line drugs. The observed steep rise in costs from 2004 to 2005 in particular warrants further analysis. In addition, the findings may not be generalizable to countries with different policies on HIV/AIDS treatment, different access to generic drugs, or different bargaining power with multinational drug companies. Nevertheless, the trends this study highlights provide important information about how AIDS treatment costs are likely to evolve in other developing countries as efforts are made to provide universal access to life-saving ARVs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040305.
Information from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information from the US Centers for Disease Control and Prevention on global HIV/AIDS topics (in English and Spanish)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco
Information from Avert, an international AIDS charity, on HIV and AIDS in Brazil and on HIV/AIDS treatment and care, including universal access to ARVs
Progress towards universal access to HIV/AIDS treatment, the latest report from the World Health Organization (available in several languages)
The National STD and AIDS Program of Brazil
doi:10.1371/journal.pmed.0040305
PMCID: PMC2071936  PMID: 18001145
16.  Patenting of University and Non-University Public Research Organisations in Germany: Evidence from Patent Applications for Medical Research Results 
PLoS ONE  2010;5(11):e14059.
Background
Patents are one of the most important forms of intellectual property. They grant a time-limited exclusivity on the use of an invention allowing the recuperation of research costs. The use of patents is fiercely debated for medical innovation and especially controversial for publicly funded research, where the patent holder is an institution accountable to public interest. Despite this controversy, for the situation in Germany almost no empirical information exists. The purpose of this study is to examine the amount, types and trends of patent applications for health products submitted by German public research organisations.
Methods/Principal Findings
We conducted a systematic search for patent documents using the publicly accessible database search interface of the German Patent and Trademark Office. We defined keywords and search criteria and developed search patterns for the database request. We retrieved documents with application date between 1988 and 2006 and processed the collected data stepwise to compile the most relevant documents in patent families for further analysis. We developed a rationale and present individual steps of a systematic method to request and process patent data from a publicly accessible database. We retrieved and processed 10194 patent documents. Out of these, we identified 1772 relevant patent families, applied for by 193 different universities and non-university public research organisations. 827 (47%) of these patent families contained granted patents. The number of patent applications submitted by universities and university-affiliated institutions more than tripled since the introduction of legal reforms in 2002, constituting almost half of all patent applications and accounting for most of the post-reform increase. Patenting of most non-university public research organisations remained stable.
Conclusions
We search, process and analyse patent applications from publicly accessible databases. Internationally mounting evidence questions the viability of policies to increase commercial exploitation of publicly funded research results. To evaluate the outcome of research policies a transparent evidence base for public debate is needed in Germany.
doi:10.1371/journal.pone.0014059
PMCID: PMC2987808  PMID: 21124982
17.  “To patent or not to patent? the case of Novartis’ cancer drug Glivec in India” 
Background
Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of Chronic Myeloid Leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec’s patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable.
Methods
The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: “India”, “Novartis”, “Glivec”, “Patent”, “Novartis Case”, and “Supreme Court of India”. The data sources were interpreted and analyzed according to the authors’ own prior knowledge and understanding of the exigencies of the TRIPS Agreement.
Results
This case illuminates how India is interpreting international law to fit domestic public health needs.
Conclusions
The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India’s decision may affect the interpretation of the article of the TRIPS Agreement, which states members shall be free to determine the appropriate method of implementing the provisions of this Agreement within their own legal system and practice.
doi:10.1186/1744-8603-10-3
PMCID: PMC3884017  PMID: 24393270
India; Novartis; Glivec; Patents; Generic drugs; TRIPS agreement; Drug industry; Pharmaceuticals
18.  Traditional herbal medicine in Far-west Nepal: a pharmacological appraisal 
Background
Plant species have long been used as principal ingredients of traditional medicine in far-west Nepal. The medicinal plants with ethnomedicinal values are currently being screened for their therapeutic potential but their data and information are inadequately compared and analyzed with the Ayurveda and the phytochemical findings.
Methods
The present study evaluated ethnomedicinal plants and their uses following literature review, comparison, field observations, and analysis. Comparison was made against earlier standard literature of medicinal plants and ethnomedicine of the same area, the common uses of the Ayurveda and the latest common phytochemical findings. The field study for primary data collection was carried out from 2006-2008.
Results
The herbal medicine in far-west Nepal is the basis of treatment of most illness through traditional knowledge. The medicine is made available via ancient, natural health care practices such as tribal lore, home herbal remedy, and the Baidhya, Ayurveda and Amchi systems. The traditional herbal medicine has not only survived but also thrived in the trans-cultural environment with its intermixture of ethnic traditions and beliefs. The present assessment showed that traditional herbal medicine has flourished in rural areas where modern medicine is parsimoniously accessed because of the high cost and long travel time to health center. Of the 48 Nepalese medicinal plants assessed in the present communication, about half of the species showed affinity with the common uses of the Ayurveda, earlier studies and the latest phytochemical findings. The folk uses of Acacia catechu for cold and cough, Aconitum spicatum as an analgesic, Aesculus indica for joint pain, Andrographis paniculata for fever, Anisomeles indica for urinary affections, Azadirachta indica for fever, Euphorbia hirta for asthma, Taxus wallichiana for tumor control, and Tinospora sinensis for diabetes are consistent with the latest pharmacological findings, common Ayurvedic and earlier uses.
Conclusions
Although traditional herbal medicine is only a primary means of health care in far-west Nepal, the medicine has been pursued indigenously with complementing pharmacology and the Ayurveda. Therefore, further pharmacological evaluation of traditional herbal medicine deserves more attention.
doi:10.1186/1746-4269-6-35
PMCID: PMC3012020  PMID: 21144003
19.  Gene patents and personalized medicine - what lies ahead? 
Genome Medicine  2009;1(9):92.
Gene patents have generally not impeded biomedical research, but some problems that arise in genetic diagnostics can be attributed to exclusively licensed gene patents. Gene patents for therapeutics have often been litigated but have received surprisingly little public outcry. In stark contrast, genetic diagnostics have been highly controversial but rarely litigated: no case has gone to trial and there is little case law to guide policy. Most recently the Secretary's Advisory Committee for Genetics Health and Society (SACGHS) released a draft report examining how patenting and licensing affect access to clinical genetic testing in the US. The SACGHS reported that patents neither greatly hindered nor facilitated patient access to genetic testing; both the harms and the benefits of patents on genetic diagnostics have been exaggerated. Problems do occur when patents are exclusively licensed to a single provider and no alternative is available. Courts have been changing the thresholds for what can be patented, and how strongly patents can be enforced. Technologies for sequencing, genotyping and gene expression profiling promise to guide clinical decisions in managing common chronic diseases and infectious diseases, and will likely be an integral part of personalized medicine. Developing such genomic tests may require mapping a complex intellectual property landscape and cutting through thickets of patented DNA sequences and related methods. Our preliminary studies have found patent claims that, if strictly enforced, might block the use of multi-gene tests or full-genome sequence data. Yet new technologies promise to reduce the costs of complete genomic sequencing to prices that are comparable to current genetic tests for a single condition. Courts, companies, and policy makers seem unlikely to allow intellectual property to obstruct such technological advance, but prudent policy will depend on careful analysis and foresight. The SACGHS report signals that the US government is paying attention, and increases the odds that policy will foster socially beneficial uses of genetic testing while preserving intellectual property incentives and mitigating the problems that arise from legal monopolies.
doi:10.1186/gm92
PMCID: PMC2768999  PMID: 19804612
20.  PA01.56. Malaria cure by Herbal / Ayurvedic Medicine in Central Indian tribal belt 
Ancient Science of Life  2012;32(Suppl 1):S106.
Malaria is one of the dreaded global killer diseases especially in the poor, forested, hilly, remote regions with little medical facilities. About 2 million malaria cases are estimated to occur in India annually as per the National malaria research institute study, but many more unreported cases also occur. Each leads to treatment cost of Rs. 1,000/ (one thousand) on average. This implies Rs. 2 billion drug market. Considering that the proposed local medicinal plants based drug will cut the treatment cost by at least 50% , the business potential with 100% replacement would be Rs. 1 billion at least. The formula is basically clinically found successful by Bombay Hospital scientists. The pharmaceutical companies do not invest in the market “at the bottom of the pyramid” due to thin margins/ loss risk. Thus, of the patented malaria medicine developed by National Research Development Council (NRDC) named “Ayush 64” (www.nrdcindia.com/pages/ayush64.htm), hardly any companies bought marketing rights or did many sales. There is huge market in N. E. India/ Africa/ S. America! Ayurveda has proven medicines to treat malaria viz. Mahasudarshan Churna, Tribhuvan kirti & Parijat vati, who treat “Visham jwara” its Ayurvedic indication. However, these are unknown, unavailable, costly & unused in the tribal areas so not popularized. Folk medicines reported, but rarely, to treat malaria include Neem, Kalmegh & Harsingar, where in a clinical study in Mumbai on 120 Malaria patients, 77% showed complete parasite eradication within 7 days of treatment with the leaf paste, and is also found safe. We also found it effective in our work in Balangir in 2011, besides also by the other NGOs in Orissa viz. Sambandh & FRLHT (www.iaim.edu.in), mainly as a prophylactic. About 30% of the family expenses today spent on Malaria treatment will be cut by about 50%, saving about Rs.2,500/ annually to spend on food, health & education. About 10% productivity will also grow, taking total benefit to Rs.4, 000/ annually, as each person per family spend lying on bed about 10 15 days in Malaria fever. This will be at a cost of just Rs. 500/ making the output: input ratio 1.5, than the total loss now! Also, local & common plants sources, simple technology ensure continued availability & low cost unlike Artemissin drug.
PMCID: PMC3800859
21.  The effects of business practices, licensing, and intellectual property on development and dissemination of the polymerase chain reaction: case study 
Introduction
Polymerase chain reaction (PCR) was a seminal genomic technology discovered, developed, and patented in an industry setting. Since the first of its core patents expired in March, 2005, we are in a position to view the entire lifespan of the patent, examining how the intellectual property rights have impacted its use in the biomedical community. Given its essential role in the world of molecular biology and its commercial success, the technology can serve as a case study for evaluating the effects of patenting biological research tools on biomedical research.
Case description
Following its discovery, the technique was subjected to two years of in-house development, during which issues of inventorship and publishing/patenting strategies caused friction between members of the development team. Some have feared that this delay impeded subsequent research and may have been due to trade secrecy or the desire for obtaining lucrative intellectual property rights. However, our analysis of the history indicates that the main reasons for the delay were benign and were primarily due to difficulties in perfecting the PCR technique. Following this initial development period, the technology was made widely available, but was subject to strict licensing terms and patent protection, leading to an extensive litigation history.
Discussion and evaluation
PCR has earned approximately $2 billion in royalties for the various rights-holders while also becoming an essential research tool. However, using citation trend analysis, we are able to see that PCR's patented status did not preclude it from being adopted in a similar manner as other non-patented genomic research tools (specifically, pBR322 cloning vector and Maxam-Gilbert sequencing).
Conclusion
Despite the heavy patent protection and rigid licensing schemes, PCR seems to have disseminated so widely because of the practices of the corporate entities which have controlled these patents, namely through the use of business partnerships and broad corporate licensing, adaptive licensing strategies, and a "rational forbearance" from suing researchers for patent infringement. While far from definitive, our analysis seems to suggest that, at least in the case of PCR, patenting of genomic research tools need not impede their dissemination, if the technology is made available through appropriate business practices.
doi:10.1186/1747-5333-1-7
PMCID: PMC1523369  PMID: 16817955
22.  Comparative effectiveness of a complex Ayurvedic treatment and conventional standard care in osteoarthritis of the knee – study protocol for a randomized controlled trial 
Trials  2013;14:149.
Background
Traditional Indian Ayurvedic medicine uses complex treatment approaches, including manual therapies, lifestyle and nutritional advice, dietary supplements, medication, yoga, and purification techniques. Ayurvedic strategies are often used to treat osteoarthritis (OA) of the knee; however, no systematic data are available on their effectiveness in comparison with standard care. The aim of this study is to evaluate the effectiveness of complex Ayurvedic treatment in comparison with conventional methods of treating OA symptoms in patients with knee osteoarthritis.
Methods and design
In a prospective, multicenter, randomized controlled trial, 150 patients between 40 and 70 years, diagnosed with osteoarthritis of the knee, following American College of Rheumatology criteria and an average pain intensity of ≥40 mm on a 100 mm visual analog scale in the affected knee at baseline will be randomized into two groups. In the Ayurveda group, treatment will include tailored combinations of manual treatments, massages, dietary and lifestyle advice, consideration of selected foods, nutritional supplements, yoga posture advice, and knee massage. Patients in the conventional group will receive self-care advice, pain medication, weight-loss advice (if overweight), and physiotherapy following current international guidelines. Both groups will receive 15 treatment sessions over 12 weeks. Outcomes will be evaluated after 6 and 12 weeks and 6 and 12 months. The primary endpoint is a change in the score on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) after 12 weeks. Secondary outcome measurements will use WOMAC subscales, a pain disability index, a visual analog scale for pain and sleep quality, a pain experience scale, a quality-of-life index, a profile of mood states, and Likert scales for patient satisfaction, patient diaries, and safety. Using an adapted PRECIS scale, the trial was identified as lying mainly in the middle of the efficacy-effectiveness continuum.
Discussion
This trial is the first to compare the effectiveness of a complex Ayurvedic intervention with a complex conventional intervention in a Western medical setting in patients with knee osteoarthritis. During the trial design, aspects of efficacy and effectiveness were discussed. The resulting design is a compromise between rigor and pragmatism.
Trial registration
NCT01225133
doi:10.1186/1745-6215-14-149
PMCID: PMC3664613  PMID: 23701973
Ayurveda; Ayurvedic; Comparative-effectiveness research; Whole medical system; Osteoarthritis of the knee; Randomized trial; Traditional Indian medicine
23.  The efficacy of Ayurvedic treatment for rheumatoid arthritis: Cross-sectional experiential profile of a longitudinal study 
Context:
Allopathic and Ayurvedic physicians collaborated on a study of traditional medicine, which was sponsored by the World Health Organization.
Aims:
The aim of the study was to test the efficacy and safety of Ayurvedic treatment for rheumatoid arthritis (RA).
Settings and Design:
This study was conducted at the Ayurvedic Trust, Coimbatore, India.
Materials and Methods:
In this unique study of classical Ayurvedic treatment for RA, allopathic physicians enrolled a total of 290 patients with a confirmed diagnosis of RA over a 7-year period, and once every 6 weeks evaluated Ayurvedic treatment outcomes on the basis of American Rheumatism Association criteria: grip strength, walking time, number of swollen and painful joints, joint count, functional class, erythrocyte sedimentation rate, and rheumatoid factor. Ayurvedic physicians administered individualized treatment, closely adhering to principles set forth in classical Ayurvedic texts. The duration of treatment varied from 1 to 6 months.
Statistical Analysis Used:
Due to limitations in computer technology in the 1970s, the data were not computerized. Therefore, data for 12 months at a time were analyzed, using repeated measures t-test. Measures of central tendency (means) and probability values were reported. Results from the patients enrolled and discharged at the end of the first year of the study (N = 33) are presented in this paper.
Results:
There was statistically significant improvement in all parameters from admission to discharge.
Conclusions:
The results indicated that classical Ayurvedic treatment was effective in this first cohort of patients who completed treatment. Even patients with severe functional limitations showed significant improvement. Although there was no control group, the results are positive enough to warrant further study of classical Ayurvedic treatment for RA in controlled trials.
doi:10.4103/0974-7788.83177
PMCID: PMC3157120  PMID: 21897637
Ayurveda; longitudinal study; rheumatoid arthritis
24.  Importance of novel drug delivery systems in herbal medicines 
Pharmacognosy Reviews  2010;4(7):27-31.
Novel drug delivery system is a novel approach to drug delivery that addresses the limitations of the traditional drug delivery systems. Our country has a vast knowledge base of Ayurveda whose potential is only being realized in the recent years. However, the drug delivery system used for administering the herbal medicine to the patient is traditional and out-of-date, resulting in reduced efficacy of the drug. If the novel drug delivery technology is applied in herbal medicine, it may help in increasing the efficacy and reducing the side effects of various herbal compounds and herbs. This is the basic idea behind incorporating novel method of drug delivery in herbal medicines. Thus it is important to integrate novel drug delivery system and Indian Ayurvedic medicines to combat more serious diseases. For a long time herbal medicines were not considered for development as novel formulations owing to lack of scientific justification and processing difficulties, such as standardization, extraction and identification of individual drug components in complex polyherbal systems. However, modern phytopharmaceutical research can solve the scientific needs (such as determination of pharmacokinetics, mechanism of action, site of action, accurate dose required etc.) of herbal medicines to be incorporated in novel drug delivery system, such as nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, solid lipid nanoparticles and so on. This article summarizes various drug delivery technologies, which can be used for herbal actives together with some examples.
doi:10.4103/0973-7847.65322
PMCID: PMC3249899  PMID: 22228938
Herbal medicines; herbs; novel drug delivery system; phytopharmaceuticals
25.  Evidence-Based Integrative Dermatology 
Indian Journal of Dermatology  2013;58(2):127-131.
American recognition for medical pluralism arrived in 1991. The National Center for Complementary and Alternative Medicine was established under the National Institutes of Health in 1998. Following this, patients and researchers began exploring use of integrative medicine. Terence Ryan with Gerry Bodeker in Europe, Brian Berman in America, and the Indian council of Medical Research advocated traditional medicine and integrative medicine. The Institute of Applied Dermatology (IAD), Kerala has developed integrated allopathic (biomedical) and ayurvedic therapies to treat Lymphatic Filariasis, Lichen planus, and Vitiligo. Studies conducted at the IAD have created a framework for evidence-based and integrative dermatology (ID). This paper gives an overview of advances in ID with an example of Lichen Planus, which was examined jointly by dermatologists and Ayurveda doctors. The clinical presentation in these patients was listed in a vikruthi table of comparable biomedical terms. A vikruthi table was used for drug selection in ayurvedic dermatology. A total of 19 patients were treated with ayurvedic prescriptions to normalize the vatha-kapha for 3 months. All patients responded and no side effects were recorded. In spite of advancing knowledge on ID, several challenges remain for its use on difficult to treat chronic skin diseases. The formation of new integrative groups and financial support are essential for the growth of ID in India.
doi:10.4103/0019-5154.108046
PMCID: PMC3657212  PMID: 23716802
Ayurveda; complementary and alternative medicine; integrative dermatology; integrative medicine; lichen planus; medical pluralism; traditional medicine; vikruthi table

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