Monday, October 23, 2017
When we watch the status of the present Indian pharmaceuticals industry and hover into some details we conclude that we, the Indians, have made considerable progress though the industry in global standard is quite small. The active pharmaceuticals ingredients (APIs) used by the industry are almost entirely based of patent –expired chemical entities many of which are produced locally and many others are imported. India has over 25, 000 pharmaceuticals factories, characterized by some 500 large industries contributing to 75% of the market, the rest being contributed by small and tiny companies. The number of formulations marketed would be more than 60,000, which are being produced by the use of over 2500 APIs. Because of the very large number of farms in existence and because of public-friendly regulatory laws in existence, the prices of pharmaceutical formulations in India are the lowest in the world. The finished formulations conform to the standards of the Pharmacopeias. Indian formulations are widely exported through the world including the developed nations, meeting part of the demands of the countries where these are exported. Indian population is server fully by the supply of these medicines at affordable prices. It is the APIs that make a pharmaceutical formulation useful. Novel formulations are manufactured from novel APIs which arise from new chemical entities (NCEs). While India uses over 2500 APIs which have arisen from 12000 NCEs, very few of these have been invented by Indians. My story is about those Indian heroes while I shall also narrate in the passing about the status of our pharmaceutical industry.
The importance of the Indian pharmaceutical Industry is globally felt, perceived, recognized and respected.
Sixteen years ago in September 2001, US was facing a monumental crisis – the World trade center had just collapsed on Sep 11, and a week later the country was in the midst of another attack – this time from biological spores called Anthrax. Letters containing anthrax spores were mailed to several news media offices and two Democratic U.S. Senators, killing five people and infecting 17 others. According to the FBI, the ensuing investigation became "one of the largest and most complex in the history of law enforcement ”.
While this story was widely covered, and well-known to everyone, what is less widely known is the role Indian Pharmaceutical industry played in helping the US government deal with the Anthrax scare.
Anthrax infection is caused by the spores of the bacteria Bacillus anthracis. These spores can be multiplied in labs and can remain active for a long time. Isolated spores would look like white powder. When inhaled or contacted with wounds or by eating food contaminated with the spores these would cause the disease. Once infected, if prompt treatment was not initiated, the outcome may be fatal! Ciprofloxacin is the antibacterial drug of choice to treat the disease the spores in powdered form were being posted along with letters posted to the USA by the enemy in October 2001.
Because of the emergency situation in the USA, there was suddenly a huge demand for the antibacterial drug by the generic name ciprofloxacin. The drug was covered under the US Patents Act and the patent right was held by the German pharmaceutical company Bayer. The then US President George Walker Bush was to take a decision on whether to waive the Bayer patent as it was clear that Bayer would not be able to produce and supply the huge demand that had suddenly arisen due to the anthrax scare in USA. The USA government which is pro-trade and is committed to assure the drug companies to charge higher prices on the premises those additional profits are means to generate additional funds necessary for conducting future R&D was at a fix whether to override the Bayer patent in order to enable USA to find alternate sources for the drug. The emergence condition in the country was to be tackled at any cost! Interestingly, the cost of treatment for anthrax by using Buyers ciprofloxacin would be USD 350 against USD 10 only, if treated by using Indian ciprofloxacin! And some 12 million US citizens were at risk! But yet the USA government did not back out but honored Bayer’s patents right and did not purchase the generic version of ciprofloxacin from India or any other cheaper sources! However, the USA cashed on the opportunity and negotiated with Bayer on one to one basis asking Bayer to reduce the price of ciprofloxacin tablets and was able to succeed. Bayer reduced their prices of ciprofloxacin tablets substantially to meet the USA requirements.
The fact that cost-effective, but equally potent ciprofloxacin drugs from Indian companies were available allowed US to successfully negotiate with the world’s leading Pharma giant Bayer. Bayer had to back down in the end.
But what made such solutions from Indian Pharma companies available in the first place? It is the history of innovation at Indian companies over decades that has enabled them to reach that state, and that is often both unknown and underappreciated in the broader world.
Over the next couple of posts, I plan to share some of the innovations from the Indian Pharmaceutical industry, and innovative Indians. Stay tuned!
1) 2001 anthrax attacks. (2017, October 2). In Wikipedia, The Free Encyclopedia. Retrieved 08:18, October 23, 2017, from https://en.wikipedia.org/w/index.php?title=2001_anthrax_attacks&oldid=803471554
2) BBC News-America's anthrax patent dilemma dated 23 October 2001,
3) Jill Carroll and Ron Winslow , The Wall Street Journal, ETBayer to Slash by Nearly Half Price U.S. Pays for Anthrax Drug-The Wall Street Journal,Oct 25, 2001- https://www.wsj.com/articles/SB1003966074330899280
Sunday, January 8, 2017
BIOLOGICAL DRUGS & SIMILAR BIOLOGICS: GLOBAL OPPORTUNITIES
Advanced biological drugs are manufactured by deploying recombinant DNA(r DNA) technology. Only over the past three decades the development of such drugs has experienced continuous growth. Chemically, such biologics are complex molecular substances which are produced by and within living cells of prokaryotic or eukaryotic origin. For the production of certain of such drugs, transgenic animals and plants have been used. The cellular machinery of living entities synthesize such substances based on the ‘instructions’ planted by tools and methods by the scientists within the living entities by utilizing r DNA technology. These molecular substances are 100 to 1000 times bigger in size as compared to the active pharmaceutical ingredients (APIs) that are used for the manufacture of generic pharmaceutical formulations.
Almost all such biologically manipulated man-made molecular substances are initially protected under the Intellectual Property Rights (IPR) by the inventors or their assignees. IPR stipulates protection in countries where such rights have been taken. IPR becomes an expensive way to protect an invention if the invention is not exploited by the owner; many inventors therefore do not invest to protect their invention in every country. Earlier, protection was usually taken and ensured by the inventors in countries where they felt that the invention was saleable and the demands for the products emanating from the exploitation of the invention were anticipated to be high. Presently however the span of protection of inventions that are anticipated to be industrially exploitable fast is extended on a much wider canvas to cover as many countries as have demand for such products and where scientific capabilities of manufacturing such products exist in their territories, especially after the enactment of the provisions of World Trade Organization in Member countries. For the protection of inventions in Member countries, WTO has a uniform provision. Protein-based biological drugs comprising mainly of simple or carbohydrate ligand-modified substances have a wide range of therapeutic applications. Proteins are polymers of alpha amino (most frequently L-α-amino) acids with defined sequences linked by peptide bonds and having usually more than forty alpha amino acids in each molecule but can go even up to 2000 amino acids or more. The business on recombinant protein-based biological drugs is very large in terms of global sale and therefore entrepreneurs have eyes on this business. The proprietary rights on such biological drugs are vested upon the inventors or their assignees as per the conditions of IPR.
The contributions of the modern biologics in human welfare have been enormous. These biologics have assisted significantly during the last three decades in treating several chronic diseases including cancer. With time as more inventions are emanating in this area, the usefulness of such substances continues to increase. Utilization of various kinds of insulin manufactured through recombinant DA technology along with other anti-diabetic drugs have resulted in the control of plasma glucose within healthy limits and death rates of diabetic patients between 1997 and 2006 have substantially fallen. Insulin has played a major role in such endeavor. Use of a large number of biological medicines to treat rheumatoid arthritis has enabled clinical remission of the disease almost completely and has contributed to great human benefits; the results with etanercept had been amazing. Treating cardio-vascular diseases by use of biological medicines such as thrombolytic agents and monoclonal have saved many lives. Biological drugs have resulted in reduction in death rates from cardio-vascular diseases by about 31% between 1998 and 2008 in USA. Development and use of erythropoietin produced by modern biotechnology has reduced the need for blood transfusion in anemic patients of different kinds including cancer patients and have reduced hospital days, thereby benefitting the society. This medicine has also prolonged lives of many terminally ill patients. Incurable viral diseases such as HBV and HCV have been controllable by use of a wide range of modern biologics are continuing to provide substantial life expectancy gains. In US, the death due to all kinds of cancer has come down steadily by 1.5% per year from and during 2000-2013, which is a reduction of around 17% over this period and is considered highly significant. Overall, the use of biological drugs has contributed to increasing life expectancy, decreasing disability and improvement in the quality of life. Therefore, wherever the burden of incidence of such diseases is showing increase, societal efforts require intensification to enable abundant availability and use of such medicines to the affected. Presently, because of increased costs of such medicines and the limited means of the payers in the poor countries, the situation becomes most vulnerable in families having to pay for the costs. The governments in poor countries also do not have adequate funds to make the necessary supply of such drugs to its citizens and in most countries the patients are the payers for the cost of their treatment.
With the passage of time, when such biological medicines get patent-expired, other new companies would come up and start producing them. Worldwide, the accepted practice for adoption of such patent-expired products for human use in medicines from manufacturers other than the original inventors are based upon proving and providing properties of the products manufactured by the new supplier/s as very similar to the products of the inventor through processes of comparison of the products physico-chemically, biologically and through accepted but limited clinical studies on human subjects. Such products introduced by new companies later on are named differently in different countries such as “biosimilars”, “biosimilar products”, “follow-on biologics”, “similar biologics”, “biologics against new biologics”, “biocomparables” and “medicamento biologic similar”. In India, these products are named as “similar biologics”. In several international journals, such products have been termed as “Copycat” and “Knockoff”.
By 2020, a dozen of “inventor’s biologicals” having estimated market sale-value of over USD 79 billion are going out of protection of IPR. This would drive entrepreneurs to enter in to the field and the prices are going to crash considerably due to market competition. In course of time more numbers of “similar biologics” would go out of IPR. Different proactive governments and the regulatory agencies all over the world are trying to harness the existing and future opportunities by creating regulatory guidelines to ease faster authorization of use of “similar biologics” in their territories. A small number of “similar biologics” have been approved for use in different countries all over the major parts of the world. More efficient technologies for manufacture of “similar biologics” are also getting developed. Together, these efforts are anticipated to ease the availability of “similar biologics” at more affordable prices to the users/ payers the world over.