Wednesday, August 8, 2018
August 8, 2018
A lonely Monarch butterfly!
You can see butterflies everywhere here. Today I ‘captured’ one Monarch butterfly in my camera. These insects became 'famous ‘to us and made 'headlines’ in newspapers sometime , more than 25y ago as Bt-plant technology was about to be released for mankind, for the first time in USA in early 1990s as Bt-cotton technology. The issue was that Bt-cotton plants produces during its growth a "toxic protein" which is toxic to "lepidopteran insets". Lepidopteran insects mean insects that belong to this order by scientific classification and produce "crawling larvae" during their life cycle, and such larvae feed on soft plant materials.
Lepidopteran insects include all butterflies and moths. It is the moths which turn out to be the real pest-insects for us! Scientists have found about 180,000 species of the Lepidoptera insects spread in 126 families. These insects constitute about 10 % of the total described species of living organisms of the world and are considered as significant life-forms in nature.
These insects go through four stages of their life cycle such as ‘eggs’ in the first stage followed by ‘larvae’ which are seen as caterpillars in the second stage, further followed by forming a ‘pupa’ in the third stage and finally emerging as the nice little ‘butterflies’, the adults! There are many such insects which in full-grown form such as in case of Monarch butterflies, are extremely beneficial to us as useful natural pollinators.
But several others, especially the moths are 'pests' because these insects in their larval stage enter in to our cultivated produce in the field by making holes in various kinds of agricultural products like gourds, peas, egg-fruit (brinjal also scientifically known as Solanum melongena), tomato, maize, cotton bolls etc. and start eating these from within as these are herbivorous eaters!. These insects thus render severe losses to us.
Genes coding for Bt-proteins were inserted into Bt-plants by ingenuous methods. Once growing, these Bt- plants also produce Bt-proteins in their body parts and body fluids. Such plants when eaten by lepidopteran pests would die in a few days because the Bt- proteins are there in the plant-juice which are toxic to lepidopteran pests! These Bt-proteins are not toxic to us, the human or to any mammals!
People thought that these Monarch butterfly insects which are important pollinators would be wiped out if Bt-plants were introduced in agriculture. Fortunately, this did not happen as Monarch butterfly larvae do not feed on our vegetables! Monarch butterflies are around here in our garden and everywhere in their habitats.
I photographed one Monarch butterfly today while it was busy making a meal on nectar! They feed on nectar. Have a look at my FACEBOOK page.
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.
Wednesday, June 1, 2016
IMPLICATIONS FOR BIOTECH INDUSTRY
Government of India had announced1 its National Intellectual Property Rights (NIPR) Policy on 12th May 2016. The NIPR Vision is to stimulate creativity and innovation by IPR. The mission is to achieve a dynamic, vibrant and balanced IPR to foster creativity, promote entrepreneurship and enhance development. The focus areas are healthcare, food security and environmental protection among others. There are seven objectives including awareness generation, announcement of legal framework for its implementation, stimulation for commercialization of IPRs, enforcement and adjudication procedures and human capital development. The Patents (Amendment) Rules, 2016 has subsequently been notified2 on 16th May 2016 to implement NIPR policy. The amendment is TRIPS compliant.
India announced its TRIPS-compliant IPR policy3 on 26th March, 1999, effective from 01/01/1995. The Patents (Amendment) Act 2002 enacted in May 2002 came into force4 on 20th May 2003 incorporating main IP laws enacted by legislature, replacing Patent Rules, 1972. The Patents (Amendment) Act 2005 effective 1st January 2005 introduced product patenting5 in all fields of technology; “Swiss Claim” and expansion of exclusion under Section 3(d) were forbidden; software patentability was enforced; provisions relating to exclusive marketing rights were deleted and modified; compulsory licensing could be enforced only under certain conditions; and certain other arrangements including defining “pharmaceutical substances”. The Patents (Amendment) Act 2012 specified securing some minimum marks for enabling to be a competent Patent Agent6. The Patents (Amendment) Act 2013 introduced provisions for recognizing the Patent Office as the Examining Authority and the Searching Authority7 on international level for filing, searching and examination of patents along with necessary fees. The Patents (Amendment) Rules 2014 provided revision of patent filing fees8 for a group of applicants of small financial means. The Patents (Amendment) Rules 2016 intend2 to stimulate creativity and innovation by IPR; the focus areas are healthcare, food security and environmental protection among others.
India is a technology dependent country. In the diverse areas of biotechnology, India has developed its industries by utilizing already invented basic technologies in biological sciences elsewhere. This is true for almost all biotech products manufactured in India in healthcare, agriculture, environment management and industrial applications. India has however made phenomenal progress in applications by innovations using components of patent-expired technologies and materials9, 10. Indian public funded institutions and engineering institutes have contributed to development of comparatively low value biotechnologies. Very few patented technologies have flown from such inventors to the industry. However, there has been considerable collaboration between such institutions and industry, and such tie-up continues10. Indian modern biotech industry comprises of about 340 units of various sizes. A handful of units conduct basic and developmental research. A few standalone “novel” products developed by some companies have small global sales. Most products that sell are those on which patent has already expired for the first inventor. The R&D expenditure by Indian companies is comparatively much smaller than transnational companies. The contributions of small and medium enterprises are not as bright however; most of the units deploy comparatively low value-added technologies, face severe market competition and suffer from shortage of capital. Government is however extending considerable support to strengthen SMEs11.
The general experience by the Indian consumers is that IPR protected imported finished biotech substances in all areas including Healthcare and Agriculture is very expensive. Life saving biotech drugs is often unaffordable by most Indians. Transnational companies have shown feeble interest in setting up basic manufacturing units in India to produce IPR-protected biotech substances. The basic R&D setup of a couple of multinational companies in India has been stopped/transferred/shifted, though some transnational companies have shown interest to build and invest in such facilities in the country12-13. It is prudent to compile the extent of investment made by transnational companies in the country for promoting basic research.
The present Indian technological scenario in biotechnology does not show that India will emerge as an “inventor” country. India would however profoundly contribute through innovation in products and processes where IPR has already expired for the first inventor. The present Indian IPR laws, which are TRIPs-compliant, have considerable flexibilities to utilize IPR for public benefits. It should be the endeavor to uphold the existing provisions through policy interventions. Separately, efforts can be made to develop and invent world-class innovative basic technologies in public funded institutions in specific areas through focused policies and directed investments on top down approach.
Small and medium biotech companies survive in the marketplace by virtue of their own innovations. Very few utilize IPR-based technologies. Wherever an IPR is taken, this is usually used as a marketing promotional advantage for capturing a share rather than for holding on the competitive advantage of the invention. Small and Medium biotech companies are tremendously hard pressed for capital and have limited capacities to purchase IPR which are almost always very expensive, requiring large initial capital.
Large biotech companies use IPR-based imported technologies. Companies’ in-house expenses are mostly on developmental costs and innovations to improve the marketability of the product by cutting costs. Basic R&D expenditure in large biotech companies is also not adequate. Large companies are progressing through international collaborations.
Under these circumstances the flexibilities available through Indian Patent laws should be utilized as much as possible even though there are apprehensions that there could be pressures from several quarters to interfere on rules and policies to make the Indian laws more stringent towards inventors.
In view of the present situation of technological competence and infrastructure available in the country, some questions arise which need to be addressed to understand what is the best roadmap for the country.
Question 1: In Biotechnology, new inventions are emerging in humanized monoclonal antibodies to treat chronic diseases, gene therapy to induct tissue and organ repair, diagnostics (based on genomics, transcriptomics and proteinomics) to predict diseases in advance and target receptors to contain diseases. GM seeds are being developed to improve agriculture and forestry. Genetically engineered organisms including microbes and plants as also engineered enzymes are being developed to deal with various industrial operations and environmental management, among other areas. Is India prepared to invent and build world class biotechnologies in these areas?
Question 2: By inducting more stringent private friendly IPR laws, will there be adequate opportunity for upholding public interest causes that are endemic and prevalent in India such as desire for adequacy of affordable medicines and enough nutritious food for the “have-nots”?
Question 3: Is there a need to move towards IPR laws more stringent than what is required through TRIPS compliance? TRIPS conditions set the benchmark for all WTO Member countries.
Question 4: Is commercialization of biotechnologies in India through more thrust on IP generation a more viable option for the country? Is there any evidence/information on this? Is there any study to assess how many IPR based technologies are being utilized presently by the 340 or so, modern biotech companies in India?
Question 5: The premier Indian biotech companies have done well to the country as well as to the world by producing quality biotech products and supplying them at more affordable prices. Why have not any of these companies been able to develop an innovative near-“jackpot” product thus far? Why some companies who have invented some new products, have not been able to get those registered in developed-country-markets like USA and Europe?
I anticipate to have stimulating discussions and comments from my readers to enable me to become more knowledgeable on the various issues as above.
3. History of Indian Patent System, http://ipindia.nic.in/ipr/PatentHistory.htm
4. India and the WTO, Vol. 4, No. 5, May 2002, http://commerce.nic.in/wto_may2002.pdf
Friday, April 1, 2016
More than one hundred years ago Paul Ehrlich, postulated creating “magic bullets” for using chemotherapeutic agents to fight against human diseases. During those years, maximum number of human deaths was due to microbial diseases. Different kinds of synthetic drugs were discovered and used over the years, the last ones being the “sulfonamides” before the ground breaking discovery of penicillin was made by Alexander Fleming in 1928. The era of “antibiotics” continued for a long time and is going strong up to the present time even though antibiotic resistant microorganisms are fast developing. The methicillin-resistant Staphylococcus aureus has created fear in the hospital-setting causing diseases to the patients, which in many cases become fatal. The development of multi-drug resistant tuberculosis strains is another example which creates significant worries among poor nations.
The present day medical research has moved from treating microbial diseases to treating human diseases emanating from systemic bodily defects such as diabetes, arthritis, cardiovascular diseases, kidney and liver diseases, nerve related diseases such as Alzheimer’s and Parkinson’s diseases, cancer and several others. To treat all these conditions mainly the aim has been to develop technologies to produce substances that body produces for its harmony such as proteins of diverse kinds including insulin, cytokines and various other enzymes. The aim was to treat patients with “replacement therapy”, providing the materials that body requires but cannot produce within the body because of defects. The other approach was to scientifically understand the concept of “ligand-receptor interaction” with reference to bodily macrolides such as proteins, nucleic acids, carbohydrates, peptidoglycans etc. and to treat most such conditions by attempting to modulate cellular communication and inter-cellular modification of substances and also to reduce cellular inflammation. In doing so, several recombinant proteins and monoclonal antibodies started getting evolved and entering into the treatment regimen of human medical armory. At the moment more than 150 such products are in use globally. Another approach to treat bodily afflictions has been to “regenerate” the defective tissues by utilizing “stem cells” with the idea that the defective tissues would be “repaired”. This approach continues today at various laboratories and several new methods and technologies are anticipated to emerge. The present approach is mainly “autologous” in nature.
In the meantime, the disease producing microbes that were contained by use of “antibiotics” have become stronger and resistant to the known antibiotics to humankind. Resistant microbes have emerged in their intense desire to survive in environments “soaked” in antibiotics. Interestingly, the natural antibiotic molecules were isolated from some microbial sources. Even though many such natural antibiotics had been “modified” by human intervention, the essential chemical structure of those molecules was learnt by human kind by studying the natural molecules. The survival instinct by which the bacteria had evolved themselves to survive in an environment surrounded by “enemy bacteria” was “stolen” and modified by the “enemy bacteria” and thus the “enemy bacteria” recreated themselves as the resistant species. Development of antibiotic resistance in nature is therefore essentially a phenomenon of “self-readjustment” and “self-recreation” with an intense desire to survive. This natural law was understood by human kind from early 70s and efforts continued to develop more powerful antibiotics. However, this approach would be abandoned in course of time and newer methods are to be evolved. In the light of such thinking, it was discovered that a large number of viruses exist in nature that can “kill” the bacteria. The natural reserve of such a pool was enormous. It was further observed that the huge pool of viruses were continuously growing into their host-microbe and were bursting open their hosts from within. This was done by producing specific kinds of enzymes by the viruses that were capable of tearing off the peptidoglycan cell walls of the bacteria. This is a natural phenomenon. Once this concept was understood, several scientists started to investigate if such proteins could be produced in large quantities to contain the target bacteria. On pursuing this concept, recently a drug has been discovered which is known by the name CF-301 and is an enzyme that kills Staphylococcus aureus in mouse model. The drug was discovered by M/s ContraFect Corporation, USA. It is anticipated that many such drugs would be discovered using the approach of identifying enzymes that can “dissolve” the peptideoglycan cell wall of bacteria from within. Once such enzymes are discovered and structures identified, these would certainly be produced in large quantities in fermentors using approprie genetically modified microbes such as E.coli and yeast and would be used to contain the “resistant bacteria”. The enzymes would “dissolve” the peptidoglycan cell wall of the bacteria and would kill. However, such discovery approaches would not be easy. Very sophisticated laboratories with highly talented scientists would have to work in R&D institutions to undertake basic and applied research to come up with new products for mankind. Only then the era of antibiotics will come to a close.
Monday, October 5, 2015
The information provided in earlier parts are indications that countries are greatly interested in introducing “similar biologics” within their territory. Defined regulatory pathways for introducing “similar biologics” in different countries are paving the way towards the goal of introducing “similar biologics” within their territories in the shortest possible time. Asian countries as well as South American countries are rich in technical skills in handling diverse aspects of fermentation based technologies with proficiencies in downstream processing techniques. Most of these countries have taken steps to introducing “similar biologics” within their territory by announcing regulatory procedures. Entrepreneurs from all over the world can now take bold steps to set up integrated facilities for the production of some of these “similar biologics” within these territories with eyes on capturing a part of the global market. If efforts are made sincerely in these directions and if access to investments to the tune of USD 25-40 million is made available and further if concerted efforts are made over a period of 3-5 years to introduce “similar biologics” by a group of professionals, it would be an excellent business proposition in these territories.
India has already made a beginning in this direction. There are presently 11 companies that are manufacturing “similar biologics”; there are other units which are importing and selling and thereby acquiring experience in sale which is indeed a tough experience to master. Of the major manufacturing companies in India, are Intas Pharmaceuticals Ahmedabad which has developed its own core competence for handling different aspects of manufacture of “similar biologics”. Intas had also signed an agreement with Canadian drug major Apotex Inc. in May 2008, to co-develop and market the low-cost version of a biotech cancer medicine filgrastim (G-CSF) in North America and Europe. Dr. Reddy’s Labs, Hyderabad has developed competence in production of a wide range of “similar biologics” including Darbepoetin Alpha, Herceptin/Trastuzumab, IFN PEG, Rituximab etc. Biocon India, Bangalore is engaged in the production of Insulin, Bevacizumab, Granulocyte Stimulating Factor (GSF), Pegylated Granulocyte Stimulating Factor (Peg-GSF), Herceptin/Trastuzumab etc. They have teamed up with Mylan Inc., USA as also with a Cuban company. Reliance Life Sciences, Navi Mumbai is engaged in the production of Erythropoietin (EPO), Granulocyte Stimulating Factor (GSF), IFN Alpha, IFN PEG, Infliximab, Palivizumab/Synagis, Rituximab, Streptokinase, Tissue plasminogen activator (t-PA) etc. Bharat Biotech, Hyderabad is engaged in the production of Epidermal Growth Factor (EGF), Human Growth Hormone (hGH), Palivizumab/Synagis etc. Cipla, Mumbai is engaged in the marketing of a selected range of “similar biologics” including Etanercept based on collaboration with foreign companies such as Shanghai CP Guojian Pharmaceuticals Co. Ltd., China. Wockhardt, Aurangabad produces a large number of “similar biologics” based on technologies originally imported from Germany; the products include insulin, cytokines, erythropoietin etc.
Production of “similar biologics” includes the stages of development/procurement of host cells, establish a host cell bank, develop facilities for growing the host cells where the target “similar biologics” proteins are secreted/included as “inclusion bodies” within the host cells; isolation of the target proteins; purification; analysis; formulation development and finally storage and handling followed by marketing.
For faster development in any region, genetically modified host cells could be procured through collaboration and thereafter these could be multiplied to produce the target “similar biologics”, which would then be transformed into formulations. A developmental laboratory set up within the facility with a group of competent and highly modified personnel can convert the procured technologies into usable ones, within the shortest possible time. Examples are the many Indian companies that have gone into production during the last one decade or so.
Presently, pegylation technologies are fast catching up. Pegylation of already used biologics is showing an upward global trend as pegylation process enhances the circulation time of biologics within the body and thus is available for manifesting biological activity for longer time. Pegylation technologies are available for purchase. Technologies for pegylated products of specific biologics are also available for purchase. Presently, the world trend is to introduce a biologically active molecule in the form of its “pegylated” version. Pegylation is a chemical reaction for introducing a highly hydrophilic moiety within the backbone of the “similar biologics” to make the “similar biologics” more effective as by pegylation, the clearance of “similar biologics” from the body is substantially delayed. At the same time, pegylated “similar biologics” do not lose their specific therapeutic activities.
Pegylated erythropoietin, Interferon alpha 2b and G-CSF have already been approved by US FDA and therefore introduction of such products would not pose any problem for introduction as “similar biologics” from and within many other countries.
There are presently more than 150 “similar biologics” which include human proteins such as insulin, erythropoietin, cytokines and a host of other products besides the more recently introduced monoclonal antibodies which are utilized for treating different life threatening conditions. “Similar Biologics” are better therapeutic agents than the generic drugs (which are small molecules) in most situations where the ailments are chronic and life threatening.
“Similar Biologics” as such or their pegylated forms are the future for the treatment of chronic diseases. These are presently the most important alterative for increasing the life span of individuals suffering from chronic life threatening diseases. Use of these medicines would also improve the quality of life of the patients. Such products are expected to reign the world for at least another 2-3 decades till better alternatives come out from nucleic acid stretches as medicines or stem cell therapy or some other most modern therapy that are yet far away for deployment as therapies for treating diseases of human kind.
Wednesday, September 23, 2015
Manufacture of “similar biologics” by entrepreneurs other than the original inventors give rise to ‘products’, which will always be different from the original ‘inventor’s products’ because of one reason or the other. Even if the “similar biologics” are manufactured using the same human “gene/s” as those used by the ‘inventor companies’, cloning of the gene/s into a “DNA vector” followed by its/their transfer into “host cells”, where production will take place can be different. Host cells can generally either be “bacterial cells” or “yeast cells” or “mammalian cells”. Usually to have access to the same host cells is always not feasible and practical. However, near equivalent “host cells” can be obtained where the cloning of the “target human gene” can be carried out using a “suitable DNA vector” for effecting transfer into “host cells”.
‘Host cells’ are the cells where the “similar biologics” are transcribed and translated (produced). Currently world over, three kinds of “host cells” are used as mentioned above. Among the “bacterial cells”, a wide range of Escherichia coli (E. coli) are used for expressing “similar biologics”. Among the “yeast cells”, use is made of a wide range of Saccharomyces cerevisiae, Pichia pastoris and Hansenula polymorpha. Among the “mammalian cells”, used as host cells are the Chinese Hamster Ovary (CHO), Bos primigenius (Bovine), Mus musculus (Mouse), Human Embryonic Kidney(HEK) cells and Baby Hamster Kidney (BHK) cells; among these again the most widely used and characterized cell lines are the CHO cell lines.
By using specific types of “host cells” close to the inventor’s host cells, while the expressed “similar biologics” would be ‘similar’ to the inventor’s products, the other metabolites remaining adherent to the “similar biologics” would be different and therefore the downstream processing technologies would have to take care of purifying/isolating the active “similar biologics” in a manner that would make the “similar biologics” closely similar to the inventor’s product. Often this is not exactly feasible to be duplicated as the downstream processing methods of different companies are different.
Further, once the bulk “similar biologics” are manufactured, these are to be formulated into finished medicines; during the manufacture of formulated products also, differences can crop up. Because of these inherent limitations, “similar biologics” are never considered to be the ‘exact copies’ of the inventor’s products, although the “similarities” would certainly be very high and often more than 99.5% coherent in physic-chemical , biological and clinical manifestations. The small differences in many situations cannot even be quantified by the instruments that are available presently to people. Generally therefore, ‘Regulators’ all over the world define physic-chemical and biological properties of the inventor’s products and ask the manufacturers of “similar biologics” to comply with such defined properties. In addition, the Regulators also insist on developing clinical data on human subjects to ensure that the “similar biologics” are mimicking all the properties of the inventor’s products in terms of efficacy and safety.
It is also the desire of the Regulators to get information generated through clinical trials for “similar biologics” to demonstrate comparable safety and efficacy to the “inventor’s/reference products” in terms of PK/PD comparability data from the Phase I trial onwards. If the Phase I clinical trial data show congruence in PK/PD comparability data moving to the Phase III trials becomes easier. Merely based on Phase III trials without supporting PK/PD data through Phase I is usually not acceptable. On a risk based approach, the three-arm Phase I trials are increasingly being used to demonstrate comparability between the “similar biologics” and the inventor’s products/reference products.
PK refers to ‘pharmacokinetic’ and PD refers to ‘pharmacodynamic’ modeling , which are techniques that require studies of time course of effects of intensity of dose -response of ‘similar biologics’ formulations in patients/target study populations . The study is integrated in to a set of mathematical expressions that enable description of the effect of the dose of ‘similar biologics’ formulations over a period of time. Presently, there exist several models of studying the PK/PD values and the manufacturers of ‘similar biologics’ are required to generate data in accordance with the requirements of the ‘Regulators’ in each country.
Even with such stringent regulatory requirements, several manufacturers have come out to develop “similar biologics” after the expiry of the patents as the market for ‘similar biologics’ is very large, the prices are quite high (remunerative), thus guaranteeing faster paybacks even though the prices are lower than the prices of the inventor’s products. Presently, some 425 “similar biologics” are in the development pipeline world over and more than 350 companies are globally involved in the development of “similar biologics”. The global interest in developing “similar biologics” is increasing very fast as is evidenced by some eight fold increase in the number of clinical trials of “similar biologics” between 2007 and 2014 (rising from 5 trials in 2007 to over 40 trials in 2014).
(Source: http://www.contractpharma.com/issues/2015-06-01/view_features/challenges-in-global-biosimilar-development-a-regulatory-perspective/ , Challenges in Global Biosimilar development: A regulatory perspective-CONTRACTPHARMA.COM, Jun 02, 2015 Issue).
Almost all countries are coming out with guidelines for introducing “similar biologics” within their territory as these would ease availability of such life saving products in the local market. The European Union came out with its guidelines on “similar biologics” in 2005. Following suit came out Australia in 2007; Malaysia, Turkey and Taiwan in 2008; Japan, Korea, Singapore and WHO in 2009; Brazil, Canada, Saudi Arabia and South Africa in 2010; Argentina, Cuba, Iran, Mexico and Peru in 2011; Columbia, Egypt, Jordan, Thailand, India and USA (Draft) in 2012; European Union with their revised guidelines in 2014; and China in 2015. At present, there are globally more than 150 reference products for “similar biologics” to emulate and that about 40 of these have sales of more than USD 1 billion per year. If any one of more of “similar biologics” companies can capture even 5-10% of the market, these would mean considerable profits besides establishment of the image of global presence. This is therefore the right time and precious opportunity for the entrepreneurs of venturing in to right projects on ‘similar biologics’ in developing and developed world.