It looks like India's leading biotech regulator, the Genetic Engineering Approval Committee (GEAC), can't avoid controversies—whether for not doing enough for the industry or for whatever decision it takes once in a few months.
The latest issue is the controversial decision of GEAC on 27 November to ask the pharma regulator, the Drug Controller General of India (DCGI) to inquire how Hyderabad-based Shantha Biotechnics has started "illegal" manufacture of the biotech drug Shankinase.
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| "According to DBT protocol, GEAC has no role to play in granting approvals for clinical trials. All clinical trials are approved by DCGI Advisory Committee, after it has been duly approved by Institutional Biosafety Committee (IBSC) and Review Committee on Genetic Manipulation (RCGM)," Varaprasad Reddy, MD, Shantha. |
More damaging to Shantha Biotechnics, a torch bearer of modern biotechnology which has won universal acclaim for its pioneering drugs, was the GEAC's prompt press release the same day which said it has "requested DCGI to conduct a full inquiry into the incident (manufacture of recombinant Streptokinase branded Shankinase without its prior approval) and the reported deaths of some patients during the trials."
"A final view on what action needs to be initiated against the erring company will be decided after getting all reports," the GEAC press release added. GEAC is the regulator for genetically modified products and is part of the ministry of environment and forests. It is chaired by additional secretary rank official, Meena Gupta and has ex-officio members drawn from other wings and scientific agencies of the government.
Ironically, the GEAC decision was taken on a day, when just 500 meters away from its office, some of the country's top biotech experts, NGO activists, industry representatives and scientists were debating the very relevance of GEAC as a bureaucratic regulator whose decisions were far removed from reality. The meeting was organized by leading genetic activist Dr Suman Sahai to celebrate the 10th anniversary of her organization, Gene Campaign. In fact, a few hours after the GEAC meeting, two senior officials of the regulatory agency put up a spirited defence of the organization for nearly two hours at the NGO meeting and unveiled the roadmap to a transparent regulatory regime.
In Hyderabad, Shantha Biotech-nics was quick to challenge the GEAC decision. Within 24 hours, Shantha released its side of the story at a media conference and reaffirmed that its manufacturing and trials of the blood-clot busting drug were perfectly in order and followed all the regulatory processes in the country. The tenor of Shantha's managing director Varaprasad Reddy was that GEAC had no business to poke its nose into something which was not in its mandate.
"According to the Department of Biotechnology protocol, GEAC has no role to play in granting approvals for clinical trials. All clinical trials are approved by DCGI Advisory Committee, after it has been duly approved by Institutional Biosafety Committee (IBSC) and Review Committee on Genetic Manipulation (RCGM)," Reddy asserted.
Shantha's argument that GEAC had no business in this issue has found widespread support in the industry. "It is evident that the roles of GEAC, DCGI and RCGM are not clearly defined. I am in agreement with Shantha's view on the matter: i.e., GEAC does not come into the picture when it comes to granting permission for pre-clinical and clinical trials. This is the role of RCGM and DCGI. Hence Shantha has certainly not deviated from the norms," asserted industry leader and president of the Association of Biotechnology-Led Enteprises (ABLE) Kiran Mazumdar-Shaw."
According to the current regulations, GEAC's role is confined to approving the use of the recombinant drug as it uses an altered genetic material and GEAC has given this approval a few months back. Then the drug goes through the normal regulatory approval, proves as prescribed by the DCGI which involves a host of clinical trials, and the data is vetted by the drug controller. After this process is over, being a gene-based drug, it will have to go to the GEAC for final approval for manufacturing and commercial release. This is clearly stated in the approval letter issued by the DCGI.
"I understand that Shantha has provided all the data pertaining to the trials along withinvestigators' report and I am inclined to accept Shantha's contention that Streptokinase which is used as a clot buster for myocardial infarctions does carry the risk of fatality and statistically the current information does not indicate any fault in the product," Mazumdar-Shaw added.
Shankinase too was approved by DCGI for Phase III clinical trials in various centers across India. Randomized multi-centric double-blind comparative trials were conducted in Hyderabad, Bangalore, Pune, Lucknow and Mumbai, in which the safety and efficacy of Shankinase was compared with the international innovator brand of Streptokinase. The conclusion of the investigators, which is signed and submitted to the DCGI, states that the product generated results that were "absolutely satisfactory and safety was comparable" with the international brand, according to the company. The trials' data was submitted to the DCGI as per the correct procedure and found satisfactory and approval was granted for manufacturing stated Reddy.
A Hyderabad-based NGO had reportedly complained to the GEAC that some deaths had occurred during the clinical trials. The GEAC decision to ask for an inquiry by the DCGI was based on this complaint.
Shantha chief clarified that there were a total of six deaths reported in the Double Blind Comparative Clinical Trial of Shankinase vs Best Known International Brand.
In the Double Blind trials, vials of both the brands are masked and the identity is not known to the investigator, the patient and the company. A total of 134 patients with myocardial infarction were administered both these products, across six hospitals in five cities in India. When the results were decoded, it was found that three deaths occurred in the group administered with Shankinase and an equal number (three) of deaths occurred in the group which was administered the international brand.
"It has to be noted with responsibility that the patients who are administered Streptokinase are patients with acute myocardial infarction (heart attack) and there is an acceptable efficacy benchmark (60-70 percent) seen throughout the world with this product. Since this is a drug for an emergency situation for seriously unhealthy patients, some deaths are bound to occur in any large-scale trial," stated Reddy.
In fact, Reddy said, it was for this very purpose that the ethical committee of the principal investigators chose to conduct a Comparative Double Blind Clinical Trial so that all biases could be eliminated. Thankfully, because of this decision by the investigator, the results submitted by the principal investigators have been accepted by the DCGI.
Firing a salvo at the GEAC for not sticking to its mandate, Reddy asked: "It would be interesting to know whether GEAC has ever taken any cognizance of the deaths in the clinical trials of Streptokinase or any other product, conducted recently or in the past by Indian manufacturers or foreign companies. It is an irony that the GEAC gives environmental clearance to imported products even before clinical trials are conducted, whereas it expects products developed in India to go through it seeking their approval for clinical trials as well as final clearance for manufacturing."
Ironically, the 27 November GEAC statement also contains the information that it had approved the introduction of many imported biotech drugs in the country. The GEAC has not clarified whether the rigorous trials of these drugs had been conducted within India.
As a process, GEAC relies on the Department of Biotechnology (DBT) for scientific inputs. The Review Committee on Genetic Manipulation (RCGM), constituted by the DBT and chaired by a scientist, and the Institutional Biosafety Committees in all organizations conducting experiments on genetically modified products are the key agencies in this sector. All pharma products are first vetted by the DCGI which uses medical experts drawn from the Indian Council of Medical Research (ICMR).
The November issue of BioSpectrum had reported the extensive use of illegal Bt cotton seeds, the country's first officially approved product, in many parts of Gujarat. A GEAC inquiry which tested 10 randomly drawn samples of these spurious seed brands had confirmed the use of "unapproved" Bt genes. Yet the GEAC is not in a position to take any action. GEAC officials have admitted that a stringent action may create a "socio-economic" crisis in the state. The Gujarat state government which has to take action against these practices is reportedly supporting the use of these illegal seeds to benefit its farmers.
It indeed is a strange regulatory system we have for genetically modified products in India.
N Suresh
The renewed friendship between India and the US after September 2001 is manifesting itself in many areas. Biotechnology and life sciences is certainly a top priority area for both countries. This was amply demonstrated by the dialogue between both countries under the Indo-US High Technology Cooperation Group (HTCG) involving top policy makers, industry organizations and captains of India's industry on November 19, 2003 in Bangalore.
"High technology is key to the cooperation between both the countries in fostering bilateral trade," remarked Kenneth I Juster, under secretary of commerce, Bureau of Industry and Security of the US Department of Commerce and the key American interlocutor.
HTCG was set up in November 2002 to take forward the discussions between Prime Minister AB Vajpayee and US President George W Bush a year earlier in Washington. The first meeting of the group was held in July 2003 in Washington D.C. The second in the series was the one in Bangalore. Both the governments have identified three key areas for cooperation in high technology. These are: 1) Defense 2) Information technology and nanotechnology, 3) Biotechnology and life sciences.
The new found friendship and cooperation has resulted in improving high tech exchanges between India and the US which were suspended following India's nuclear tests in May 1998. "Now less than one percent of India's exports to the US involve higher scrutiny and licensing. There were some 700 applications for technology export/import licenses from India compared to 900 from Japan. The approval rate for Indian applications was over 90 percent," informed Juster.
India has a lot to gain from the cooperation, said leading Indian technocrat and DG, Council of Scientific and Industrial Research (CSIR) Dr RA Mashelkar. Dr Mashelkar is the key Indian interlocutor in the Indo-US high tech dialogue. "India's real advantage is not just cost but the value offered. That is why over 100 of the Fortune 500 companies have set up their research and development centers in India in recent years," he told the Bangalore gathering.
The American cooperation in life sciences was reiterated by former US ambassador to India, Thomas Pickering, a vice president of Boeing Corp. and the private sector chairman of HTCG. "India's proven capabilities in biotechnology makes the country a promising future destination. India should be quick in integrating into the global drug production and new drug discovery networks," Pickering advised.
Top policy makers, industry representatives and CEOs of Indian and American companies participated in three parallel sessions on the priority areas. They thrashed out the various issues in the smooth transfer of technologies between India and the US. The dialogue process has gained momentum in 2003, indicated by the active involvement of the key movers from both sides, two times this years. Industry leaders from both sides expect the removal of various irritants on priority basis so that they could look forward to a bumps-free ride on the Indo-US High Tech Corridor.
N Suresh
| 12 steps to biotech
prosperity
After a three-hour intensive dialogue between representatives of Indian and US Life Sciences sectors, as part of the Indo-US High Technology Cooperation Group (HTCG), in Bangalore on November 19, 2003, a set of 12 recommendations were finalized. India's leading business chambers, FICCI, coordinated the dialogue. While Bharat Biotech International chairman, Dr Krishna M Ella, chaired the discussion, the US side was led by Suresh Patil, chairman, Hawaii Biotech. BioSpectrum was part of the team that compiled the recommendations and participated actively in the discussions. These 12 issues were taken up for detailed discussions between the top officials of both India and the US in New Delhi on November 20. In due course, most of these recommendations will eventually get implemented, paving the way for the growth of the biotech cooperation between both the countries. 1. Adherence to all Intellectual Property Rights agreements including the modified Indian Patents Act incorporating product patents in pharma and agriculture 2. The US government should remove unnecessary restrictions and delays caused to Indian exports of biotech products which fall in the dual use category—civilian commercial and defense use 3. India could consider adapting the US Department of Agriculture (USDA) fund sharing mechanism 4. India should harmonize all the legislation related to the introduction of genetically-modified(GM) products –such as Seeds Act, Environment Protection Act and Prevention of Food Adulteration Act and Patents Act 5. A fast track mechanism for clearance of biotechnology products for commercialization, clinical trials 6. US and India should take up mutual accreditation of professional qualifications to avoid duplication of various mandatory product tests 7. India should either abolish or enhance the eight percent upper limit imposed on payment of technology import fee 8. India's Patents Act should be amended to include "gene constructs" under the permitted categories to avoid hassles related to interpretation by customs 9. India should set up a "single window" clearance for biopharma and GM products 10.Some clarifications related to some of the "draconian" provisions in the Biodiversity Act which hamper the handling of biotechnology products 11.India should provide for data exclusivity to clinical trials and not permit use of the same data to introduce generic drugs in the same category 12.Streamlining of the customs clearance process for the import of biotech materials required for research
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Patangrao Kadam, the Minister for Industries, government of Maharashtra launched the Confederation of Indian Industry (CII)'s biotech initiatives by inaugurating the Maharashtra Maha BioYatra this year. This is a network forum acting as communication and marketing network for the state's bioscience community, started last year in August.
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| View of the exhibition on PharmaExpo 2003 |
New age biotechnology
The CII in association with the government of Maharashtra, Maharashtra Industrial Development Corporation and International Biotech Park organized the second in series of the Biotech Day on the theme "New Age Biotechnology in Maharashtra" on Nov 14. The conference was inaugurated by the industry minister Patangrao Kadam. Speaking to BioSpectrum Kadam informed that the state government would create a biotech fund for the benefit of small and medium entrepreneurs.
There were five sessions covering diverse topics but it seemed difficult for the audience to digest it all. The hall was packed with audience when the conference started. As the day progressed the crowd became thinner and thinner. In the final session of the day, on clinical research organizations, there were about 20-25 people left in the audience. But surprisingly, there were a good number of people present for the same topic at the PharmaExpo, again, organized by CII, at another place on Nov 15. CII made efforts in organizing the event. But at the end of the day who are the gainers?
Although there are many members both from industry and scientific community in the biotech task force and biotech commission constituted by government of Maharashtra their participation in the conference organized by the state government on Maharashtra biotech day was not seen. This is not a good trend. The organizers must take it seriously by seeking the suggestions of the members and involving them in the activities. Their participation definitely will have its impact on the event. Unless this happens the state may see sluggish progress in bringing awareness about the opportunities in biotechnology and the latest happenings in this knowledge based industry.
The event featured speakers from India and abroad but due to paucity of time the speakers were asked to complete their presentations in the middle. To create awareness about the topics the speakers should be given enough time. There should be some time for discussions too. Otherwise the audience will end up getting more confused. Similar situations were seen even at the three-day Bangalore Bio 2003 and at Vibrant Gujarat, the Pharma Biotech summit held in Ahmedabad last month. The organizers have to look into the reasons for the poor attendance, otherwise these summits and conferences will be of no use.
Herbal World-2003
In addition, Prabodhan, a charitable trust in association with Khadi and Village Industries organized a two-day seminar on "alternative and traditional medicines, nutraceuticals and cosmetics of herbal origin" and a four-day exhibition (Nov 13-16) on 'Herbal World 2003'. The exhibition attracted many herbal medicine companies like Zandu, Bhaidyanath, Charak Health Care, etc. and a few agri biotech firms like Alpine Biotech, Nirmal AyurLife, etc. to showcase their herbal products. Even nurseries and many ayurvedic colleges participated in the exhibition. The exhibition attracted good crowd.
PharmaExpo–2003
PharmaExpo–2003, a two-day international conference on India Pharma Inc—New Horizons was also held in Mumbai in mid November. It was organized by CII. As many as five sessions including a panel discussion on "evolving Indian pharmaceutical industry: what would be the post 2005 scenario?" were arranged as a part of the conference. The sessions covered the subject of regulatory procedures and standards, which is a very apt topic for discussion at this time, as the pharma industry has to implement/upgrade to Schedule M. The other topics covered at the conference were the IP watershed for Indian pharma industry and emerging trends and opportunities in clinical trials and information management for pharmaceutical industry. Representatives from companies like Wockhardt, Well Quest, Infosys Technologies, etc. made presentations. The conference saw representatives from over 40 pharma companies.
At the exhibition organized by PharmaExpo, apart from distributors and suppliers to pharma companies, MIDC and Genome Valley, Hyderabad attracted good industry crowd to their stalls. Most of the companies received quite a number of enquiries and were satisfied with the turn up of the industry people.
On Nov 20, Assocham (Associated Chambers of Commerce and Industry of India), Organization of Pharmaceutical Producers of India, Indian Merchants Chamber, CropLife, ABLE (Association of Biotechnology Led Enterprises) and PhRMA (Pharmaceutical Research and Manufacturers of America) came together and jointly organized a day's seminar on "India: The new emerging R&D hub for knowledge based industries". The speakers at the seminar covered topics on pharma, biotech, agrochem and IT sectors.
After a gap of a few months, activities have picked up in biopharma, biotech and agri biotech areas. This is good sign. With good economic growth and good monsoon this season, companies are investing in R&D activities. To support their initiatives organizations are arranging conferences and seminars, which will prove beneficial for the industry. In continuation with these programs, University of Pune, the bioscience division of IIT, Mumbai, Small Industries Service Institute are planning to organize programs in bioinformatics, biomaterials and biotechnology in the next few weeks.
Narayan Kulkarni
The pharma and healthcare sectors hold unique positions among the growing segments of the Indian industry. The healthcare market of India, as of today, is worth Rs 100,000 crore and is expected to reach Rs 200,000 crore in the next three years. But there is a common concern among the industry over the existing pharmaceutical regulatory system. With the increased thrust on pharma, now everyone is talking about growth and accepting more challenges. But the question is how can this be achieved?
Most of the big players of the pharma industry are of the opinion that if the Indian drug regulatory scenario becomes strong, fast and independent, then this industry will grow at an accelerated speed. In this regard, the Mashelkar committee has prepared a comprehensive road map for revamping the Indian drug regulatory system. It has suggested a three-phase switch over from the current state licensing system to a central licensing regime for drug manufacturing facilities across the country.
If the Mashelkar committee recommendations have their way, then a Central Drug Administration (CDA) will take over the responsibility of issuing licenses to drug manufacturing facilities of 19 states during 2004-05, where the pharma industry has a bare minimum presence (5 percent). It is also expected that centralized licensing in most other states will be implemented from 2006 onwards. States like Andhra Pradesh, Goa, Gujarat, Karnataka, Maharashtra, Tamil Nadu and West Bengal where almost 75 percent of the drug manufacturing units are located, will be the last to be under CDA control as the authority needs to substantially strengthen its infrastructure and manpower for effective discharge of responsibilities in these states.
Appreciating the Mashelkar Committee's recommendation for centralized drug administration, JVR Prasada Rao, secretary, department of health and family welfare said, "the centralization will also give tremendous boost to the image of Indian drug industry. A drug regulatory system with centralized control would only help to streamline the licensing functions and thereby improving the quality standards in the Indian pharma industry."
The committee is yet to suggest the licensing functions of the remaining Category II states, where 20 percent of manufacturing activity has concentrated which can be taken over by the proposed CDA from 2005 onwards. The states that come under this category include Bihar, Delhi, Haryana, Kerala, Madhya Pradesh, Orissa, Punjab, Rajasthan and Uttar Pradesh.
Pharma majors like DS Brar, CEO and MD, Ranbaxy stated, "India has lot of potential in pharma and bio-pharma segments of the industry. We can achieve success in this segment if the system gets more effective and speedy."
Similar statements have come from other companies like Eli Lilly. "The industry requires the single-window outlet for drug regulatory issues. It is not a easy job to do but the government should start taking initiatives in that direction," commented Rajiv Gulati, MD and chairman Eli Lilly.
Meanwhile, in a recent development, the Drugs Controller General of India (DCGI) has announced the approval of 24 new drugs this current year. While Sun Pharma got four of their applications cleared, it was three each for Cipla and Glenmark. Microlabs, Ranbaxy and Hetero received two new drug approvals each during the period until October 2003.
On import registrations front, the DCGI has approved 61 bulk drugs and 28 formulations during the last one-month (Sep 15 to Oct 15). While 22 of the bulk drugs cleared are to be imported from France, 15 are from China. Bulk drugs from Korea and Switzerland have also been cleared during the period.
Looking at the current developments, it can be assumed that the future of this segment of the pharma industry is bright and the government has taken the responsibilities to facilitate its growth. But all this depends on the competitiveness of the industry and attentiveness from the government's side. We can only hope that both these factors will lead to further growth of the industry.
Faiz Askari
