Tuesday, August 22, 2006

Data Exclusivity

Generic drugs manufacturers are concerned that data exclusivity laws will make their operations unviable and create incentives to delay the entry of new medicines into the Indian market.
FAR away from public scrutiny in the corridors of power attempts are under way to alter the laws that govern the Indian pharmaceutical industry. There is widespread apprehension that the changes proposed would result in a greater concentration of monopoly power in the drug industry, impose barriers to the entry of cheap generic alternatives and generally push up drug prices.Apparently under pressure from the pharmaceutical lobbies, an inter-ministerial group is considering proposals to amend the Drugs and Cosmetics Act (DCA), 1940, which could incorporate `data exclusivity' (DE) clauses for new drugs and pharmaceutical products. Before any new drug is launched in the market, pharmaceutical companies are required, under the DCA, to submit evidence of its safeness, effectiveness and quality to the Drugs Controller General (India) (DCG-I). This is usually test and clinical data from trials on patients. Currently, if a generic competitor can prove that its copycat drug has the same therapeutic quality as the original (bioequivalence), the DCG(I) can use the original company's test data to judge whether the drug is safe and effective. Data exclusivity would prevent this and provide multinational companies with exclusive rights to the test data they submit to the DGC(I) for a negotiated period of time.
The issue of DE has been in cold storage for over three years and debated and rejected since the alteration of the Patents Act in 1995. Despite the fact that DE is outside the ambit of India's commitments under the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement at the World Trade Organisation (WTO), the government is still considering DE proposals. Why?The United States pharmaceutical industry, with the support of its government, initiated discussions with India on DE earlier this year. While President George W. Bush is said to have raised it with Prime Minister Manmohan Singh when he visited India in March, evidence of lobbying has come from two levels: the Pharmaceutical Research and Manufacturers of America (PhRMA) and the U.S. India Business Council, and the U.S. Trade Department, Department of Commerce, and the U.S. embassy.
A confidential PhRMA document, in the possession of Frontline, sets out what the U.S. is looking for: five years of "protection" for new chemical entities (an active ingredient, including salt or ester, which has not been previously approved in any other application) and three years for other products that require clinical investigation.There are several key points in the document that are worth highlighting. First is the conflation of DE and data protection under the label of `protection'. Second, the period of exclusivity is to begin from the date of first commercial sale in India, not the date of marketing approval, which is not the case anywhere else in the world. Third, an earlier date of approval in any other country is irrelevant to the multinational company's entitlement. (In most other countries, the period of exclusivity is dated from the first date of market approval anywhere in the world.) Fourth, no application for generic drug approval can be submitted during this time, which would further delay generic entry. Finally, the demand for the dismantling of price controls could impact adversely the affordability of medicines.
Representatives from PhRMA, leading multinational pharmaceutical companies, the U.S. India Business Council, the U.S. departments for Trade and Commerce and the Federation of Indian Chambers and Commerce and Industry (FICCI) met in New York on June 23 at the India-U.S. Round Table on Pharmaceuticals. The meeting was co-chaired by Franklin L. Lavin, Under Secretary, U.S. Department of Commerce and S.N. Menon, Commerce Secretary. Records from the Indian Embassy in Washington show that a significant proportion of time was given over to `data protection'.
What is at stake?
The cumulative success of the lobbying is evident in the interim report - `The Interim Report of the Committee constituted to consider the steps to be taken by the government in the context of the provisions of Article 39.3 of the TRIPS agreement" - of the inter-ministerial group, a copy of which is in the possession of Frontline. The group includes officials of the departments of Scientific and Industrial Research, Commerce, Economic Affairs, Biotechnology, Chemicals and Fertilizers, Chemicals and Petrochemicals, and the Ministry of Health and Family Welfare.The report, which suggests a three-year DE period along the lines put forward by PhRMA, reveals a mindset that exaggerates the benefits of DE and ignores the adverse implications for public health. On the issue of data protection, it accommodates the misgivings of multinational companies (MNCs) about the Indian intellectual property regime, and notes that, on the negative side, the U.S. includes India in the IPR defaulters list of countries under the "Special 301 provisions".The three perceived gains of data exclusivity are an increase in foreign direct investment (FDI) in the sector; gains for the export market; and the arrival of newer medicines for Indian patients. All of these gains, however, are misjudged.The argument in favour of increased FDI rings hollow because FDI in pharmaceuticals has nothing to do with the level of intellectual property protection. D.G. Shah, CEO of Vision Consulting and Secretary-General of the Indian Pharmaceutical Alliance (IPA), told Frontline: "In India, in 1970, when product protection was abolished, several foreign companies came and made major investments. In 1995, when India signed the TRIPS agreement and agreed to an intellectual property regime by 2005, these very foreign companies divested their manufacturing certificates... and reaped the foreign investment. So this is actually the direct opposite of the argument being made."
Further, K.M. Gopakumar, research officer, Centre for Trade and Development, made the following point in an interview with this correspondent: Since data generated by trials outsourced to India are not even registered with the DCG(I), the protection of trial data is not the overriding concern of multinationals when considering investment. In any case, he said, trial data are adequately protected by the Official Secrets Act and Common Law. So there is no relation between FDI and any increase in clinical trials.Over the last 10 years, the volume of trials of the number of molecules being tested in India has gone up almost 20-fold. Pharmaceutical companies will continue to invest in clinical research and introduce new drugs in India because there are substantial cost savings (60 per cent, according to one estimate).The argument in favour of gains in the export market also appears to be on shaky ground. It rests on the hope that other countries may somehow be induced by the U.S. not to implement stringent TRIPS plus provisions so Indian exports of generic medicines are benefited. The U.S. has rarely, if ever, gone out of its way to promote the interests of another nation's trade over its own. Canada, a developed country with a good generic export industry and a five-year DE period, is facing increasing pressure from the U.S. to raise this to eight years. So it is naïve to expect any gains in this sphere.The argument that DE laws will encourage the introduction of new medicines into the Indian market betrays a misunderstanding of their implications. According to Shah, the IPA, which includes many leading domestic pharmaceutical companies and represents about 30 per cent of the domestic pharmaceutical market, is worried that DE would actually provide incentives to delay the entry of new products for two reasons. First, MNCs would prefer to keep prices high in developed markets by delaying their entry into the developing world at lower prices. Second, they can delay generic entry into the U.S. market immediately on the expiry of the patent."Big Pharma is feeling the pinch of the aggressive entry of Indian generics in the U.S. market," he said. Big Pharma's protectionist lobby, backed by the U.S. government, has been intense. "Into the last three months the government has seen a delegation from Washington and PhRMA representatives every 15 days. A U.S. embassy official concerned confided in me that DE is a Key Result Area," he said.The interim report of the inter-ministerial group recognised that the domestic generic industry would object to a tight DE regime. It noted that "Domestic Pharma companies may perceive it [DE] as a barrier for their growth and are likely to raise objections to it." It also noted that finding an alternative way to protect data other than DE would help keep prices down and "avoid giving monopoly rights to the innovator".Producers of generic drugs operate with very low margins, and depend on volumes. However, DE fosters an anti-competitive atmosphere in which generics are pushed out of the market. The high costs associated with clinical trials would make their operations unviable. Shah believes that Indian generic producers would rather wait for a drug to emerge out of exclusivity than invest in clinical trials. This will put India at a disadvantage if India adopts a DE regime; companies in other countries will have access to an inexpensive and streamlined approval process via their regulatory bodies.Further, there is an ethical question as to whether a population should be subjected to repeated testing. Multinationals stand to gain twice over at the expense of the same population, first from cheaper costs in the original trials, (the data of which are not passed to the DCG(I) until the companies decide to launch in India) and then by preventing generic competition for three years.Leena Menghaney, project manager-India, Medicines Sans Frontiers and the Campaign for Access to Essential Medicines, voiced concern that the availability of medicines for many disease areas could be affected by the resulting market monopoly. Furthermore, DE would render redundant the use of compulsory licence, a market exclusivity waiver on patents provided by the TRIPS agreement in the event of a global health emergency. "They will not be able to obtain a market approval for the drug produced. A compulsory licence will have to be coupled with a waiver on the DE clause," she said.Unless a considerable amount of attention is paid to detail, the following categories of drugs could be affected: those created prior to the 1995 patent agreement but are only now getting market approval; drugs that are not patented because they have been produced through public funding or incorporate knowledge that is part of the public domain; and, importantly, drugs that are not eligible for patent because they are merely modifications, such as new dosages or new dosage forms of existing drugs.The last category is especially significant since the DCA currently allows a wider scope for new drugs that require regulatory approval than for new chemical entities specified in Article 39.3 of the TRIPS agreement. If DE is enacted for all new drugs thus defined, then companies will enjoy a market monopoly on trivial changes. According to Gopakumar, these are, in fact, the targets of multinationals. They will gain market exclusivity where they would not otherwise because the drugs are not innovative enough to be patented. It would effectively render useless a provision in the Patent Act against such practice.In the national interest?According to news reports, at its meeting on July 26 the inter-ministerial group agreed that DE was not mandated by the international TRIPS agreement. Advocates of a DE regime insisted that it was being pursued only in the national interest. It appears that national interest just happens to coincide with the interests of Big Pharma, say its critics.The inter-ministerial group is now considering a `compensatory liability model', in which generic companies would pay a royalty to the originator for the DCG(I) to make use of data filed to it. This is a practice already used in the agrochemical industry, but it would be a world first for the pharmaceutical sector. Royalty payments not only leave intact the problem for generics of operating at low margins, but open a Pandora's box of issues. These include the lack of industry standards of royalty, transaction costs involved, market- and cost-differentiation between countries, disclosure issues when calculating originator costs and whether and to what extent it applies to the export market, and the administrative burden of the scheme. How can these be overcome? R.A. Mashelkar, Secretary, Department of Scientific and Industrial Research, who is the chairman of the inter-ministerial group, did not want to comment. Two other members, G.S. Sandhu, Joint Secretary, Department of Chemicals and Fertilizers, and Rita Teaotia, Joint Secretary, Ministry of Health and Family Welfare, declined to speak to Frontline.If the U.S. had its way, it would export its own intellectual property regime, known as the Hatch-Waxman regime, to a country with very different income and needs. One of its main proponents, Representative Henry A. Waxman, said at a Congress Committee meeting in 2003 that "to impose such a system on a country without a [health care] safety net, depriving millions of people of life-saving drugs, is irresponsible and even unethical".If India does not need to implement such stringent measures under the TRIPS agreement, if it brings no gains and is detrimental to both India's generic drugs industry and its public health, in what sense is DE in the national interest? One thing at least is clear: too much is at stake for DE not to be given proper public debate.

Friday, August 11, 2006

4th free full text journal

Journal of Physiology and Pharmacology
http://www.jpp.krakow.pl

Wednesday, June 28, 2006

3rd free full text journal

Applied Clinical Trials
to know click on the link below
http://www.actmagazine.com/appliedclinicaltrials/

US FDA to modernize regulations on clinical trials

Wednesday, June 28, 2006 11:00 IST Maryland
The US Food and Drug Administration (FDA) announced a series of new policy and regulatory developments to strengthen the Agency's oversight and protection of patients in clinical trials and the integrity of resulting data in an effort to modernize the agency's approach to bioresearch monitoring as part of the Critical Path Initiative.

The Human Subject Protection and Bioresearch Monitoring (HSP /BIMO) Initiative will facilitate the modernization of the regulation of clinical trials and bioresearch monitoring, specifically the protection of human subjects and the integrity of data in clinical trials, and encompasses devices, foods, human drugs, biological drug products and veterinary medicine.

The new effort is part of an HHS-wide initiative to employ recent advances in basic science, including genomics and molecular analysis, in order to bring about more effective development and review of therapies, and to enable increasingly targeted and individualized care management for patients.

"As clinical trials continue to evolve, in particular becoming increasingly large, decentralized and global, the FDA's approach to bioresearch monitoring and human subject protection must also evolve and modernize," said Janet Woodcock, FDA Deputy Commissioner for Operations at this year's Drug Information Association annual meeting. "BIMO will help FDA modernize biomedical research monitoring making the most efficient use of its resources to help ensure the safe conduct of clinical trials, including taking appropriate opportunities to leverage existing oversight done by private entities to accomplish the Agency's risk minimization goals.

" Clinical trials have evolved dramatically since FDA first began inspecting them in 1977. In an effort to protect the rights and welfare of human subjects and to verify the quality and integrity of data submitted for review, FDA established over time a bioresearch monitoring program that included the development and implementation of compliance programs to provide guidance for inspections of investigators, sponsors, contract research organizations, institutional review boards and bioequivalence facilities. With the expansion of clinical trial studies and sites, electronic record-keeping in the studies, and greater participation by vulnerable subjects in clinical trials, the role of FDA's bioresearch monitoring compliance programs must expand and evolve as well. The HSP/BIMO Initiative addresses that need. Over the past year and a half, FDA has carefully inventoried its programs and identified issues to launch the HSP/BIMO Initiative. As this initiative moves forward, FDA will continue to gather additional issues for the initiative and related information from internal and external stakeholders, e.g., industry, academic, and government activities and programs, and intends to conduct workshops and create other opportunities for public input.

Janet Woodcock, M.D., Deputy Commissioner for Operations, will chair the HSP/BIMO steering committee which is comprised of representatives from the Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), Center for Food, Safety, and Nutrition (CFSAN), Center for Veterinary Medicine (CVM), Office of Regulatory Affairs (ORA), and the Office of the Commissioner (OC). Highlights of what has been completed to date include: Draft Guidance; Process for Handling Referrals to FDA Under 21 CFR 50.54; Additional Safeguards for Children in Clinical Investigations, published May 2006; Guidance for Industry - Using a Centralized IRB Process in Multicenter Clinical Trials, published in March 2006; Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees, published in March 2006; Information Sheet Guidances for IRBs, Clinical Investigators, and Sponsors, five published in final January 2006; Projects in progress: Modernizing adverse event reporting to institutional review boards (IRBs) to accommodate major trend toward multicenter trials (March 2005, held Part 15 Hearing - Adverse Event Reporting to IRBs, currently working on draft guidance); Published proposed rule: Institutional Review Board - Registration Requirements, FDA reviewing comments; Finalizing rule: Foreign Clinical Studies not Conducted Under an IND (21 CFR 312.120)

Saturday, June 17, 2006

2nd free full text journal

Indian Journal of Pharmacology . To go on the journal site click on the link below

http://www.ijp-online.com/

Monday, May 15, 2006

free full text medical journals

i will posting free full text medical journals every week for the benifit of all
so the first one is The New England Journal of Medicine. Click on the link below
http://content.nejm.org

Friday, April 21, 2006

story of TGN1412

March 15, 2006
Volunteers taking part in a clinical trial involving TeGenero’s study drug monoclonal antibody TGN1412 have experienced adverse events. The study, sponsored by TeGenero, involves TeGenero’s TGN1412, an immunomodulatory humanized agonistic anti-CD28 monoclonal antibody that is being developed for the treatment of immunological diseases with a high unmet medical need, such as multiple sclerosis, rheumatoid arthritis and certain cancers.“These events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteers”, commented Dr. Benedikte Hatz, Chief Executive Officer, TeGenero AG. The clinical trial performed by the contract research organization, PAREXEL International, adhered to standard clinical research guidelines.” The clinical trial was approved by the Medicines and Healthcare products Regulatory Agency, the UK regulatory authority responsible for clinical trial approval, and the local Ethics Committee. “The drug was developed in accordance with all regulatory and clinical guidelines and standards. In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected,” said Dr. Thomas Hanke, Chief Scientific Officer of TeGenero AG.
March 15 2006
Thomas Hanke, Chief Scientific Officer of TeGenero; “Our first concern right now is for the patients and families and that they get all treatment possible. We are confident in the excellent treatment at this hospital and have made ourselves available to answer any questions from the doctors about the drug. The drug being tested, TGN1412, is an innovative new treatment for the devastating illnesses of leukaemia, rheumatoid arthritis and multiple sclerosis.The investigation must proceed as quickly as possible into these shocking developments in the testing of a new medicine which showed no signs of any safety problems in previous testing.Our thoughts are with the patients and the families.”Notes:Parexel was conducting the first human testing of TGN1412 for TeGenero AG. The trial was approved by the MHRA and the local ethics committee.There is no further human testing of TGN1412 being pursued.
March 17 2006
“We are encouraged by the signs of progress in the conditions of the patients but remain deeply concerned for them and their families. They are receiving excellent treatment at Northwick Park Hospital in London. We are working closely together with the doctors and have made ourselves available to answer any questions on the drug and to support them in choosing the most suitable treatment.At the same time we have offered every support possible to the institutions in charge of investigation, the MHRA in the UK and the German authorities. We will respond to any questions and provide information beyond the material already available. We are doing everything we can to unravel as quickly as possible how these unexpected symptoms could have developed.The tested substance TGN1412 is a new treatment for the devastating illnesses of leukaemia, rheumatoid arthritis and multiple sclerosis. We are shocked about the symptoms we have seen in the volunteers. Extensive pre-clinical tests showed no sign of any risk. We observed strict standards for this clinical test and we obtained all required approvals both in Germany and Great Britain. The drug was tested extensively in laboratories and has been tested on rabbits and monkeys. We saw no drug related adverse events and there were no drug related deaths. Our thoughts are with the patients and their families.”
March 29 2006
Northwick Park Hospital has yesterday (28th March) confirmed that two of the volunteers in the trial of TGN1412 have been discharged from hospital having responded well to treatment. They will continue to visit the hospital for check ups.Three other volunteers have left Critical Care and are making a good recovery, although they continue to receive specialist care and observation. One volunteer remains in a critical condition but is continuing to respond to treatment. TeGenero remains in close contact with the doctors treating the volunteers to provide all possible assistance to them.Everyone at TeGenero is pleased at the improvement in the conditions of the volunteers and is grateful for the excellent work of all the staff at the hospital. Our thoughts remain with all the volunteers and with their families. We are continuing to do all we can to support the investigations into what went wrong in the trial but have received no update from the investigators at this time.TeGenero will issue further statements when there are significant developments.For the latest updates on the condition of the volunteers please visit the website of the North West London Hospitals Trust, www.nwlh.nhs.uk
April 5 2006
Statement from TeGenero AG responding to the report of the MHRA’s findings on 5th April 2006“We are grateful to the MHRA for their conduct of this investigation.”“We are of course saddened that preliminary findings suggest that the unforeseen side effects resulted from the drug itself. For a company dedicated to developing medicines to help millions it is devastating that such events could occur.”“The preliminary findings of the investigation underline that we observed the highest standards in developing this drug and that these symptoms were both unexpected and unforeseeable. The information released today shows that there was no sign of risk from the pre-clinical tests of TGN1412.”“The animal study results show that there were no drug related deaths in the tests with just one animal sadly having to be put down during the trial after suffering severe diarrhoea caused by an unrelated bacterial infection.”“The announcement of a new expert commission to supervise future trials of monoclonal antibodies challenges all of us in the biotechnology industry to think again about the safest way to develop new medicines in the future.”“Everyone at TeGenero is extremely pleased that 5 of the 6 volunteers have now been discharged from hospital and that the sixth is making steady progress and is no longer in critical care. We are grateful for the excellent work of all at the hospital.”For the latest updates on the condition of the volunteers please visit the website of the North West London Hospitals Trust, www.nwlh.nhs.ukFor further information of the MHRA please visit the website of the MHRA, www.mhra.gov.uk

About TeGenero AG TeGenero AG is a privately held biopharmaceutical company dedicated to the development of innovative, highly effective and broadly applicable therapeutic drugs for the treatment of severe immunological disorders. The company was founded in 2000 and is located in Würzburg, Germany.Contact:TeGenero AG Science Park Würzburg Friedrich-Bergius-Ring 15 D-97076 Würzburg Phone: +49 (0) 931-35 96 2-0Fax: +49 (0) 931-35 96 2-11Email: info@tegenero.com