Dear friends,

Please find attached article: A Call to Reduce the Incidence of Alzheimer’s Disease.

Kind regards,

Attachments
 Alzheimers disease.pdf [182 KB] ::

From People's Democracy: In recent months there have been a spate of reports that raise concerns about the conduct of clinical trials on human subjects in India. These ranged from reports of a number of deaths in trial subjects in the All India Institute of Medical Sciences in 2008, to the gross ethical violations alleged in trials of a vaccine to prevent cervical cancer among adolescent girls in Andhra Pradesh and Gujarat in 2010. There have also been reports of growing number of deaths in trial subjects that led, in one instance, to the Drug Controller General of India stepping in to stop the concerned trial in Bangalore. What is disturbing about all these reports is the absolute lack of transparency regarding how these trials are being conducted. The government, when forced by media reports to make a statement, has chosen to maintain this veil of secrecy to the extent possible.
 
These reports, raising misgivings about the way clinical trials are being conducted in India, coincide with a very rapid expansion of the number of clinical trials conducted in the country. The flood gates opened in 2005 when India changed the rules regulating clinical trials in the country. To understand how this happened we need to understand the process involved while conducting clinical trials.
 
CLINICAL TRIALS AND ETHICS
When new drugs are researched, they need to be tested on human subjects before they are given a marketing approval by drug regulatory agencies. Before a new drug is tested on human subjects, they have to be tested on animals to establish the safety and efficacy of the drug. However, this is not enough to establish the safety and efficacy of the drug in humans. The final step involves testing the drugs among human subjects. These tests are carried out in four phases. In the first phase of human trials, the drug is tested on a small number of human subjects to show that the drug is indeed safe for human consumption. Generally phase I trials are conducted on healthy subjects and the intent is to establish the safety of the drug. Phase II and III are conducted on subjects who have a condition that may benefit from the use of the drug, and thus these trials are designed to establish that the drug is effective in treating a particular disease. Phase IV trials are also called post-marketing surveillance and are designed to collect data from an even larger sample of patients, after the drug is introduced.
 
Because clinical trials are essentially experiments that are conducted on human beings, all countries have rules that regulate how these trials should be conducted. Globally, the Helsinki declaration, sets the benchmark of how such rules should be framed. All rules related to drug trials are concerned with the ethics of how trials are conducted. The first, and perhaps the most important aspect of these rules, are those related to “informed consent”. Because trials are an experiment they carry a potential risk. So it needs to be ensured that those who participate in clinical trials should be aware of the risks and should formally consent to be part of the trial after the risks are explained in details. The concept of informed consent is also premised on the assumption that trial subjects consent to be a clinical trial subject without being coerced, directly or as a consequence of the circumstances in which the person might find himself. The second fundamental concern about ethics in clinical trials is that trials should be allowed in a population who would later benefit from the introduction of the drug that is tested. In other words clinical trials should not be permitted where trial subjects in a particular country or community are used as mere guinea pigs.
 
There are several other critical issues that determine whether a trial is ethical. In recent years, a major concern has related to “placebo” controlled trials. A placebo is a substance that has no significant effect on a human subject – it could be a capsule containing a small amount of salt or sugar, for example. In placebo controlled trials, some trial subjects are given the placebo while others are given the drug that is being studied. Through this route researchers can decide if the drug is a better alternative to no treatment. However placebo trials are unethical if a treatment already exists for the disease for which the new drug is being tested, for it means that those who are given the placebo are being denied treatment, even though a treatment for the disease exists. The Helsinki declaration clearly states that in general placebo trials should be avoided if treatment already exists. However there is no unanimity on this among researchers. Laws in the US, for example, have different standards for placebo controlled trials depending on whether the trials are being conducted in the US or being conducted in a third country.
 
CHANGE IN LAW OPENS FLOOD-GATES
Before 2005, the Indian law was designed to actively discourage the use of Indians as mere subjects for experimentation by foreign companies. The law required that if a foreign company wished to conduct trials in India, it needed to repeat the trials from the same phase in India as had already been conducted in locations outside India.  Thus if a company had already conducted phase I trials outside India, it could not directly start phase II trials in India – it would have to conduct phase I trials again in India, before permission was conducted to conduct phase II trials in the country. This allowed Indian regulatory agencies greater control over the kind of trials being conducted in India and was a vital tool for protection of trial subjects against unethical trials. In 2005, however, this requirement was waived (by and amendment to schedule Y of the drugs and cosmetic rules) and concurrent phase II and III trials were allowed. This means that a phase II or III trial can be conducted concurrently in India, along with similar trials in other centres in the world, even if the drug has not undergone a phase I or II trial in India.
 
The result of this change in the law has been spectacular. In 2005, less than a 100 trials were being conducted in India. The number jumped to over 250 by 1997-98 and is projected to exceed a 1000 by the end of 2010. It is now estimated that one in four clinical trials in the world are conducted in India, and the turnover for the industry is expected to touch US$ 1.52 billion by 2010. The Association of Indian Contract Research Organisations (ACRO) chairman Dr S P Vasireddi is quoted as claiming: "We have now a share of 24 per cent while China has 33.3 per cent of the global business."
 
REASONS BEHIND BOOM IN CLINICAL TRIALS
What explains this boom in clinical trials in the country? Does it indicate a rapid expansion of capability and capacity for conducting medical research in the country? Unfortunately the answer to this is largely in the negative. While capacity and capability have increased, the sudden rise in number of trials far outstrips the enhancement in capacity and capability. Even industry sources admit that at present levels there is a need for about 5,000 new professionals trained in good clinical practice (GCP) in the industry to augment the 600 odd who are available in the country. What is perhaps an even bigger concern is that regulatory capacity has not kept pace with the sudden spurt in clinical trials. While the law was changed in 2005, it was only in late 2009 that the government deemed it prudent to make it mandatory to register clinical trials in the country. While rules now specify that all clinical trials need to be overseen by institutional ethics committees, the constitution and functioning of these ethics committees are fraught with numerous problems. Primary among these is the issue of conflict of interest -- ethics committee members can have vested interest in ensuring that a trial is given permission because they have links with the company or the local contractor or the researcher who is engaged in promoting the trial.  Further, there is little interaction between ethics committees in different locations, thereby allowing the practice of "ethics committee shopping": sponsors whose trial is rejected by one ethics committee approach a different centre for approval.
 
The sudden boom in clinical trials, in fact, can be explained precisely because of the incapacity to regulate clinical trials. Companies are rushing to India to conduct trials which they would have problems in justifying in their home countries. This is happening in a situation where most patients in India are particularly vulnerable because they have poor or no access to public health facilities. Thus, poor and vulnerable patients sign up for trials as they see this as the only opportunity to access treatment for their disease. A study done by the Mumbai based Centre for Studies in Ethics and Rights quotes a survey that showed that just 11 per cent of trial subjects enrolled to advance scientific knowledge. In contrast the rest joined the trials because they were looking for better or free treatment, or they were advised by their treating physician to enroll. Five per cent even admitted that they joined because they were paid money to do so! Poor access to public health in India has another advantage that trial sponsors seek to exploit – most Indians are treatment naïve, that is they have not been exposed to treatments before enrolling in a trial. In other words, all that is wrong with the public health system in the country has become the primary motive force for India becoming the favoured destination of clinical trials in the world.
 
MIDDLEMEN MILK THE SYSTEM
The story would not be complete without a mention of the prime movers of the clinical trials industry in India. There has been a mushrooming of Clinical Research Organisations (CROs) and Site Management Organisations (SMOs) in the recent past. To put it bluntly, they are the middlemen or fixers who grease the machinery and ensure that more and more clinical trials are outsourced into India. They liaise between the drug companies and the clinical researchers (many of them of extremely dubious quality). They ensure that the drug regulatory authorities are kept happy, they draw up the protocols, advise the researchers as to how patients are to be recruited and even help in formation of the ethics committees. Their prime motivation is not an interest in research but the billions of dollars that are flowing into the industry. When researchers are drawn from the private sector, they are paid on a pro rata basis depending on the number of subjects who are recruited. Such payments can range from $1,500 (Rs 70,000) to $3,000 (Rs1,40,000) per patient.
 
Recently, in a reply to a question in parliament, the ministry of health reported that deaths among clinical trial subjects increased from 132 in 2007 to 637 in 2009, and 462 deaths had already been reported till June 2010. While deaths can occur among clinical trial subjects (largely in cases where the subjects are suffering from terminal diseases such as cancers), such a rapid increase is a cause for concern. The concern is compounded by the fact that there appears to be an absolute lack of transparency in reporting regarding how trials are being conducted and the outcomes of these trials.
 
This is not to suggest that good quality researchers are not present in India and that excellent research is not being conducted in several centres. Unfortunately these would constitute a small minority of the total number of clinical trials being conducted in the country. Given the huge and growing concerns about the dubious quality and ethical gaps regarding most clinical trials being conducted, there is a danger that the entire system of clinical research will stand discredited in the global arena. If this is to be avoided drug regulatory authorities and the Indian Council of Medical Research must step in to ensure transparency, ethics and quality in clinical research. At the same time, there is a clear need to separate the unethical and the incompetent from genuine researchers. Only better regulation with much larger regulatory capacity and resources can ensure this. Finally, there is also an urgent need that CROs and SMOs be regulated and perhaps phased out of the entire system of conducting clinical research in the country.

Dear friends,

Please find attached article on novel applications of nootropics in CNS disorders.

Thanks and regards,

Attachments
 nootropics.pdf [317 KB] ::

Dear All

Please find enclosed review article on Sodium-Glucose Co-Transport Inhibitors: Progress and Therapeutic Potential in Type 2 Diabetes Mellitus.

Kind regards,

Attachments
 SGLT inhibitors.pdf [164 KB] ::

Dear Friends,

Please find attached article on PPARγ Agonists as Therapeutics for the treatment of Alzheimer's Disease.

Kind regards,

Attachments
 PPAR AD.pdf [787 KB] ::

Dear Friends,

Please find attached review article on: Novel therapeutic applications of cardiac glycosides.

Kind regards,

Attachments
 cardiac glycosides.pdf [497 KB] ::

Dear Friends,

The JSM 2010 Invited Session, "Use of Graphics in Clinical Trials" was standing room only - if you missed out you can download the presentations online: http://stat-computing.org/events/2010-jsm/

Kind regards,

Dear friends,

The Knock Out Rat Consortium (KORC) is formed by individuals and institutions interested in the goal of creating knockout rats using multiple different technologies. Knockout rats can be used for functional genomics and also for drug discovery.  The mission of the KORC is to create rats with single gene disruptions (knockouts) using all available technology.  KORC goal is create at least one rat with a null mutation corresponding to every gene in the rat genome.  KORC will create all mutations on the same background strain of rat, namely Fischer.  Each knockout will be bred into at least one male rat, which will be sacrificed for tissue collection and cryopreservation of sperm.  Cryopreserved sperm can be used to create knockout rats with specific null mutations by the process called intracytoplasmic sperm injection (ICSI).

Visit at http://www.knockoutrat.org/

Kind regards,

Dear Friends,

Please find attached article on Bortezomib in the management of multiple myeloma.

Kind regards,

Attachments
 bortezomib.pdf [831 KB] ::

Dear Friends,

Please find attached Report: "ETHICAL CHALLENGES IN CLINICAL RESEARCH AT BOTH ENDS OF LIFE" of the EFGCP–EUCROF Joint Workshop on Common Lessons to be Learnt from Paediatric and Geriatric Clinical Development held at the Crowne Plaza, Antwerp, Belgium 27 and 28 April 2010.

Kind regards,

Attachments
 Final Report.pdf [244 KB] ::

Dear friends,

Please find attached article on antibiotic resistance superbug: New Delhi metallo-β-lactamase 1 (NDM-1). 

Kind regards,

Attachments
 NDM-1.pdf [359 KB] ::

Dear friends,

Please find attached article on Icatibant, a selective antagonist of the bradykinin type 2 receptor, for the treatment of acute hereditary angioedema in adults with C1-esterase inhibitor deficiency.

Kind regards,

Attachments
 icatibant.pdf [232 KB] ::

Dear friends,

Please find attached an interesting and informative article on the various new drugs for hypertension which are in Phase II / III clinical trials. Some of the notably new drugs are 

• Azilsartan - AT1 receptor blocker with PPAR gamma activity
• Ilepatril - Neutral endopeptidase (NEP) inhibitor
• Daglutril - Combined AT1 receptor blocker and NEP inhibitor
• Darusentan - Endothelin A receptor antagonist
• Monoxidine - Imidazoline receptor blocker
• Sapropterin - Tetrahydrobiopterin analogue 

Please go through the attached article for more details.

Kind regards, 

Attachments
 Novel therapeutic targets for hypertension.pdf [319 KB] ::

Dear Friends,

Outstanding opportunity now available for a qualified leader to become the Medical Director of the Medanta Duke Research Institute (MDRI), an early-phase, Proof-of-Concept (POC) collaboration between Duke University and Medanta – The Medicity, a premier healthcare facility in Gurgaon, India. The Medical Director oversees a 60-bed POC unit within a new, state-of-the-art, 1,500-bed tertiary and multi-specialty quaternary care facility.  The Unit focuses on industry and academic biomedical research, and the Medical Director will provide strategic and operational oversight of all research and education/training activities. The Unit is poised to become a regional and global leader in providing innovative solutions to sponsors and investigators in early phase and POC clinical trials.  The applicant should be an MD (or equivalent) with at least 5 years experience in either academic or industry First-In-Man/Phase-I/Early-Phase/POC clinical research environments.  Additional education or training in Clinical Pharmacology is desired, not required.  Interested applicants should submit a cover letter and CV to MDRIemployment@duke.edu 

Please find attached document for details.

Kind regards,

Susan Clayton
Assistant to Robert M. Califf, MD
Vice Chancellor for Clinical Research
Duke University Medical Center
Director, Duke Translational Medicine Institute
1117 Davison Building, Box 3701
Durham, NC  27710
Tel:  (919) 668-8820
Fax: (919) 668-7103

Attachments
 FINAL MDRI Medical Director Recruitment.doc [23 KB] ::

Dear friends,

FDA has issued revised information sheet guidance on "Clinical Investigator Administrative Actions - Disqualification."  This document replaces a previous information sheet titled "Clinical Investigator Regulatory Sanctions."

The revised document is now available from FDA's website using the following web link:  http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214008.pdf.

Kind regards,

Dear friends

FDA has issued final information sheet guidance on "Frequently Asked Questions - Statement of Investigator (Form FDA1572)."

The document is now available from FDA's website using the following web link:  http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf.

Kind regards,

Dear friends,

Growing clinical trial complexity continues to challenge the ability of pharmaceutical and biotechnology companies to contain the ever-rising cost of developing new drugs, according to a study recently completed by the Tufts Center for the Study of Drug Development.

The study found that the median number of procedures per clinical trial increased by 49% between 2000-03 and 2004-07, while the total effort required to complete those procedures grew by 54%.

The new study updates an analysis conducted by Tufts CSDD two years ago, which provided the first quantitative assessment of the impact of protocol design on clinical trial performance.

“More complex and burdensome protocols are extending study cycle times, increasing costs, and challenging patient recruitment and retention,” said Tufts CSDD Senior Research Fellow Ken Getz, who conducted the study. “Wide observed differences in complexity and execution burden by phase and therapeutic area indicate that pharmaceutical and biotechnology companies can target their efforts to improve protocol design and improve clinical trial operating performance.”

According to Getz, the rise in the number of eligibility criteria used to screen volunteers has contributed to a decline in volunteers enrolling in clinical trials. And once volunteers enroll, he said, the larger number of procedures per protocol is dissuading study volunteers from staying in trials through to completion.

The new analysis, reported in the May/June Tufts CSDD Impact Report, released today, also found that:

Wide variability exists in complexity and execution burden per protocol between therapeutic areas and clinical study phases, indicating opportunities to streamline design.

Between 2002 and 2007, protocols targeting diseases in oncology, immunology, and the central nervous system saw the most rapid growth in the total number of procedures and in the burden to execute those procedures.

Overall growth in complexity and execution burden grew at the slowest rate for protocols in Phase III studies, as companies, looking to contain costs, gathered more data in early phases of clinical research.

To view summary click here

Kind regards,

Dear friends,

The European Medical Research Councils (EMRC) mandated the undertaking of a foresight study on ‘Investigator- Driven Clinical Trials’ (IDCT). This project marks the most comprehensive examination and analysis of the issue in Europe and proposes particular steps towards better clinical research in Europe. Investigator-driven clinical trials - trials instigated by academic researchers aimed at acquiring scientific knowledge and evidence to improve patient care – deal with potential diagnostic and therapeutic innovations that do not attract or could be even against commercial interest.