Doctor’s actions play an integral part in Pharmaregulations & at times even credible regulations may become ineffective - Marisa De Andrade


CBEC Conference on Emerging Ethical Issues

Doctor’s actions play an integral part in
Pharmaregulations and at times even credible
regulations may become ineffective-Marisa De Andrade

Currently out of 156031 clinical trials, 2724 were being
conducted in South Asia- Ms Sandhya Srinivasan

We do need CROs in Pakistan but are concerned
with the ethical issues - Dr.Rana Muzzafar

KARACHI: A number of important topics related to emerging ethical issues were discussed by various speakers from Pakistan and overseas at the two day international conference organized by Center for Bioethics and Culture (CBEC) at SIUT from December 6-7th 2013 partly reported in our last issue. Ms Marisa De Andrade in his presentation talked about Big Pharma and the Transnational Corporate Physicians: Ethical Dilemmas in the Global Arena. A journalist by profession she pointed out that GSK was fined 3B US dollars (Three Billion US$) for concealing hazards of Avandia. The drug was reported to have 30% increase in heart attacks. If antidepressants are used early in pregnancy by the pregnant women, there is three times more likelihood of the children developing autism. Now she is working in a Business Management School. Referring to the Corporate Social Responsibilities of the big business, she referred to the voluntary codes of ethics and regulations and then talked about the Pharma business and their relationship with corporate physicians. Many doctors, she said, do not disclose that they are being paid by the industry. While getting their manuscripts published, some do not disclose about their funding source.
Continuing Ms Marisa Andrade said that doctor’s actions play an integral part in Pharma regulations. Even rules and regulations can be broken up if they do exist and at times even credible regulations may become ineffective. Pharma industry is always keen to win heart and mind of the physicians to increase their sales. Tobacco industry and Pharma industry are both similar in many ways and use similar marketing techniques. The tobacco industry is now coming up with reduced risk products and e cigarettes are going through Pharma licensing in UK. They are likely to be registered as Medicine in UK. Tobacco regulations are being undermined. Tobacco industry is now working with doctors as well as public health community and they are seen sitting at policy making tables, she added.
Ms Sandhya Srinivasan form Bombay India an investigative journalist and health advocate discussed ethical concerns regarding outsourcing clinical trials in developing countries. It all happens through collaboration between Pharma industry, NGOs and government authorities. Referring to the public health trials, she talked about testing VIA for cervical cancer. She wondered that even if this is proved to be safe and effective, it is very expensive and may not be available in India at affordable price, hence what is the benefit of conducing this trial in India. Referring to different phases of drug trials, she stated that in Phase-1 drug is tested in healthy human subjects. In Phase-II it is tested in diseased people to find out its efficacy. In Phase-III the drug is tested in a larger population to compare its safety and efficacy compared to an outstanding drug while Phase-IV consists of post marketing trials.
Government of India policy, she said was to encourage drugs trails in the country. Until 2005, Phase-I trials were not allowed in India only Phase-II and III trials had to be repeated. Later the Government amended the relevant Act and now Resperidone was being tested at seven centers for acute manic episodes for registration of this drug in USA. These are the only Resperidone trials being conducted in acute mania. The advantage of conducting trials in India is the lost cost, easy availability of manic population with acute and chronic disease. These CROs are also being provided incentives like tax exemptions while they also get quick IRB approvals. Giving details of the clinical trials she said that out of 156031 clinical trials, 2724 were being conducted in South Asia. This includes 2331 in India, 235 in Pakistan, 162 in Bangladesh, 35 in Nepal. Clinical trials started in India in July 2007 and it became compulsory in 2009. Out of 670 trials, 456 are being sponsored by big Pharma including 292 being sponsored by foreign companies. Again 125 out these 670 trials are on cancer drugs, one hundred ninety are placebo control trials while 477 out of 670 are Phase-III and IV trials. The major focus of these trials is on expensive cancer drugs which eventually do not become available in India at affordable prices. Placebo trials put people at harm by depriving them of effective drugs. Health systems and doctors in these countries are willing collaborators for these trials. We have unregulated healthcare and doctors oppose any regulations. One of the infants with cardiac condition died during these trials. There are reports that Bhopal Gas survivors have been enrolled in clinical trials with their consent. Government hospital doctors are reported to have earned about five crore rupees from seventy six trials which recruited three thousand patients. Some of the hospitals in India are accused to be sponsoring trials without IRB approval. These CROs offer incentives to government hospitals for recruitment of patients as they get 15% of the budgeted expenditures. In addition these hospitals also get equipment and salaries of the investigators. It also offers the advantage of offering travel overseas to attend various conferences. It is important to find out that if the physicians and investigators have some conflict of interest. The recruitment incentives are also offered to private hospitals and these healthcare facilities are paid from sixty thousand to one hundred twenty thousand rupees per patient which is a lot of money. Primary healthcare physicians are also involved in this and they refer patients to the principal investigator for recruitment in these drug trials. In once case 21% of the patients were referred by the primary healthcare physicians and in 75% of cases primary physician was also the Principal Investigator. Physicians promote trials for treatment as it offers free treatment in private hospitals. An investigation of forty two drugs out of 2167 approved in November 2010 showed that in many cases data was missing, some of the drugs had been withdrawn from the country of their origin. The Parliamentary Committee was conducting the investigations in these cases.
Continuing Sandhya Srinivasan said that one hundred fifty seven clinical trials have been stopped in India for scrutiny after order by the Supreme Court. Independent Ethics Committees, she said were essential. So far they have noted 14,616 Adverse Drug Reactions which includes 2644 deaths, eighty were related to the trials and forty relatives of the victims have so far been provided compensation. It is media, politicians, advocacy organizations, researchers, doctors and the courts all have to play their role to ensure safety of patient, she added.
Dr. Rana Muzzafar from SIUT Pakistan spoke on Contract Research Organizations. She pointed out that CROs are for profit organizations and they conduct research in less time and at less cost. These CROs had a budget of 218 Billion dollars in 2013. At present 44% of drug trials are being conducted outside USA, 41% in USA. Research and Development budget of US based companies in 2008 was 47.4 Billion US dollars. Currently 50% of trials are outsourced to CROs which provide these services at a much lower cost. To save cost, the drug trials are conducted in low cost countries. There has been a boom of CRO industry in Brazil, India, China, and USSR which have large populations because multinational pharmaceutical companies find it difficult to recruit patients for these trials in the developed world. Currently there are 369 CROs working in Seoul, 202 in Taipi, 154 in Hong Kong, 102 in Bangkok. CROs wish to conduct trials in Pakistan because we have competent physicians who can conduct these trials; we have a large English speaking population of physicians. Trade Development Authority of Pakistan has also recommended that CROs should be allowed to function in Pakistan and provide incentives. Currently eight CROs are working in Pakistan. We do need these CROs but we are concerned with the ethical issues Dr. Rana Muzzafar stated. India has over one hundred CROS of which thirty are well established international CROs. We have a corrupt healthcare system, poor regulations with no proper inspection; ethical oversight inspection of these institutions is very poor. As such we need to safeguard our population since many clinical trials are currently being done in Pakistan, she added.
In the afternoon session Maryam Hassan from SKMT Lahore made a presentation on genetic screening and discussed at length the human aspects of this technology, genetic diseases and its human understanding. She talked about the genetic research being carried out at Shaukat Khanum Cancer Hospital Lahore to understand its impact. It is not possible to understand every thing about genetics because it was a very vast fluid field. Gene identification and hereditary disorders can lead to differences in Wirasat which is a very sensitive issue. Genetic testing, she said, is very different from screening as it is one of the subsets of genetics. Speaking about diagnosis and classification of genetic diseases she said that identity is unaffected by careers of defective genes. One should detect a serious genetic disease before symptoms appear. She also talked about reproduction genetic testing and said that it is less invasive, requires blood or tissue sample. It gives those affected control over their life decisions. Speaking abut Huntington disease she said that facilities for genetic testing are available. Death occurs ten to thirty years after its onset. At present no treatment or preventive strategy exists for this disorder. As regards genetic breast testing, 10% cancers are hereditary. Tests for these genes Braca-2 pedigree are available. Risk is variable. The information received is not always helpful for the patient. Premature removal of both ovaries and both breasts is not a viable option for most of the patients.
Part-II of her presentation was about ethical issues in genetic testing. Informed consent in genetic testing is important and in children and adolescents, they must have the decision-making capacity. She also discussed the impact of predictive testing for late onset of disorders. The impact of life decisions she said, has greater significance for the patients. Telling affected side of the family not to marry can save the future generations but one has to follow professional ethics while doing genetic counseling. She also talked about pre and post test counseling, communicating problematic risk information, premature bilateral removal of ovaries and breasts. Some of the important problems in this area include genetic testing for diagnosis, research, their ethical review, commercialization, access and how access to these expensive tests will be possible in Pakistan? These are some of the issues which need to be discussed and decided. During the discussion increased awareness about the diseases, spirituality and religious coping mechanism, neglecting their children and family which are the main concerns were highlighted.
Ms. Natasha Anwar molecular biologist from Lahore talked about Copying, Editing and plagiarizing the Human Genome. She gave details of the Human Genome project and what they are doing with the information they get, what are its implications besides the concerns which exist in genetic research. She pointed out that there are three billion Bases of DNA, twenty to twenty five thousand genomes, twenty four thousand chromosomes and twenty amino acids. The four letters it contains is the language of life. Genetic information is personal and defines an individual. It is permanent and one cannot change it. It has a predictive value provides relative risk of disease but it was not confirmative. It can be prejudicial, discrimination and once this information is known, no one will employ you and the insurance premium will also go up. There are family concerns as family matters. Human Genome is like Pandora’s Box. We use it for diagnostic purposes, it is predictive. It is used for screening, selection of population as careers. As regards pharmacogenetics, one can have individualized personalized medicine. Drugs, she stated, has no morality, it is neither good nor bad but how you use it determines its true nature. Reading and understanding, she pointed out, are two different things. She also talked about fears associated with genetic research, ethics and genomics survey and referred to the advertisements of 23 and MeStore Home DNA the journey through your DNA and then remarked that one has to see whether these tests are reliable. FDA did issue notice to some of these companies. Genetic health professionals are not confident in interpreting their results. In 2002 a ban was put on human cloning. She then discussed in detail reproductive and therapeutic cloning, genetic selection and the designer babies. Basic requirement for CCB is the sperm donor. One can correct and remove the bad genes by editing the genes. Gene therapy can be used for therapeutic purposes through genetic engineering and having super humans by gene therapy may be a possibility.
Speaking about the future of therapeutic cloning Ms Natasha Anwar said that human genes cannot be patented but synthetic versions of genes can be patented. There is no clinical input in the studies being done in Pakistan as it is only an academic work. Genetic research is good and important as we can prevent some diseases but the question arises who should decide and what do we research, she asked? Who will protect data and who will regulate it are some of the questions which need to be looked into, she concluded. During the discussion, Prof. Anwar Siddiqui stated, genetic research was being done in agriculture and there are no labs and no pathologists there. Prof.Farhat Moazam remarked that DNA is always secondary evidence in rape cases as the witnesses are the primary evidence. It is often and can be much more important when you have no primary evidence, she added.
Dr. Jamshed Akhtar Paediatric Surgeon from NICH was the next speaker who talked about ethical issues involved in biobanking. He discussed the issues related to personalized medicine, molecular medicine, pubic perspectives, fears and expectations. It could lead to potential harm to people in future. One needs to look at how these biobanks are functioning. They collect specimens of human fluids, tissues, categorize and type them, distribute them. These are the biospecimens in human banks. There are multisite biobanks and it poses lot of challenges for the future. He was of the view that people should have a right to know where their specimens are going and what they are doing with it. Genetic human material provides information for the family. It can pose legal and regulation challenges and Ethics Committees cannot be expected to perform the Policeman’s role. We all should be aware what is happening. We need a national policy on Genome therapy and biobanking.
On December 7th Day- two of the conference Prof. Anwar Naqvi from SIUT was the first speaker who gave a regional perspective of organ transplantation. Speaking about the global activity he pointed out that as per 2011 figures the number of organ transplants being performed globally every year was as under:

Global organ transplants (2011)

1. Kidneys 76,118
2. Liver 23,721
3. Hearts 5741
4. Lungs 4278
5. Pancreas 2564
6. Small bowel 209

Almost 50% of kidney transplants and 20% liver transplants are from live donors. The concept of deceased donation is essential for any transplant programme. He gave the following figures related to global transplants in various regions:

Global Transplants

1. AMRO region 46.6%
2. EMRO region 13.1%
3. SEARO region 4.1%
4. WPRO region 8.3%
5. AFRO region 1%

China, Prof. Anwar Naqvi said is the second largest and Japan 4th largest economy of the world but they have few transplant programmes. There is very little deceased donor programme in the developing world and most of the kidney transplants are through live donors. Eleven countries in the developing world do liver transplants and most of them are living donations. As regards the emerging economies, sixteen out of thirty nine are doing transplants in Asia. He laid emphasis that we need to start convincing people, put our head and heart together if we wish to improve our transplant programmes. There are religious and social issues involved and we have to tackle them only then transplant programme will flourish, he added.
Speaking about the impediments in transplant he mentioned economic reasons and religious issues. It is argued that Islamic laws prohibit mutilating the human body. Man is trustee of God and we must respect the dead body. He was of the view that there is a need for a dialogue between the Ulemas and religious schools of Pakistan and Iran as well as Saudi Arabia. In Iran and Saudi Arabia, brain death is allowed. There are cultural influences on organ donation and the issue of brain death is unclear and confusing for some. In USA twenty million people have got donor cards. In Pakistan organ donor card could be extremely helpful. ID card can contain this information but we cannot force people to donate. Commercialization has to be kept away from the transplant programmes. It stated in a big way in India and brought a bad name to the country and the transplant programme as well. Dr. Anwar Naqvi also disclosed that SIUT was following up 2500 donors. Studies revealed that after donation 50% suffered from anxiety and hopelessness, depression was seen in 51% and suicidal tendencies were observed in 6%. There are social problems as well as donors become ill. Commercialization of transplant programme injures the trust in the medical profession and it also has negative effects on deceased donation. In Iran government of Iran subsidies the transplant programmes. Prof.Malik Al-Hussani in Shiraz is running a very successful liver transplant programme. At SIUT we will be doing about 450 kidney transplants this year in 2013.Therer are 29 centers doing kidney transplants in Pakistan and 54% of kidney transplants in Pakistan are being performed at SIUT. He also referred to deceased donation programme in Chennai India and Thailand. Prof.Anwar Naqvi concluded his presentation by emphasizing that preventing chronic kidney disease and chronic liver disease is the key and we should all strive for that.
During the discussion Prof. Anwar Naqvi stated that dialysis is an option and we have patients on dialysis for thirty years. Buying kidney for transplant is not good, we need deceased donor programme to save lives. Dr.Amir Jafary said that if window of purchase is available, donation will not progress. Mr.Shaukat Ali Jawaid pointed out that brain death has to be declared and certified by a team of healthcare professionals and until they put up some mechanism of self monitoring and accountability, public will not have faith in the doctors who can declare a patient brain dead. Dr. Anwar Naqvi stated that refusal rate to donate kidney at SIUT has considerably reduced.
Prof. Farhat Moazam’s presentation was on public perceptions about deceased donation. She highlighted the findings from a study they had conducted which included 113 patients of which 105 were Muslims. It consisted of twenty two questions and the face to face interview lasted from thirty to forty minutes. Seventy seven did not share their position while 41 did not know that taking organs was possible. Twenty were illiterate while the rest were educated. The feelings expressed were that Islam does not allow it, Body is an Amanat of God, deceased body must be respected, and pain and suffering to the body is not permitted. Some said family consent was also essential. If need be, 73 said, they will buy kidney and only thirteen knew about the transplant laws.
Prof. Farhat Moazam was of the view that we do need deceased donor programme; related donor alone is insufficient to meet the needs. There is reluctance on the part of the family and the potential donors. Risk exists of harming the living donors. We need to take the public on board. The slogans like Gift of Life will not work but if we use the Word Sadqai Jaria, it will work, she added.
Ms. Sandhya Srinivasan from India gave details of the Tamil Nadu model of deceased donor transplant programme. She pointed out that China has 71.2% deceased donation of organs, USA 64.3% while in India it was only 5.1%.She highlighted the importance of ethical medical practice and upholding ethics in healthcare. Provision of health, she stated, should be responsibility of the government while private sector needs to be regulated. Distrust of private doctors does exist because there have been instances where doctors were coercing people to donate their organs and medical profession was also involved in criminal practices. Transplant of Human Organ Act 1994 banned trade in organs. The law clearly states who can donate organs like siblings, parents, child and spouse etc. Almost 70% of Road Traffic Accidents victims are brain dead and they are a potential source of donation. Those brought dead to hospital needs to be identified. We need to have trained consultants who can then approach the family for their consent to donate organs while the hospitals and specialists must have the facilities to be able to maintain brain dead.
Tamil Nadu which was once the capital of Indian Transplant Trade today has a deceased donor transplant programme. This started in 2008 after series of organ trade scandals. From October 2008 to October 2013, the programme has registered 418 deceased donors. It is important to submit records of transplants performed, makes charges public and how brain death will be certified. There is collaboration between government, NGOs and Hospitals. Transplant surgeons working in private hospitals are consulted. ICU staff is fully trained to identify brain death patients. Trained counseling, she opined, can increase consent percentage. When the government runs such a programme it is more trusted as they have no profit motive. Five to six states in India started government sponsored transplant programmes but only Tamil Nadu model is a success. Distrust of the medical profession is a major problem. She was of the view that doctors may charge for these transplants but they must make it public. Four Chennai hospitals provide over 70% organs for transplants. Hospitals share only one kidney and the remaining is used by hospital priority over city waiting list. Sometimes doctors are hesitant to declare brain death because they fear being accused by the relatives. One does not see the agents in the hospitals any more and the Tamil Nadu model is working successfully. Almost 90% of Indians, she said, cannot afford dialysis which cost over ten thousand rupees per month hence prevention of kidney diseases is the only answer, she remarked.
During the discussion it was pointed out that the donor hospitals and the transplant teams have to be different and there should be some coordinator working between these two. Private hospitals, it was, said are more likely to have donors but the transplant cost is very high.
Dr. Amir Jafarey from SIUT was the last speaker in the session who discussed donation after cardiac death. He pointed out that there were five deceased donations at SIUT and they were all brain dead from Pakistan. He discussed at length taking organs from new born dead, from permanently unconscious patients, patients in vegetative state, donation from euthanized, cloning of organs and xenon transplantation. He was of the view that we have to rely on the dead at present as it was the only way forward. We have to define death. He also referred to the Harvard Commission on Brain Death rule which relates to irreversible damage of brain. Dead heart can become alive. He also talked about neurologically determined death and said that people have changed the dead donor rule as heart beating donor is an ideal donor. There are four categories of Non Heart Beating Donors which are dead on arrival, awaiting cardiac arrest, cardiac arrest and cardiac arrest in brain stem death. Speaking about the ethical issues in NHBD, he said, that we are told to fight on but accept futility. Do more is doing more harm to the patient. The waiting time for harvesting the organ for donation is between 75 seconds to ten minutes. Need for transplants are pushing boundaries .Whether the doctors are life takers or life savers. These issues will have to be taken up and it is a very slippery situation. Organs with ischaemic injury are useless for the recipient, he added.

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