Basic and Clinical Research improves Health Outcome-Prof. Herbert Lyerly

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Proceedings of Clinical Trials Symposium at AKUH

Basic and Clinical Research improves
Health Outcome - Prof. Herbert Lyerly

Developing new drugs takes about 7-8 Years
and it may cost up to US$ 2 Billion

KARACHI: Prof. Herbert Kim Lyerly Prof. of Surgery from Duke University, USA was the Keynote speaker in the inaugural session of the recently held Clinical Trials Symposium organized by Aga Khan University Hospital. Making a presentation through Video link, Prof. Lyerly said that in the Year 2005 total deaths were 58.2 million of which deaths from Non-Communicable Diseases (NCD) accounted for 35.7 million. Studies show that deaths due to NCD are continuously increasing. The prevalence of stroke and COPD has increased and now Lower Respiratory Infections are on the top of the list. He was of the view that basic and clinical research does improve the overall health outcome.
In United States deaths from HIV, AIDS have reduced significantly. This decrease started in 1992. The numbers of deaths which have been prevented due to coronary heart diseases are 815,000 and the number of people dying between the ages of 30-40 years has also decreased. Giving details about the US Clinical Trials infrastructure, Prof. Lyerly said that it is sponsored either by the CROs or by the Government. There is a vaccine studies dedicated infrastructure for clinical research and cancer cooperative groups who spend between 200-250 Million US$ annually. About 3% of cancer patients are registered in US cancer trials which are being performed at large cancer centers. HBV and HCV are the causative agents for cancer in 24.8% of cases, HPV accounts for another 27.9% besides EBV and other infections. Interventions have reduced both incidence and mortality due to cervical cancer tremendously just like reduction in heart diseases.
Developing a new drug, Prof. Lyerly said takes many years. Understanding the diseases takes many years and the whole process of drug development is long and expensive. Clinical trials are conducted for seven to eight years before the FDA approves any new drug and it may cost between 1.5 to two billion dollars. Now we can screen patients worldwide for genetic changes in tumours. There are genetically informed clinical trials but we have to screen many more patients to see dramatic results. As regards priorities for research, he laid emphasis on vaccines for serious diseases, treating hypertension, new therapy for early stage of cancer and advancer cancer. He opined that there are many opportunities for international collaboration in clinical trials. National and global interests can be taken into consideration but we need resources to facilitate international alliances, he remarked.

Panel Discussion

This was followed by a panel discussion and the panelists included Prof. Martin, Prof. Farhat Abbas, Prof. Saeed Hamid and Mr. Salman Burney who represented the pharmaceutical industry. The speakers emphasized that we need to improve health of our people and reduce the disease burden. We need to find local solutions. There are barriers to health research. We need to establish clinical trials infrastructure. There are a small number of academic clinical trials which are supported by the government because improving healthcare remains the State priority. Investment in high quality research does have an impact and results in improved health care.
Prof. Farhat Abbas referred to the increasing burden of NCD and reduction in infectious diseases. There is increase in the population in this region hence we will see much more NCDs with the result that total burden will continue to increase. It is estimated that by 2025, two third of cancer diseases burden will be in South East Asia. Cancer treatment is very expensive. In Pakistan longevity is increasing and it will further add to the burden of NCDs. We do not have a Cancer Registry. Policy makers and the academic, he said, should join hands because it requires a very concerted effort as we do not have the brand organization involving all the stake holders.
Mr. Salman Burney said that we have significant disease burden, hence we have opportunities. We have population, community and clinical facilities available are some of the opportunities. We have competent physicians who can conduct clinical trials and there are many companies who are keen to promote research in Pakistan. He also referred to the funds collected by the Government from the Pharma industry every year in the name of drug research but it has never been utilized. These funds should be used to build infrastructure. We do have some pockets of excellence but the challenges are the IRBs, Ethics Committees, our pipe line is dry and frequent changes in the Ministry of Health, DRAP have remained a major barrier.
Prof. Saeed Hamid opined that we have about 8% population suffering from Hepatitis B and C which makes about 16 million cases. We did take some historical steps to control infectious diseases. Despite the fact that effective treatment for HCV is available but we are not there at the international level. We do not have a strong patient database; hence we do not attract cutting edge clinical trials. We do not have database for many disease categories. Liver cancer is now second commonest global cancer and it may become No.1 cancer in the world. It is driven by Hepatitis B and C. We need to treat infectious diseases effectively to reduce cancer.
Clinical Trials, he said, is a commercial activity. We need to bring back academics in clinical trials. We do not have NGOs supporting clinical trials research while profit making by the industry has its own adverse effects.
One of the participants pointed out that there are many obstacles we face to bring clinical trials including the capability of the healthcare professionals to monitor Good Clinical Practice compliance. Capability of the regulatory authorities is a big question mark. FDA approval for any drug, it was suggested, should be considered good enough for Drug Registration. There are conditions of local trails for drug registration. One finds it difficult to talk to the senior health administrators for initiating Phase-II trials. Many of them are not interested in such research. Moreover, cost of doing research at Aga Khan University is very high. In India, there are local FDA inspectors, if we can have such people which are important to attract funding.
Participating in the discussion Prof. Farhat Abbas said that many quality clinical trials units have been established in India. For ensuring GCP compliance, we need to invest and we must invest. Education and training to develop capacity was another important issue. Mr. Ansar Sheikh from DRAP pointed out that the credibility of the submitted data is questionable. When we asked for it, data provided was not verifiable. Added to this is the professional rivalry between different groups of healthcare professionals who write contrary reports when their opinion is sought.
Dr. Iffat Yazdani from GSK pointed out that there are tremendous opportunities but we lack good interaction between industry and government authorities. Almost six billion US dollars are spent on research globally.GCP compliance is not the responsibility of MOH but sponsors and other agents. But it is important that we all audit our work. Regulatory authorities, she said, were the greatest barriers to clinical trials. A representative from CROs said that regulatory authorities did not approve any trials in the last three years. We can attract lot of funding if we start doing clinical trials. Unless the trials are approved, how can we start doing research, he asked?
Dr. Khawar Mehdi from Getz Pharma was of the view that we lack right people at the right place in Drug Regulatory Authority, units in clinical trials and in the area of pharmacovigilance. Results of trials must be published. PMRC research survey was poorly planned and fraudulently conducted. In one place the prevalence was as high as 33%. It is important that our objectives should be clear. Money can come from any source. Another participant remarked that Singapore was doing a lot in clinical trials. It is a key clinical trial provider. We should learn from the Indian experience and do not make those mistakes. It was also suggested that we should not follow the West blindly where most of the trials being conducted are related to cancer. Results of many trials are never published. Recently BMJ reported that as many as 30% of registered trials were never published. It is important that we develop our own system in reporting and ensure accountability. Dr. Aamir Jafary from CBEC said that now India has strict regulatory frame work in place, there should be distinction between the academia and the industry. There are problems in review process and GCP. However, Mr. Salman Burney opined that let us go along with the world, academia and industry should go together, academia should be involved at every stage in research.

Second Session

Dr. Huma Qureshi from PMRC was the first speaker in the second session. Speaking about ethical challenges in clinical trials in Pakistan, she referred to value, scientific validity and fair subject selection, favorable risk benefit ratio, independent review, informed consent and respect for the enrolled subjects. She also referred to the functioning of the NBC which has been rather slow because of too frequent changes in the Ministry of Health. Many institutions have formed Ethics Committees but their composition is not correct. Lot of research was being done in the country without any ethical approval. Women are mostly ordered and not asked for consent. Activities of CROs need to be regulated and evaluated. They get Pharma research done but there is no CRO Registry. Many hospitals, labs, doctors who are not approved are working for these CROs. In some cases these CROs have been sending blood samples and other tissue samples abroad without permission. Clinical trials are not published and industry gets these trials conducted through hospitals and doctors of their choice which speaks a lot for this brotherhood between the Pharma industry and the medical profession. Pharma industry representatives take away the conference participants when presentation on their competitor’s product is being made. NBC prepared the Physicians, Pharma Industry interaction guidelines which have not been implemented. Ethics needs to be taught in medical colleges and speakers at conferences should be asked to make a disclaimer, disclosure before making their presentation.
Prof. Farhat Moazam Chairperson of CBEC talked about understanding the cultural differences. To begin she remarked that she was not against technology or research. She talked about culture of the pharmaceutical industry and the shifting of moral focus in clinical trials, outsourcing of drug trials in developing countries, the Wild West of the industry and the situation of clinical trials in Pakistan. She pointed out that it was in 1960s after the Thalidomide tragedy that four phase clinical trials were started to ensure safety of the drugs. CROs say to the Pharma industry leave the trials to us. They have rapidly expanding operations all over the world and these CROs are for profit organizations. In the recent past we have seen outsourcing of clinical trials from North to South which is welcomed by the governments of these countries as it brings in investment. CROs are welcomed who bring these clinical trials to these countries but there has been a shift in the moral center during these drug trials. She also talked about the ethical variability in developing countries. There has been a recent shift in clinical trials market from the academic centers and now 90% of clinical trials are done by the Pharma companies. The West offers generous funds to establish IRBs in developing countries. In the recent past twenty Pharma companies including Pfizer, Novartis, Merck, GSK had to settle out of court cases and paid heavy fines for their involvement in unethical practices. Novartis is now being investigated in Japan for manipulation of data regarding its product Diovan. In some cases drugs tested are never made available in those countries. Many of the IRBs are just rubber stamps, she added.
Dr. Rozina Karamaliani from AKU presented case study of how informed is the informed consent. She pointed out that informed consent was a process and not just an event. Ethics has to keep a balance between the right and wrong. One needs to use reassuring confidentiality of the information being shared. When you draw the blood, tell the patient what you are going to do with this blood. Poverty, domestic violence is responsible for depression in the community. Literacy was an overactive placebo. She then talked about respect for the community, participation of the community in research and said that most often the least qualified person in the team takes the informed consent. We do not want to share the bad news. Peace and health all look towards one angle. Prof. Farhat Moazam said that IRBs should be the institution’s responsibility. She also referred to virtue ethics, virtual research i.e. Kirdar which matters a lot. Prof. Saeed Hamid remarked that we need to re-set our moral computers from time to time. Video tapes of informed consent as suggested by someone will create moral ethical issues.

Third Session

Dr. Nadeem Mustafa CEO AKUH was of the view that the patient should be at the center of the clinical trials. There should be partnership between the patients, practitioners and their families. Patient is an individual to be taken care of and not a medical condition to be treated. He also talked about access to information, healing environment, compassionate interaction. The way the care is imparted is important in caring. We have established Patient Centered Care Group and hold meetings after every fifteen days. It has lead to improvement in the behaviour. Greet, smile and Thank You is all very important. We have done some ground work for this cultural transformation. We need to engage the heart and minds of those we work with. We must allow active participation of patient and disseminate results of studies at public forums. Certain visits can be done by phone and compliance messages can be sent through text messages.
Mr. Amin Jivraj spoke about protecting the patients’ rights and said that quality of informed consent was important. Justice is seen as a balance. GCP guidelines, PMDC, PMRC have come up with some guidelines but they need to be followed. Informed consent should be properly documented and there should be adequate provision for protecting privacy, provision for monitoring and data collection. One must provide adequate information to obtain informed consent because it is just not a Form to be signed. Mrs. Shabeen Tahir who participated in a clinical trial described her personal experiences and was quite satisfied with the whole procedure which ensured her and her baby’s safety.
Dr. Omrana Pasha talked about conduct of patient centered trial in a developing country. Study question she remarked was most important, if you do not know it, do not conduct the study. Points of concern are the interventional studies. We have to ensure that the treatment intervention we are giving will be better than the available one at present. It won’t make the patient worse but whether it will make the patient better or not cannot be said with certainty. Standard of care has to be there for everyone participating in the study. She then referred to randomization procedure, eligibility criteria, study subjects, compliance, recruitment, measurement, assessment and external validity of trials. We offer twelve courses which covers all these issues in detail for the course participants. She laid emphasis on improving implementation and meeting the ethical standards, empathy based approach, patient centric approach in developing countries, pre-conception, maternal nutrition, standard of antenatal and delivery care. We have provided access on interment as informed patient will be a better participant. However, well informed patient, she said, does not reduce the responsibility of the investigator. One also has to be careful of the negative impact of information available on the internet. She concluded by saying that we do not convince people to take part in clinical trials and one should not try to convince those who have bad relationship.

Session IV

Dr. Azizunnisa Irumnaz from AKUH speaking about identifying the Gaps said that there was an enormous pool of treatment naïve patients; we have lower healthcare cost and the desired expertise, no language barriers. We have internationally trained investigators and GCP compliance facilities are available at many centers. We have noticeable clinical trial activity. So far 311 clinical trials have been conducted in Pakistan starting from 1999 but real activity started from 2005. We have amongst the lowest clinical trials per year in the region. We do register trials. Geopolitical situation is no barrier. We have regulatory infrastructure, investigators are interested and trained but all institutions are working in isolation. One does not know who is responsible for the policy. There is no national infrastructure. At times it is asked do we really have trained professionals, research curriculum and adequate resources and documentation. Many hospitals do have some research but the question arises can we get clinical trials in developing countries and can we do it better, cheaper and faster, she added.
Dr. Faisal Sultan Chief Executive of SKMT from Lahore made a presentation on challenges in clinical research at cancer center. He pointed out that Medline search showed that from 1947-2013, the total number of trials were 21,343. During 2003-2013 there was enormous increase in publications. Two hundred forty three clinical trials were registered in Pakistan. Trials fail because cancer trials have long gestation and enormous cost. There are too many cooks, site recruitment, site accreditation, desire, ability; means, dissemination, usefulness were also discussed in detail. We lack qualified trained investigators, ability to ask for funds, low quality of applications. Suggesting solutions he said that HEC has made its contribution and last year Pakistan was the fourth largest growth country as regards international publications. Solution to the problems we face lies in having structured collaboration, training, holding of research methodology workshops, statistics workshops and workshops on medical writing.
Dr. Iffat Yazdani in her presentation referred to the love and hate relationship between the physicians and the pharmaceutical industry. She opined that everything should be ethical. We must choose right sites, put emphasis on quality, CRO and Pharma are working in partnership. ASEAN countries have joined hands and established ASEAN Clinical Trials Network. KoNECT is working in Korea. She laid emphasis on global standardization; right investigators, patient recruitment, monitoring and some of these gaps have been filled. GSK has initiated three Billion Dollars risk based monitoring system. We have centralized legal resource at each site and we are moving towards the target of quality of clinical trials. India has over thirty FDA regulators. Now clinical protocols have become more complex. We must say what we do and do what we say, prove it and improve it. She also disclosed that eighteen multinational pharmaceutical companies have joined hands to improve patient safety known as TransCelerete BioPharma Inc. They have common GCP training, risk based monitoring. Most of the trials are being outsourced. CROs and Pharma industry are in partnership and CROs can do the work better and more efficiently.
In future we must work for collaboration between Pharma industry and government, look at the disease pattern in the region and work for cost effectiveness of clinical trials. Ten countries consortium of ASEAN countries are looking at clinical trials cooperation, she added.
Dr. Moghis Sheerani from AKU spoke about challenges in postgraduate medical education. He pointed out that most of the PGME is governed by CPSP while few universities also have MD, MS programmes. Research is mandatory but timeline. PGs have to follow CPSP guidelines as well as institutional guidelines which at times create problems. CPSP wants prospective data. He also talked about residency Fellowship programme at AKU. We ask our PGs to go to CPSP first and then come back. All programmes have dedicated time for research and we also provide some funding to the PGs.
Ms. Carol Ariano also from AKU discussed human resource challenges and developments in this field in Pakistan. She opined that they have overcome the challenges in AKU over the years. Writing is a challenge. We have analytical approach and during the last five years, we had 32% increases in human resource at AKU. We are better placed gender wise, we pay handsome remuneration to retain staff. We invest in those who wish to stay with us. There is a huge potential in the country and we must not lose heart, she added. During the discussion it was stated that there are more investigator initiated studies than those coming from the Pharma industry. It was also suggested that a body should be formed which should represent all the stake holders with Government of Pakistan. We should also form a Clinical Trials Advocacy Group. Dr.Faisal Sultan said that at SKMT we have scientific review and then ethical review of the research protocols. This two step slows down the process but eventually we do manage to get funds. One of the participants said that we must respect what other institutions are doing and it is not the cost but value we should look for.
During the panel discussion on Day-II, Mr. Ansar Sheikh from DRAP said that the applications received for clinical trials are deficient and we find it difficult to determine whether to process them further or not. We are taking some measures. We have shortage of staff at the federal level who can give us their input, hence we have asked the CROs to become our partner despite their commercial interests. We have started ADR reporting system at the federal level. DRAP has taken the responsibility of drug registration and clinical trials. Competitors at times use this ADRs information to start a campaign against those companies. Some clinical trials are not permitted in Pakistan but some hospitals and doctors are being used. One has to get a license to import a drug for clinical trials and mention this on the import application. Once the trial is approved, permission to import the drug is granted. Mr.Shaukat Ali Jawaid pointed out that in Pakistan Pharma industry does not like the ADRs to be reported.

Session VI

Dr. Anita Zaidi gave details of a Trial on saving newborn lives. She pointed out that Pakistan has the highest child mortality in South Asia with 52% neonatal deaths. Almost 50% of deliveries take place at home without skilled birth attendants. Most neonates with sepsis never receive any antibiotics. Infections account for 30% neonatal mortality. There are cultural issues, people do not trust hospitals, and there are communication problems, no place at the hospital for the father to stay. Mothers are not independent and hospitalization of a sick child is very expensive. Talking about rational community based management of neonatal infections she referred to expanding access to therapy to save lives. Home based antibiotic care, she opined, can reduce neonatal mortality. Pakistan has done pioneering work in pneumonia treatment. What we need is recognition and management of sepsis, oral or injectable or combination of both. The study aimed at simplified regimen of management of sepsis in young infants at first level or health care or in OPD. Infants from 0-59 days were recruited in this study. Only those where the family had refused hospital treatment were included and they must also be living in the area. Critically ill and those with congenital malformations were excluded. A total of 2780 infants were eligible for recruitment in all the three arms of the study but eventually 2453 were included. Baseline characteristics were similar in all the three arms of the study. There was lot of early onset of sepsis in all groups and high proportion of LBW babies in all arms. Failure to therapy was also similar in all the groups which were between 10-13%. There was no difference as regards hospitalization during the first week and no difference in death during the first week. She concluded that OPD treatment of antibiotics works with few injectable followed by oral antibiotics. In severe infections, high dose of Amoxicillin and Gentamycin IM works better.
Dr. Fauziah Rabbani from AKUH gave highlights of the NIGRAN project, improving the existing health infrastructure. Success or disaster, she stated, is a state of mind. Infants are born, loved and then they die before parents give them any name. Almost 99% of neonatal deaths take place in developing countries. Pakistan has stagnant, less than five particularly neonatal mortality. Diarrhoea and Pneumonia account for 50% of the neonatal deaths. It is reported that almost 50% of the Supervisors do not visit homes served by LHVs. Study will be conducted in Badin District in Sindh, 34 clusters have been identified, 17 in randomized intervention and 17 in the control arm. One hundred households will be assigned to each LHV. They will be asked to give us written feedback. We have prepared a modified Supervisory check list but the problem is that the LHVs have not got salary for the last three four months. Poverty, lack of motivation, workload and giving them due respect are some of the issues which needs to be looked into.
Dr. Faisal Sultan from SKMT was the last speaker in this session and his presentation was on development of Hospital Information System which is a Key enabler to Research. Developing Hospital Information System, he said, improves quality of healthcare and facilities for research. Many years ago medial errors accounted for being the 5th leading cause of death in USA. They started spending 2-3% of healthcare on Information Technology with the result that now the situation has improved a lot. In 2009 almost 81% of hospitals had no Electronic Health Records. That has now improved under the law. We at SKMT have developed Tests and Medication order form and it helps to order correct dose and correct tests with the result that chances of errors are reduced. We have also developed clinical decision support system which has reduced the duration of medication therapy. This reduction has been almost 60% in some cases. Pharmacy order helps the prescriber. There is a critical lab results alert automatic system. Entire SKMT data is now preserved on Electronic Health Record System. We have established the Lahore Cancer Registry with 25 centers in Punjab. We have established Clinical Research Office and will have Clinical Trials Unit soon. Scientific Review and Ethical Review both have helped us, he remarked.

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