The Star Online: Lifestyle: Health
The Star Online: Lifestyle: Health |
| Volunteering for clinical trials Posted: 04 May 2013 08:48 PM PDT It takes courage to volunteer your own body to help try out an unproven medical treatment. IT began innocuously enough with a dry cough. But it was a stubborn cough that just wouldn't go away, despite being bombarded with a few rounds of antibiotics. So, the doctor advised English teacher S. Kamakshi to go for some blood tests to check for infectious diseases. But it wasn't an infection that turned out to be the culprit; it was something far more dreaded. A full blood count revealed that the then 44-year-old had an unusually high number of white blood cells floating around in her system. This immediately triggered an alarm, and she was sent off to the hospital to do a bone marrow aspiration – a procedure where a needle is inserted into the pelvic or breast bone to obtain samples of bone marrow fluid in order to examine it under the microscope. That test confirmed her diagnosis; it was leukaemia, more specifically, chronic myeloid leukaemia (CML). Chromosome crossover Also known as chronic myelogenous leukaemia, this relatively rare condition is a cancer of the white blood cells that usually occurs in adults. It is caused by a chromosomal abnormality that develops in the blood cells after birth, meaning that it is not an inheritable disorder. Humans have 23 pairs of chromosomes containing all the genetic information that make up our very complex bodies. In about 90% of CML patients, a part of the chromosome 9 in their blood cells gets swapped with a part of the chromosome 22. (See Gene swap) It is this modified chromosome 22 that is the trouble-maker. Also called the Philadelphia chromosome after the American city it was discovered in, the rearrangement of genetic material due to this exchange creates a new gene called BCR-ABL. This gene causes over-production of a protein called tyrosine kinase, which in turn, stimulates the continuous and rapid division of certain white blood cells called granulocytes. All our blood cells, whether red blood cells, white blood cells or platelets, are produced in the bone marrow – the spongy material located inside our bones, and all originate from a single type of blood stem cell. This blood stem cell can differentiate into myeloid stem cells and lymphoid stem cells. The myeloid stem cells further differentiate into red blood cells, platelets and the white blood cells known as granulocytes. (See Blood cell genesis) The granulocytes produced in CML patients are abnormal and cannot function properly. Because of their continuous production rate, they also crowd out other blood cells and damage the bone marrow. As CML is a slowly progressing disease and the symptoms are so general, many patients can have the illness for years before being diagnosed. Resistant to treatment At the time of Kamakshi's diagnosis in 1992, only three in 10 CML patients were expected to still be alive five years after their diagnosis. But Kamakshi was unaware of this statistic. She says: "At that time, I didn't know the seriousness of it. I just took it as an illness." She adds that she just trusted her specialist, having faith that he would know what would be best for her. As per standard treatment at that time, she was put on hydroxyurea. However, the chemotherapy drug only worked for a short time. She was then prescribed busulfan – another chemotherapy drug commonly used to treat CML. But that too proved ineffective for her. Her doctor subsequently put her on the immunotherapy drug interferon-alpha, while also suggesting that they consider a bone marrow transplant, due to her poor response to the first two drugs. Her husband, H. Subramaniam, says: "So, we did the HLA-matching (to find a suitable donor). We contacted all our siblings and family members, including those in India. We basically called the whole village!" However, despite testing 20 to 30 samples from her relatives, no match could be found for Kamakshi. The next best option was an autologous transplant. This involves harvesting healthy stem cells from the patient's own bone marrow in order to put them back in after the existing bone marrow with the cancer cells is destroyed through chemotherapy, and sometimes, radiation. As Subramaniam, a Star Online sub-editor, explains: "In case interferon didn't work, we wanted an alternative in case the leukaemia got worse." As autologous transplants were not available in Malaysia or Singapore in 1994, they went to St Vincent's Public Hospital in Sydney, Australia. There, they stayed for about three weeks as Kamakshi's healthy stem cells were harvested through a machine, then stored in liquid hydrogen for future use. Subramaniam shares: "About four to five years ago, she was very ill, so her doctors said that they may have to consider doing the transplant. "They asked St Vincent's if they still had her stem cells, and they said yes, they were still keeping them." He muses: "We only paid AUD50 (RM157) one time, and they are still keeping it for us." Fortunately however, after returning from Sydney, Kamakshi's condition improved significantly with the interferon. Becoming a 'guinea pig' She remained on interferon for over six years, from 1994 to 2000. However, by 2000, the interferon was starting to lose its effectiveness, although it was still able to control the leukaemia. At this time, Kamakshi was informed by her doctor that there was a clinical trial recruiting patients for a new drug for CML called imatinib in Singapore. She decided to volunteer for it, despite the fact that she and her husband would have to go to Singapore regularly for the required check-ups on their own expense. There were a couple of practical reasons for their decision. Firstly, interferon was then delivered in a syringe and had to be transported in ice, which was troublesome as Kamakshi frequently followed Subramaniam – then a reporter with the Associated Press – on his international trips. Secondly, they were worried about the lack of alternative drugs available for Kamakshi, should the interferon completely lose its efficacy on her. But they also had a more idealistic point-of-view; as Subramaniam put it: "When they asked us why we wanted to go (for the trial) when the interferon was still working, we said that if no one wants to try, then how will medicine progress?" As it turned out, imatinib was to be a game-changer in the treatment of CMl, and indeed, other types of cancers. The international, multi-centre Phase II clinical trial Kamakshi participated in was one of three similar trials that convinced the United States Food and Drug Administration (FDA) to fast-track the approval of imatinib for public use. In fact, imatinib holds the record for one of the fastest drugs ever approved by the FDA. From an initial 30% five-year survival rate, now around 90% of CMl patients are expected to make it to five years after diagnosis with the aid of tyrosine kinase inhibitors (TKI) like imatinib. While Kamakshi initially did quite well on the oral drug, with only an initial fever at night as a side effect, she eventually lapsed into the accelerated phase of the illness about seven months after the end of the trial in 2002. She had to go for three rounds of chemotherapy to clear it up, before going back onto imatinib. Trial after trial Five years later, Kamakshi suffered another setback. Subramaniam shares: "They found her bone marrow cells had mutated, which was why (imatinib) stopped working. Her white blood cell counts started going up." And worse, she had acquired a particularly resistant mutation known as T315I. In addition, she had been diagnosed with Parkinson's disease – a chronic motor degenerative disorder, earlier that year. At first, Kamakshi decided to volunteer for the AMN107 clinical trial in Singapore. Known as nilotinib, this TKI is more potent than imatinib and works on various mutations of the BCR-ABL gene. However, she did not fit the criteria for the trial. Her Singaporean haematologist, senior consultant Dr Charles Chuah, then suggested she try out for the MK0457 clinical trial. However, this proved to be logistically difficult, as they would have had to relocate to Singapore for the duration of the trial. This is because MK0457, which was proven in pre-clinical tests and a phase I/II trial to be effective against the T315I mutation, had to be administered continuously intravenously via a body pump. In case of any problems, Kamakshi had to be within easy reach of Singapore General Hospital, which was running the trial. This method of administration proved to be generally problematic, and resulted in Merck – the pharmaceutical company developing the drug – eventually abandoning the clinical trial, according to Subramaniam. "My (imatinib) dosage was increased after the Merck trial didn't work out, but it still didn't improve my condition," says Kamakshi. Her doctors suggested that she might want to go abroad to seek more medical opinions. The couple decided to go to McMaster University Medical Centre in Ontario, Canada, as their nephew was studying medicine there and Subramaniam's sister resided there. They consulted haematologist Dr Parveen Wasi, who suggested that Kamakshi go back on interferon. Says Subramaniam: "After the tests, etc, Dr Wasi said that after the mutation, the cells might have forgotten how to 'fight' interferon. So, we came back here and went back on interferon, and it worked." The bad and the good But after nine months on interferon, Kamakshi's condition worsened again, and she had to revert to hydroxyurea to help control the white blood cells. "Then, the doctors said there was a new trial," she says. This was for a new injectable drug called homoharringtonine (HHT), also known as omacetaxine mepesuccinate. Initially designated as CGX-635, the drug's phase II clinical trial was specifically indicated for patients who had failed previous imatinib therapy and had the T315I gene mutation. It was on this trial that Kamakshi experienced quite disturbing side effects. Subramaniam shares: "One of the effects was that she lost her teeth – they became completely brittle and broke off easily, and her skin looked terrible, like she had a skin disease." However, he adds: "Before starting the trial, we were already told that the side effects might include fever, dry skin and other problems, so we weren't shocked or surprised when it happened." He speculates that Kamakshi's body might have gotten used to the drug, because the severity of the side effects eventually lessened over time, and with the help of some Ayurvedic massage and cream for her skin. She remained in the HHT trial for over two years before dropping out to join another new clinical trial in January 2011. "HHT was working, but the side effects were horrible, and it was an injection," Subramaniam explains. "The new trial was a (oral) drug." He adds that the doctors had also mentioned that there were signs of HHT starting to loose its efficacy on Kamakshi by that time. The new phase II trial called Pace, which tested the drug called ponatinib, proved to be the jackpot for Kamakshi. Specifically designed to inhibit the activity of the BCR-ABL gene and its various mutations, including the highly-resistant T315l mutation, ponatinib successfully decreased her white blood count within three months. By the end of that year, there were no longer any traces of the Philadelphia chromosome in her bone marrow or blood cells, and by April 2012, even the amount of BCR-ABL gene activity had dropped beyond detectable traces. "At first, I was taking three pills, now I'm only taking one pill. My leukaemia is under total control," says Kamakshi happily. In fact, Subramaniam shares that if there was a clinical trial to test new drugs for Parkinson's disease, they would be willing to participate in it. "We feel that if there is some way we can help, we should help," says Kamakshi. "And if the doctor feels we will benefit, then I would volunteer again." 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| Posted: 04 May 2013 08:48 PM PDT CLINICAL trials are an essential component of medical science. Without them, we would not be able to know definitively, whether or not a particular drug or treatment, screening technique or preventive method, works as we expect it to in humans. Because while laboratory and animal tests are a useful precursor to establishing the mechanisms and efficacy of a particular drug, you never know how it might actually react in the complex human body. According to the World Health Organization, a clinical trial is defined as "any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes". Due to the high costs of running a clinical trial, which can go up to millions of US dollars, most trials are financed and run by major pharmaceutical companies. The process of developing a new drug usually starts in the molecule "library" of these companies. These unique molecules have different properties, which may lend themselves to treating or diagnosing various diseases. Based on initial research results, scientists will then further explore the safety, efficacy and bioavailability (the proportion of the molecule that actually reaches the targeted cells in the body) of the molecule via laboratory and animal studies. If the molecule proves successful in these initial stages, then the next step is testing in humans. This is done in clinical trials, which are divided into four phases: I, II, III and IV. In phase I, the drug is tested on a few healthy volunteers in order to evaluate its safety in humans, determine the dosage range, and to observe any side effects. If the drug proves to be safe, then it is moved on to phase II to see if it can actually treat the disease it is targeted at. At this stage, the number of trial participants is increased, and consist of patients with the condition the new drug is meant to affect. Phase III involves thousands of patients, and is frequently expanded to include several medical centres across different countries. During this phase, the new drug is compared to either the current standard treatment or a placebo, to see if it provides a statistically significant improvement over either the standard treatment or the placebo. Running the trial simultaneously in several countries allows the drug to be tested on different ethnic populations, more patients to be recruited more quickly, decreased operational costs by including developing countries in the trial, and allowing potential life-saving therapy to a wider patient population. Factors that affect the choosing of international trial sites include the type of medical infrastructure and regulations present, the size of the potential market for the drug in that country, the medical expertise available, and the willingness of local specialists to carry out the trial, among others. Phase IV, also known as post-marketing surveillance, is when the product has already been made available to the public. Among the areas monitored in this phase are long-term side effects of the drug and its interaction with other drugs or products for patients on multiple medications. Ethics and volunteers Because of the potential danger in introducing a new chemical substance or mechanical device into humans, clinical trials must undergo stringent regulatory and ethical approval procedures. Medical and research centres usually have their own ethics committee that examines and approves or rejects any applications to run clinical trials in their centre. Many countries also have laws and/or government agencies that regulate such trials within their own borders. On an international level, pharmaceutical companies usually seek the approval of the United States Food and Drug Administration (FDA) and/or the European Medicines Agency – the two most influential drug regulatory agencies in the world. Researchers themselves are also supposed to be ethically governed by the Declaration of Helsinki, which is "a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data" developed by the World Medical Association, and the Nuremberg Code, a set of medical research principles that grew out of the World War II Nazi experimentation on Jews and other minorities. One of the essential practices in recruiting patients for a clinical trial is informed consent, which means that the patient needs to be told both the potential benefits and risks of the drug, the details of the study, and any potential side effects. Patients are usually not paid for their participation, although they generally receive free healthcare for their condition while in the trial, and may receive reimbursement for things like transportation and food. While many might view testing out an unproven product in your own body as being too risky and scary, chronic myeloid leukaemia patient S. Kamakshi feels that patients should help medical science when they can. As her husband H. Subramaniam says: "Our thinking is that the drug companies want FDA approval to market their product; if they are not very sure after testing on animals, they wouldn't move onto humans." As Kamakshi's Singaporean haematologist, senior consultant Dr Charles Chuah from Singapore General Hospital, says: ""Medical discoveries do not happen by chance. Through clinical trials like the ones that Madam Kamakshi had participated in, we learn how to diagnose, treat, cure or prevent diseases. "For patients who do not respond to any forms of treatment, participating in a clinical trial gives them renewed hope as they will be given new treatment that may not be available in the market. "These trials are conducted in many hospitals around the world. Our participation in trials is important. Not only do patients benefit from new treatment, but we are also able to determine if the new treatment is safe and effective in our local population." He adds: "Observations that trial patients share are useful. They help us manage their condition and enhance our understanding of side effects that other patients in the trial may have. "Through inspiring patients like Madam Kamakshi who participate in clinical trials, we have learnt and benefited tremendously to advance medical and scientific knowledge, and most importantly, to help other patients in the future." Related Stories: |
| Posted: 04 May 2013 08:49 PM PDT Those interested in ongoing and past clinical trials can refer to the following two websites: ·clinicaltrial.gov maintained by the US National Library of Medicine at the government-run National Institutes of Health, which currently contains 144,546 study records from 186 countries; more suitable for medical professionals. ·myclinicaltriallocator.com recently founded by American Dr Bruce Moskowitz as a non-profit endeavour, which currently contains 141,923 trials from around the world; aimed at connecting potential trial volunteers with researchers. Related Stories: |
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