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Medical Wonder DrugsRightly there is great upset over the drug TGN 1412 testing trials at Northwick Park hospital. The articles below help put these trials into context and explain the huge medical advances currently in hand.Martin
Frost 2006-03-25
Human guinea pigs The world's new "wonder drugs" Horror at the hospital Herceptin A drug to unclog arteries See also: Two previously healthy young men remain critically ill after a clinical trial for a new drug- TGN 1412- went tragically wrong Is this the first trial to go badly wrong? No, but disasters are still very rare thanks to the stringent rules governing testing. In Ireland, a young, healthy volunteer died in 1987. And during a 1999 drugs trial in Pennsylvania an 18-year-old died, though in that case the doctors were judged at fault. Have the rules always been stringent? No. In 1796, Edward Jenner deliberately infected a young boy with cowpox, having noticed that people with the disease seemed not to catch the far more deadly smallpox. After the boy recovered, he injected him with smallpox pus: the lad remained well and Jenncr went on to develop the vaccine which has saved billions of lives. Had Jenner done the same today, he'd have ended up in jail. But since his time the rules have got ever stricter. A key development was the publication in 1967 of Maurice Pappworth's influential Human Guinea Pigs, which laid down greater protections for volunteers. Every trial is now overseen by an independent ethics committee made up of lay people, scientists and statisticians. Guinea pigs have to give "informed consent" and the safety measures that must he in place in the event of an adverse reaction are clearly spelt out. So who does the testing on the human guinea pigs? It used to be the drug firms themselves, but now they tend to use specialist outfits such as Parexel, the American company whose clinic at Northwick Park hospital was the scene of the TGN 1412 trials. Such companies recruit volunteers, get ethical approval and have their own medical staff to apply the experimental drugs. On Parexel’s UK website they advertise for healthy male volunteers (not usually women because of potential risks to any foetus if they get pregnant). Most turn out to be students - whether from the UK, or passing through on a gap year from Australia or South Africa - in need of money. The TGN 1412 guinea pigs got about £150 a day for a commitment of around 15 days. So how do drugs get licensed? When researchers in the UK come up with an idea for a drug, they first carry out tests "in vitro" (test-tube) and "in silico" (computer programs modelling how substances react with human physiology). Some 99% of new drugs don't make it past this stage; for those that do, the company involved applies to the Home Office for a licence to carry out tests on animals, usually mice or rats. If the animals die or exhibit disturbed behaviour in the ensuing tests, the new drug is binned once again (or should be): adverse animal reactions prevent about 80% of putative treatments from moving on to the next stage - tests on humans. But to be allowed to embark on those, the drug firms must submit their animal data to the Medicines and Healthcare products Regulatory Authority (MHRA), which decides whether human trials can proceed. How do the human trials work? In three phases. In phase I (the one TGN 1412 was at) a new drug is given to a few healthy volunteers to ensure it has no serious side-effects. In phase II the drug is given to a small number of patients suffering from the condition the drug seeks to treat, with researchers looking for the right dosage levels. Phase III trials involve thousands of patients, the drug being tested against an established drug and/or placebo. Once all these hurdles have been passed, the company, armed with boxes of data, can apply for a licence. The MHRA gives the go-ahead for around 1,000 trials a year, of which around 350 are phase I trials. What went wrong in the TGN 1412 trial? There are three main possibilities being investigated by the MHRA: first, that the wrong dose of drug was given; second, that the batch was infected; third, that the drug had a reaction on the human body that could not be picked up by testing on animals. This last possibility, touted as the most likely, has major implications for the use of animal experiments. Why would the adverse effect be exclusive to humans? TGN 1412 is not a chemical product but one of a new class of "wonder drug" based on monoclonal antibodies (MABs), developed at Cambridge in research that won the 1984 Nobel Prize for Cesar Milstein and Georges Kohler. MABs are genetically engineered products with huge potential to help people with deficient immune systems: they do the work of the antibodies produced in people with healthy immune systems -namely, seeking out and destroying the germs responsible for a given infection. However, unlike traditional chemical products, MABs are specifically designed to be accepted by the human body; that's what makes it so hard for researchers to work out from animal testing what dose would be toxic to humans. TGN 1412 apparently passed its animal tests but since it was "humanised" it may have been rejected by the animal immune systems as "foreign" before it could exert its full effect. Does that let Britain's regulatory regime off the hook? Not necessarily. The reason half of all phase I trials in Europe take place in the UK, say the critics, is because the regime is laxer here. The MHRA is funded by the industry it's supposed to police, and is expected to pass judgement on trials that even specialists find hard to understand. In the case of TGN 1412, there is concern about the extraordinary rapidity with which the doses were administered (a few minutes) when best practice guidelines suggest doses should be interspersed with waits of hours, if not days, to give researchers time to study side-effects. Some scientists say that the rules governing animal testing of MABs should now be redesigned to ensure the animals involved are genetically engineered to have a human immune system. But the danger of yet tighter rules is that the drug companies will flee Europe and the US and test their medicines in the laxer regimes of developing countries. Indeed, they are already doing so in droves. MABs are already used in medicine and fall into two distinct classes: those that act to block or neutralise a human protein (the anti-cancer drug Herceptin is an example) and those that stimulate a process in the body. The blocking type is safer since if things go wrong the anlidote is to add more of the protein being blocked. TGN 1412, however, was in the more dangerous category: it was designed to stimulate the white blood cells of the immune system. The hope was it could treat a disease called B-cell chronic lymphatic leukaemia (as well as auto immune diseases such as rheumatoid arthritis and multiple sclerosis) by kicking the body's defences into action and thus mounting a more effective attack on the multiplying B-cells that cause leukaemia. Patients who would be the target of such drugs have impaired immune systems. But in the healthy guinea pigs it seems that TGN 1412 may have unleashed a chain reaction in which T cells released cytokines - messengers that control the immune system – in huge numbers causing what doctors call a "cytokine storm". "The effect on fit young men," says Robert Matthews in the Sunday Telegraph, "may have been like fitting a Porsche with a rocket motor: the result is not a better car but one ton of uncontrollable metal Raste Khan was lucky: he was given a placebo. But his six fellow "guinea pigs" at London's Northwick Park Hospital, participating in a clinical trial for TGN 1412, started to suffer horribly within five minutes of taking the anti-inflammatory drug. "It was like a vomiting bath," Khan told The Sunday Times. "Nurses had big black bin liners for them to vomit into. People were fainting and coming back to consciousness. The gentleman on my left was screaming. It was horrible." The girlfriend of Ryan Wilson (who has earned almost £60,000 from drug trials) almost fainted when she saw him in intensive care. "His head had swollen to three times its normal size," she told The Sun, "and his neck was wider than his head." Four of the six arc now out of danger but Wilson and one other are still critically ill and could be in a coma for a year. "1 was doing it for money," says Khan. "But £2,000 isn't worth your life." This raises some really worrying questions, said the Evening Standard. The maker of TGN 1412, the German company Te Genero, is one of a small clutch of bio-tech firms hunting for miracle cures: it has never produced a drug for the marker before nor carried out tests on humans. Why was it given permission to do so, and why in Britain rather than Germany? Te Genero claimed that no animals tested for the drug were adversely affected, said The Mail on Sunday, yet it turns out that at least one monkey suffered an ominous swelling of the lymph nodes. And why were the six patients given the same dose at the same time, contrary to the "best practice" advice given in the Textbook of Pharmaceutical Medicine? What bothers me, said Peter McKay in the Daily Mail; are the ads used to entice hard-up youngsters to volunteer. "You'll have plenty of free time to read or study, or relax - with digital TV, pool table, video games, DVD player and now FREE internet access!" No doubt there are warnings of the risks hidden in the small print of the consent form, but it's unlikely that many of the young volunteers bother to read them. The problem goes beyond the question of human error, said Robin McKie in The Observer. It lies in the sheer volume and complexity of modern drug cures. In the past, treatments were based on simple chemicals; today, we harness the power of living entities (e.g. bacteria) to make new medicines and, spurred by DNA discoveries, expect them to correct an ever-widening range of disabilities. TGN 1412 for example, was intended to treat rheumatoid arthritis, leukaemia and multiple sclerosis. In short, we demand "miracle" pills for every illness, said The Independent, yet refuse to accept the risks inherent in testing them. The public outcry in this case could destroy the human testing industry: volunteers are unlikely to come forward to play what now looks like "a game of biological Russian roulette". On the contrary, said Ian Sample in The Guardian. Since this well-publicised disaster, medical groups have been inundated with people wanting to sign up for drug trials. Below
is a patient guidance sheet on herceptin.
Your doctor has recommended a medication called Herceptin as
treatment for your breast cancer. This information sheet provides a
brief introduction to Herceptin and explains the common side effects
you may experience. This does not mean you will definitely get them. It
is also possible you may experience a side effect not mentioned here. WHAT IS HERCEPTIN? It is not chemotherapy or a hormone therapy. It is called a monoclonal antibody which utilises the natural immune system to kill tumour cells. Although cancers grow mainly beyond normal growth control, they are sufficiently similar to the own body’s cells to enable them to hide from the immune system (the body’s defence mechanism against “foreign” attack). There are, however, some subtle differences between cancer cells and normal cells. Some of these differences may be detected with special sensitive laboratory tests. In the case of breast cancer there may be too many copies of a cancer-causing gene called an oncogene. This oncogene called HER2 is part of a family of genes called c-erbB-2 (otherwise known as her-2/neu). Each HER2 gene results in the expression of a receptor on the surface of the cell. If the gene makes too much receptor, it is referred to as being "over expressed". Cells that over express too much of the HER2 gene can be a specific target for therapies such as Herceptin. Technology now exists to make antibodies in the laboratory called monoclonal antibodies. Specific antibodies have been made to detect and attach to the HER2 receptors. The antibody is therefore known as anti-HER2 called trastuzumab or its commercial name Herceptin. HOW HERCEPTIN WORKS? Herceptin works in a different way than standard cancer therapy, such as chemotherapy or hormone therapies. Herceptin® (Trastuzumab) is believed to function in three main ways: 1) Blocking tumour cell growth:
Herceptin binds to the HER2 (receptors)
on the tumour cell surface and this stops the receptor signalling
the cell to grow and divide.
2) Signalling of the immune system:
Certain immune system cells,
called natural killer (NK) cells, attach to Herceptin when it is bound
to the tumour cells. The NK cells then detect an abnormality, and kill
the tumour cell.
3) Working with chemotherapy:
Herceptin and chemotherapy work in
different ways, but when given together, the two drugs can form a
partnership (synergy) so kill tumour cells more effectively than either
Herceptin or chemotherapy when given alone.
WHO IS ELIGIBLE FOR HERCEPTIN? Patients must have tumours which over express the HER2 protein (see above). Herceptin is currently approved for use in patients whose cancer has spread from the breast to other sites (metastasised). It is usually given in combination with chemotherapy drugs called taxanes. It is sometimes given with other chemotherapy drugs at the discretion of the oncologist but these combinations have not yet gained regulatory approval. Herceptin can also be given on its own (monotherapy) if patients have received a taxane or anthracycline containing chemotherapy regimens previously (or cannot tolerate these drugs). For these indications the aim of treatment is not to cure, but to control specific symptoms caused by the cancer. This is otherwise known as palliative treatment. It is hoped that treatment improves the quality of life; therefore the side effects from the treatment should not outweigh the benefits of shrinking the tumour. There is now emerging evidence that Herceptin is likely to have a benefit after the initial diagnosis of HER2+ve breast cancer (adjuvant). These trials are very new and regulatory bodies have not yet given their approval. PREPARATION FOR HERCEPTIN. As Herceptin is a very specific treatment, your doctor needs to find out if your tumour over-expressesHER2 receptors before even considering treatment. This is usually achieved by performing a special laboratory test on a small piece of you original tumour (from the time of your original surgery or biopsy). Occasionally, your doctor may need a more recent tumour for analysis and may recommend a further biopsy. In either case the tumour is usually send to a lab which specialises in specific tests called immunohistochemistry. A report will be issued by the pathologist on whether your tumour over expresses HER2 and how much is expressed. Research has shown that 20-25% of women have tumours which do over express HER2. If the cancer does over express HER2 it will look brown/red down the microscope (see 1st left picture). Pathologists have a scale of 0-3 depending on the intensity of staining, if it 1 or 0 it is regarded as HER-2 negative and Herceptin should not be used as treatment If it is grade 2 then a more sensitive test called FISH is performed, which looks at the DNA of the tumour cells (second left picture). All tumours which are FISH positive or have 3+ intensity staining on immunohistochemistry are eligible for Herceptin. HOW IS HERCEPTIN ADMINISTERED Herceptin cannot be taken orally as it would be destroyed by your stomach. It is, therefore, given as a drip into a vein usually over 90 minutes followed by a period of observation. Occasionally, it is possible to get an allergic reaction, particularly to the first treatment. The nurses will therefore be checking "how you are feeling" and measuring your breathing, pulse and blood pressure blood regularly. If all goes well the drip can last 1-2 hours, but sometimes, in response to mild reaction, it may have to be slowed down over several hours. Rarely if the allergic reaction is prominent it has to be stopped altogether and abandoned. To avoid a mild reaction often paracetamol and an antihistamine are given before the infusion. The dose is calculated by the weight of the patient, this is most often 4mg/kg on the first day then 2mg/kg once a week. This treatment continues until the tumour stops responding. However, based on recent information your doctor may choose to give Herceptin every three weeks particularly if this coincides with the chemotherapy visits. Herceptin is usually given within a cancer department or hospital. In some areas of the country, after the first few treatments it may be possible to receive the Herceptin infusion in your own home provided these facilities have been set up and are available locally. As mentioned above, Herceptin may also be given in conjunction with chemotherapy. The dose, frequency of treatment and side effects will also depend on the chemotherapy drugs used. The rationale and the specific regimen will be explained to you by the doctors and nurses before therapy starts. ARE THERE ANY SIDE EFFECTS TO HERCEPTIN? When given with chemotherapy most of the side effects relate to the chemotherapy drugs. Herceptin generally does not make these worse. Herceptin does have some mild side effects on its own which may occur in addition to those caused by chemotherapy. As mentioned above this does not mean you will definitely get them. It is also possible you may experience a side effect not mentioned here:- The early effects often are related to an "allergic" reaction. If they do occur, it is often while the drug is being infused or shortly afterwards. Potential side effects include: Fever and sweating
Runny nose Chills Skin flushing - redness Tightness in the chest or difficulty breathing Discomfort in the throat Agitation If associated with a fast pulse and lower blood pressure these symptoms indicate an early allergic reaction. As mentioned above if these symptoms are prominent the infusion has to be slowed down or abandoned altogether. To avoid a mild reaction often paracetamol and an antihistamine are given before the infusion. The ongoing effects may occur at any time whilst you are receiving Herceptin. These are usually worse a day or two after the infusion and could include:- Weakness, lethargy or tiredness
Headache Sore eyes Joint pains Nausea Diarrhoea Skin rashes Shortness of breath on exertion Late side effects may occur after receiving Herceptin for some time. The most important of these is heart damage - this is rare (In clinical trials around 4%). To ensure patients receiving Herceptin do not experience any damage to the heart, all patients must have a test for heart function before starting treatment and at regular intervals (usually every few months) after starting Herceptin. These tests include an echocardiogram or MUGA scan. The risks of the development of heart damage are higher if you have previously received chemotherapy containing drugs called anthracyclines or if you already have an underlying heart or lung problem. HOW WILL YOU KNOW TREATMENT IS WORKING? Your doctor would require evidence that treatment is helping particularly after a 2-3 months. This can be achieved from a number of sources including; an improvement in a specific symptom such as pain, a shrinkage of a lump on examination, improvements in a blood test or often evidence from repeat X-rays and scans such as CT or MRI. If there is no palliative benefit by this time treatment may be stopped. Further detailed information on Herceptin can be found on the official pharmaceutical website http://www.herceptin.com Scientists have found what has been described as the "Holy Grail" in the fight to combat heart disease: a drug that not only lowers cholesterol but also unclogs narrowed arteries. Results of a trial released in the US last week showed that rosuvastatin can reduce the build up of fatty deposits in arteries by up to 9% when given to people with mild heart disease. "This is the first time we have seen significant reversal of the fatty deposits that clog arteries," said Dr Neal Uren, one of the leaders of the international study. Taking the drug for two years could make a narrow artery three or four years "younger"; taking it for ten years could reduce an artery's age by up to 15 years. The two-year study involved 349 patients who were given 40mg of rosuvastatin (trade name Crestor), the highest licensed dose. Two-thirds of them saw a reduction in arterial clogging. Some experts were very positive about the findings; others, however, warned that Crestor has more side effects than other treatments, and questioned whether the benefits outweighed the risks. See also Drugs to beat Radiation Sickness |
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