There is an interesting article on placebos in last week's New Scientist.
Placebos are a vital element of Randomized Clinical Trials (RCT) because the very act of seeing a doctor and being prescribed a treatment can make a patients feel better. To avoid this placebo effect, an inert substance is given to the control group. The more spectacular the placebo procedure the more beneficial the effect. The most dramatic placebo effect I have heard about is sham plasmapheresis, where a machine with many flashing lights attended by a pretty nurse, removes the patient's plasma by a sort of spin-drying effect and replaces it with donor plasma. Twenty years ago a doctor using this technique got himself on the front page of Time Magazine because of his remarkable success in alleviating rheumatoid arthritis.
Unfortunately, it was later shown that the same effect could be obtained by sham plasmapheresis, where the patient's own plasma was returned after the same dramatic procedure. Recently sham acupuncture - where no concern was made to place the needles in the Chinese meridians - was found to be equally as effective as proper acupuncture.
So not all placebos are equal was one of the messages of the article. The other was the difficulty in keeping a trial double blinded. If patients are given an inert substance as the placebo, they will soon recognize it because they will have no side effects. One solution to this is to use a placebo that gives the side effects but not the benefit. Atropine has been suggested as a placebo in trials of antidepressants since it produces the same side effects - dry mouth, headaches, insomnia and drowsiness. But would it be ethical? I don't think so.
Perhaps it would be better simply to ask the patients whether they thought they were receiving active drug or the placebo. At least then we would know the extent of the unblinding that had taken place.
Showing posts with label clinical trials. Show all posts
Showing posts with label clinical trials. Show all posts
Monday, December 13, 2010
Saturday, October 16, 2010
How to make new drugs available earlier and cheaper.
In today's BMJ there is an open letter to the Secretary of State for Health from Professor Peter Lachmann, the retired professor of immunology from Cambridge University and past-president of the Academy of Medical Sciences. In it he makes this interesting suggestion:
About 60% if drug development is taken up by late stage, Phase III trials. Phase I trials ensure safety and phase II trials demonstrate efficacy. Both require small numbers of patients and are relatively cheap to run. Phase III trials are expensive to run and require large numbers of patients, but still cannot detect side effects that occur in fewer than one in a thousand patients.
He says that the population now believes that drugs have to be absolutely safe ans that if anybody comes to harm from them they should be able seek compensation from the courts, and that this has led to drugs being hugely expensive and very slow to bring into use. It is now estimated that to develop a novel drug costs several hundreds of millions of dollars and takes at least 10 years.
In his opinion there is a strong case for making drugs available after phase II trials have shown that they work and to rely on post-marketing surveillance for detecting rare side effects. This would make new drugs much cheaper and available much earlier. It is arguable that phase III trials save fewer lives from avoided side effects than they cause by delaying their availability.
Initially patients should be able to get these new drugs by signing a waiver indemnifying the manufacturer from damages should there be any harm from the drug.
In any case the practice of suing drug companies for adverse effects is pointless. It does the company no financial harm, since the cost is passed on to the consumer. Only lawyers benefit. Legal redress should be reserved for negligence of other malfeasance.
It is probable that many useful drugs are never developed because the potential market is too small and the financial risks too great.
I can see merit in this approach, but Lachmann misses out on the benefits of phase III trials. Phase II trials will show you that a drug has activity in a particular disease and by doing randomized phase II trials (which are a bit more expensive) you can even see if it is more active than the best available alternative, but without phase III trials you will never know whether the new drug gives you a better lifestyle or a longer life than what went before. And you certainly won't know whether it is worth buying.
About 60% if drug development is taken up by late stage, Phase III trials. Phase I trials ensure safety and phase II trials demonstrate efficacy. Both require small numbers of patients and are relatively cheap to run. Phase III trials are expensive to run and require large numbers of patients, but still cannot detect side effects that occur in fewer than one in a thousand patients.
He says that the population now believes that drugs have to be absolutely safe ans that if anybody comes to harm from them they should be able seek compensation from the courts, and that this has led to drugs being hugely expensive and very slow to bring into use. It is now estimated that to develop a novel drug costs several hundreds of millions of dollars and takes at least 10 years.
In his opinion there is a strong case for making drugs available after phase II trials have shown that they work and to rely on post-marketing surveillance for detecting rare side effects. This would make new drugs much cheaper and available much earlier. It is arguable that phase III trials save fewer lives from avoided side effects than they cause by delaying their availability.
Initially patients should be able to get these new drugs by signing a waiver indemnifying the manufacturer from damages should there be any harm from the drug.
In any case the practice of suing drug companies for adverse effects is pointless. It does the company no financial harm, since the cost is passed on to the consumer. Only lawyers benefit. Legal redress should be reserved for negligence of other malfeasance.
It is probable that many useful drugs are never developed because the potential market is too small and the financial risks too great.
I can see merit in this approach, but Lachmann misses out on the benefits of phase III trials. Phase II trials will show you that a drug has activity in a particular disease and by doing randomized phase II trials (which are a bit more expensive) you can even see if it is more active than the best available alternative, but without phase III trials you will never know whether the new drug gives you a better lifestyle or a longer life than what went before. And you certainly won't know whether it is worth buying.
Wednesday, March 10, 2010
Clinical Trials
One of the things that I do is oversee clinical trials. I no longer participate by entering patients into trials but I assess whether a trial should take place on grounds of both ethics and funding, I monitor the data produced and make judgements on how the trial has been conducted and I assess the results.
I sit on the Gene Therapy Advisory Committee, which is the Ethical Review Committee for all trials conducted in the UK involving either gene therapy or stem cells.
The science involved in these studies is challenging, but it is necessary for the committee to understand it in order to assess how likely it is to succeed and how dangerous it is likely to be. Of around 160 studies that we have looked at over the past 10 years, the majority have been ineffective and did no harm, but of late there have been trials that have been both effective and very toxic. There has been a steep learning curve for us members.
Some of the more arcane elements of gene therapy are outside my field of expertise, but it does help to have a good understanding of general medicine and of the nature of cancer. One of our most pressing concerns is the quality of the patient information leaflet. We insist that it is written in terms that a lay person can understand. It is important that the information does not give an over optimistic outlook for the treatment. Remember that what is taking place is an experiment. The likelihood is that it will not benefit those taking part, though information gathered from the trial might benefit later patients. It is easy to attract patients to trials of treatments for hopeless diseases. Whatever you say to them they believe that they will be the one to benefit.
I also sit on CTAP which is the grant awarding part of the Leukemia Research Fund. It funds phase 2 trials, which look at efficacy of a new drug or combination of drugs in a small number of patients. It is not a wealthy organization so we only want to fund the best. Our concern is not to fund trials that are already taking place elsewhere, and to ensure that the maximum amount of information is obtained from the trials we do fund. The major LRF funded trial in recent years is the one that demonstrated clearly that FC is better than either single agent F or single agent chlorambucil for CLL.
In addition I sit on a number of Data Monitoring Committees and Independent Review Panels for CLL trials. Here we have to monitor how the trial is being conducted, whether unforeseen complications occur and to recommend protocol variations if they do, and to assess whether a trial should move on to the next phase.
I am in the middle of a succession of such meetings at the moment, which I why I have been a rather silent blogger.
I am, of course, sworn to silence about individual trials, but I have some observations about trials in general, which may be of interest to my readers.
First, clinical trials are essential. Without them we have only a series of anecdotes and opinions. Trials should be designed so as to find out if the hoped for conclusion is unlikely to happen. For example, if you believe that all swans are white and there are stories that black swans exist in Australia, then there is no point in only looking at swans in America or Europe. Your theory must be tested under conditions most likely to prove it wrong.
The ultimate test of a new treatment is the randomized controlled trial in which the new treatment is compared with the best of the old in a population randomly allocated to either treatment. Ideally, both patients and their medical teams should be unaware which treatment the patient is given and the success or otherwise should be assessed independently by someone unconcerned with the trial who also does not know which treatment the patient received. Sometimes it is impossible to meet these conditions. For example if a new treatment makes you sick and the old one doesn't then it is pretty plain who is having what.
It is noticeable that some people, such as homeopaths, don't buy into RCTs. All I can say is that any assertion that such an untested treatment works is likely to be spurious. I am quite willing to believe that many patients feel better when they purchase the whole package, with the time it takes, the sweet talking and the impressive procedures, but such packages are impressive placebos.
Any substance put forward as a treatment will already have demonstrated activity in a test tube and should have been given to at least two species of animals to demonstrate its safety. The first type of trial that is done is a phase 1 trial to determine a safe dose. Such trials are often done of normal volunteers, but they can go disastrously wrong as happened at Northwick Park. Six young men reacted disastrously to minute doses of an antibody the first time it was administered at a much lower dose than had apparently been safe in monkeys. Who would volunteer to take part in such a study? Many young men earn a sizable living from such studies, getting up to $5000 a time.
But most phase 1 studies are pretty safe. Cancer drugs are almost always tested in cancer patients, often in patients who have reached the end of the line, having exhausted all the licensed drugs. They are hoping for another Gleevec, for it was in a phase 1 trial that Gleevec first showed its superiority in CML. The idea of a phase 1 trial is to find the highest dose that is safe. Usually cohorts of three patients are treated with a single escalating dose. Eventually a dose will be found that causes toxicity and the last dose below this is chosen.
1. 2. 3. 5. 8. 13. 21. 34 ... is known as the Fibonacci sequence and the rate of escalation is a modified Fibonacci sequence.
A phase 2 study is looking to see whether the chosen dose has any activity. Fourteen patients need to be treated without benefit before concluding that the drug has no effect. After that more may be treated to determine exactly how great the effect is. However, around 40 patients is usually enough. Randomized phase 2 studies enable us to compare an immediate effect with the standard treatment. For example, drug A might cause 40% remissions against only 25% with the standard therapy. This doesn't tell us that drug A is better. Remission rate often correlates with survival, but not always. If drug A puts 40% into remission but kills 60% it is not such a good treatment as drug B which only puts 25% into remission yet only kills 5%, the remaining 70% living for more than 2 years.
What we are usually looking for is length of overall survival, and if that is the same for both treatments then the quality of life during that period of survival comes into it. To determine whether a given treatment is better than a competitor, then we need to do a randomized phase 3 trial. The endpoint is overall survival and the number of patients required is determined by how much better than standard treatment the new treatment is suspected of being. A small difference requires a big trial; a big difference only a small trial. When improvements in outcomes are only nibbling at the problem then very large trials are needed.
For diseases like CLL where current treatments are associated with very long survivals in most patients you have a problem. You can either pick out some characteristics associated with very poor survival (like del 17p) and do your trials on this group, or you can find a characteristic associated with very long survival (like MRD negativity) and use that as a surrogate end point.
One of the problems with CLL is that as time passes we know more about the disease, so that ongoing trials become superfluous. Take the definition of a complete remission. Only about 15 years ago, all you needed to have a complete remission was no symptoms, a normal blood count, no lymph nodes to feel in armpits groins or neck, no liver or spleen to feel, and a bone marrow with fewer than 30% small lymphocytes in it. Today that is not sufficient. CT scanning has shown that enlarged lymph nodes may be present in the abdomen in many patients with what would previously have been called a CR. The spleen has to be three times the normal size before you can feel it and livers can be felt even though they may be a normal size. You can't make livers and spleens disappear completely so who knows whether a liver or spleen is of normal size or slightly enlarged? CT scans are so sensitive that a normal lymph node may be seen and called as pathological.
To get round this problem, a new standard is emerging. Tiny numbers of CLL cells can be detected in the blood using idiotypic PCR or 4-color flow cytometry. Increasingly, trials are being designed with negative minimal residual disease as an endpoint, and in my opinion this is to be encouraged.
Finally, when a patient volunteers to take part in a clinical trial, the doctor conducting that trial has been given a great gift and it behoves him to conduct the trial properly. I have seen too many occasions when the recording of observations is frankly slapdash. I think that some centers enter patients into trials for pecuniary reasons or just to get their names on a paper, without any curiosity about the outcomes. Improperly conducted trials are unethical and should not be allowed. When a pharmaceutical company finds that a particular center does not comply with the protocol the center should be excluded from future trials. For a patient to quit a trial midway is also an affront to all the other patients involved. I understand that the toxicity may enforce abandonment, but there will be follow-up blood tests and examinations that ought to be done. For a pharmaceutical company not to publish the results of a trial (even if it is offensive to their shareholders) is an insult to the professionals and the patients who took part.
I sit on the Gene Therapy Advisory Committee, which is the Ethical Review Committee for all trials conducted in the UK involving either gene therapy or stem cells.
The science involved in these studies is challenging, but it is necessary for the committee to understand it in order to assess how likely it is to succeed and how dangerous it is likely to be. Of around 160 studies that we have looked at over the past 10 years, the majority have been ineffective and did no harm, but of late there have been trials that have been both effective and very toxic. There has been a steep learning curve for us members.
Some of the more arcane elements of gene therapy are outside my field of expertise, but it does help to have a good understanding of general medicine and of the nature of cancer. One of our most pressing concerns is the quality of the patient information leaflet. We insist that it is written in terms that a lay person can understand. It is important that the information does not give an over optimistic outlook for the treatment. Remember that what is taking place is an experiment. The likelihood is that it will not benefit those taking part, though information gathered from the trial might benefit later patients. It is easy to attract patients to trials of treatments for hopeless diseases. Whatever you say to them they believe that they will be the one to benefit.
I also sit on CTAP which is the grant awarding part of the Leukemia Research Fund. It funds phase 2 trials, which look at efficacy of a new drug or combination of drugs in a small number of patients. It is not a wealthy organization so we only want to fund the best. Our concern is not to fund trials that are already taking place elsewhere, and to ensure that the maximum amount of information is obtained from the trials we do fund. The major LRF funded trial in recent years is the one that demonstrated clearly that FC is better than either single agent F or single agent chlorambucil for CLL.
In addition I sit on a number of Data Monitoring Committees and Independent Review Panels for CLL trials. Here we have to monitor how the trial is being conducted, whether unforeseen complications occur and to recommend protocol variations if they do, and to assess whether a trial should move on to the next phase.
I am in the middle of a succession of such meetings at the moment, which I why I have been a rather silent blogger.
I am, of course, sworn to silence about individual trials, but I have some observations about trials in general, which may be of interest to my readers.
First, clinical trials are essential. Without them we have only a series of anecdotes and opinions. Trials should be designed so as to find out if the hoped for conclusion is unlikely to happen. For example, if you believe that all swans are white and there are stories that black swans exist in Australia, then there is no point in only looking at swans in America or Europe. Your theory must be tested under conditions most likely to prove it wrong.
The ultimate test of a new treatment is the randomized controlled trial in which the new treatment is compared with the best of the old in a population randomly allocated to either treatment. Ideally, both patients and their medical teams should be unaware which treatment the patient is given and the success or otherwise should be assessed independently by someone unconcerned with the trial who also does not know which treatment the patient received. Sometimes it is impossible to meet these conditions. For example if a new treatment makes you sick and the old one doesn't then it is pretty plain who is having what.
It is noticeable that some people, such as homeopaths, don't buy into RCTs. All I can say is that any assertion that such an untested treatment works is likely to be spurious. I am quite willing to believe that many patients feel better when they purchase the whole package, with the time it takes, the sweet talking and the impressive procedures, but such packages are impressive placebos.
Any substance put forward as a treatment will already have demonstrated activity in a test tube and should have been given to at least two species of animals to demonstrate its safety. The first type of trial that is done is a phase 1 trial to determine a safe dose. Such trials are often done of normal volunteers, but they can go disastrously wrong as happened at Northwick Park. Six young men reacted disastrously to minute doses of an antibody the first time it was administered at a much lower dose than had apparently been safe in monkeys. Who would volunteer to take part in such a study? Many young men earn a sizable living from such studies, getting up to $5000 a time.
But most phase 1 studies are pretty safe. Cancer drugs are almost always tested in cancer patients, often in patients who have reached the end of the line, having exhausted all the licensed drugs. They are hoping for another Gleevec, for it was in a phase 1 trial that Gleevec first showed its superiority in CML. The idea of a phase 1 trial is to find the highest dose that is safe. Usually cohorts of three patients are treated with a single escalating dose. Eventually a dose will be found that causes toxicity and the last dose below this is chosen.
1. 2. 3. 5. 8. 13. 21. 34 ... is known as the Fibonacci sequence and the rate of escalation is a modified Fibonacci sequence.
A phase 2 study is looking to see whether the chosen dose has any activity. Fourteen patients need to be treated without benefit before concluding that the drug has no effect. After that more may be treated to determine exactly how great the effect is. However, around 40 patients is usually enough. Randomized phase 2 studies enable us to compare an immediate effect with the standard treatment. For example, drug A might cause 40% remissions against only 25% with the standard therapy. This doesn't tell us that drug A is better. Remission rate often correlates with survival, but not always. If drug A puts 40% into remission but kills 60% it is not such a good treatment as drug B which only puts 25% into remission yet only kills 5%, the remaining 70% living for more than 2 years.
What we are usually looking for is length of overall survival, and if that is the same for both treatments then the quality of life during that period of survival comes into it. To determine whether a given treatment is better than a competitor, then we need to do a randomized phase 3 trial. The endpoint is overall survival and the number of patients required is determined by how much better than standard treatment the new treatment is suspected of being. A small difference requires a big trial; a big difference only a small trial. When improvements in outcomes are only nibbling at the problem then very large trials are needed.
For diseases like CLL where current treatments are associated with very long survivals in most patients you have a problem. You can either pick out some characteristics associated with very poor survival (like del 17p) and do your trials on this group, or you can find a characteristic associated with very long survival (like MRD negativity) and use that as a surrogate end point.
One of the problems with CLL is that as time passes we know more about the disease, so that ongoing trials become superfluous. Take the definition of a complete remission. Only about 15 years ago, all you needed to have a complete remission was no symptoms, a normal blood count, no lymph nodes to feel in armpits groins or neck, no liver or spleen to feel, and a bone marrow with fewer than 30% small lymphocytes in it. Today that is not sufficient. CT scanning has shown that enlarged lymph nodes may be present in the abdomen in many patients with what would previously have been called a CR. The spleen has to be three times the normal size before you can feel it and livers can be felt even though they may be a normal size. You can't make livers and spleens disappear completely so who knows whether a liver or spleen is of normal size or slightly enlarged? CT scans are so sensitive that a normal lymph node may be seen and called as pathological.
To get round this problem, a new standard is emerging. Tiny numbers of CLL cells can be detected in the blood using idiotypic PCR or 4-color flow cytometry. Increasingly, trials are being designed with negative minimal residual disease as an endpoint, and in my opinion this is to be encouraged.
Finally, when a patient volunteers to take part in a clinical trial, the doctor conducting that trial has been given a great gift and it behoves him to conduct the trial properly. I have seen too many occasions when the recording of observations is frankly slapdash. I think that some centers enter patients into trials for pecuniary reasons or just to get their names on a paper, without any curiosity about the outcomes. Improperly conducted trials are unethical and should not be allowed. When a pharmaceutical company finds that a particular center does not comply with the protocol the center should be excluded from future trials. For a patient to quit a trial midway is also an affront to all the other patients involved. I understand that the toxicity may enforce abandonment, but there will be follow-up blood tests and examinations that ought to be done. For a pharmaceutical company not to publish the results of a trial (even if it is offensive to their shareholders) is an insult to the professionals and the patients who took part.
Saturday, November 07, 2009
Other trials in CLL
I managed to attend my first Committee meeting yesterday. I went to London to meet with other CLL experts to discuss the forthcoming British CLL trials.
If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.
But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.
A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.
Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.
Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.
ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.
A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.
A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.
A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.
It looks like GA-101 and ofatumumab will be competing for the same market.
For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.
For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.
Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.
For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.
All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.
Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.
If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.
But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.
A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.
Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.
Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.
ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.
A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.
A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.
A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.
It looks like GA-101 and ofatumumab will be competing for the same market.
For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.
For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.
Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.
For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.
All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.
Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.
Thursday, October 15, 2009
New ways of doing trials
I met Eli Estey on a trip to MD Anderson in Houston. I found him to be a charming and thoughtful guy. He has now moved to the 'Hutch' in Seattle and has penned an interesting article entitled "Do commonly used clinical trial designs reflect clinical reality?" in the journal Haematologica.
We normally rely on randomized phase III clinical trials which compare two treatments using endpoints like overall survival, progression-free survival or time to next treatment. We rely heavily on p<0.05 which means that there is less than a 1 in 20 chance that any difference between the two could have occurred accidentally. In other words we are pretty sure that any positive result is not a false positive. In leukemia trials there is a tradition, which comes from St Jude's Memphis, that we inch forwards in our improvements. Childhood ALL is curable in the majority of cases. Treatment involves the use of several drugs in a particular order over a couple of years. Successive trials made small changes to the protocol that gave small improvements in survival. In order to be sure that these small improvements were not false positives the trials needed to utilize large numbers of patients so that a 'p' value of <0.05 could be obtained. Childhood ALL trials started with drugs that gave a high rate of complete remissions (vincristine and prednisone) so there was a good chance that adding more chemotherapy would improve things, but not by much. Hence, it was necessary to be certain that adding these new drugs did make a difference and were not false positives.
With adults, the problem is not that we are doing pretty well already, but that we don't cure very many at all. Therefore, our problem is not that we have too many false positives; it is that there may be drugs out there that help, but we reject them because we have too many false negatives.
The cure rate for CLL and adult AML is so poor that we are not really interested in drugs that make a small difference - we want agents that make a big difference - we should be willing to accept a higher risk of a false positive.
When trials are designed the numbers needed in each arm are partially determined by the power calculation. Traditionally an 80% power is required. What does this mean? It is actually the false negative rate. It means that one trial in five is discarding a treatment incorrectly because the negative answer was a false one.
Estey argues that this way of doing things is not clinically relevant. On the contrary there have been quite massive improvements in adult leukemia that did not come from these sorts of trials at all. He cites the value of imatinib in CML, CDA in hairy cell leukemia, arsenic trioxide and ATRA in acute promyelocytic leukemia and high-dose ara-C for core-binding factor AML as examples where the effect was so large that it didn't need an enormous trial to detect its value.
I raise this problem for CLL recently in this way. John Byrd recently reported that there are 107 different agents being studied at teh preclinical and clinical level for teh treatment of CLL. The typical phase III trial in CLL requires 800+ patients. There are simply not enough patients to test all those agent singly let alone in combination. WE must find a better way of doing things.
The better way that Estey proposes is the use of Bayesian statistics. Thomas Bayes (c. 1702 – 17 April 1761) was a British mathematician and Presbyterian minister, known for having formulated a specific case of the theorem that bears his name: Bayes' theorem, which was published posthumously. I have read the paper several times but I am none the wiser. Would someone please explain Baysian statistics to me.
We normally rely on randomized phase III clinical trials which compare two treatments using endpoints like overall survival, progression-free survival or time to next treatment. We rely heavily on p<0.05 which means that there is less than a 1 in 20 chance that any difference between the two could have occurred accidentally. In other words we are pretty sure that any positive result is not a false positive. In leukemia trials there is a tradition, which comes from St Jude's Memphis, that we inch forwards in our improvements. Childhood ALL is curable in the majority of cases. Treatment involves the use of several drugs in a particular order over a couple of years. Successive trials made small changes to the protocol that gave small improvements in survival. In order to be sure that these small improvements were not false positives the trials needed to utilize large numbers of patients so that a 'p' value of <0.05 could be obtained. Childhood ALL trials started with drugs that gave a high rate of complete remissions (vincristine and prednisone) so there was a good chance that adding more chemotherapy would improve things, but not by much. Hence, it was necessary to be certain that adding these new drugs did make a difference and were not false positives.
With adults, the problem is not that we are doing pretty well already, but that we don't cure very many at all. Therefore, our problem is not that we have too many false positives; it is that there may be drugs out there that help, but we reject them because we have too many false negatives.
The cure rate for CLL and adult AML is so poor that we are not really interested in drugs that make a small difference - we want agents that make a big difference - we should be willing to accept a higher risk of a false positive.
When trials are designed the numbers needed in each arm are partially determined by the power calculation. Traditionally an 80% power is required. What does this mean? It is actually the false negative rate. It means that one trial in five is discarding a treatment incorrectly because the negative answer was a false one.
Estey argues that this way of doing things is not clinically relevant. On the contrary there have been quite massive improvements in adult leukemia that did not come from these sorts of trials at all. He cites the value of imatinib in CML, CDA in hairy cell leukemia, arsenic trioxide and ATRA in acute promyelocytic leukemia and high-dose ara-C for core-binding factor AML as examples where the effect was so large that it didn't need an enormous trial to detect its value.
I raise this problem for CLL recently in this way. John Byrd recently reported that there are 107 different agents being studied at teh preclinical and clinical level for teh treatment of CLL. The typical phase III trial in CLL requires 800+ patients. There are simply not enough patients to test all those agent singly let alone in combination. WE must find a better way of doing things.
The better way that Estey proposes is the use of Bayesian statistics. Thomas Bayes (c. 1702 – 17 April 1761) was a British mathematician and Presbyterian minister, known for having formulated a specific case of the theorem that bears his name: Bayes' theorem, which was published posthumously. I have read the paper several times but I am none the wiser. Would someone please explain Baysian statistics to me.
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