I feel ambivalent about pharmaceutical companies at the present time. There is no doubt that they have contributed greatly in the fight against disease; without them we would not have a fraction of the drugs that we do. However, we are not allies in the fight against CLL, we are co-belligerents. We are certainly fighting the same enemy, but I would not want to be associated with some of the methods they are using.
We have a different regulatory framework in the UK to that in the US. The FDA examines a drug to see if it is efficacious and safe. It is a balancing act. Efficacious drugs are not always safe. Even an aspirin can kill you. The FDA has to balance the good that they might do with the harm that they might do. They may put restrictions on their use. In the UK a body known as the MHRA does the same thing.
In making this assessment the FDA relies on the pharmaceutical company releasing to it all the information concerning efficacy and toxicity. As we have learned in recent times Big Pharma sometimes withholds information about toxicity, or seeks to belittle it. It is also possible to talk up the efficacy of an agent. A recent analysis of a new drug for CLL demonstrated an effect in a subset of patients. This was not an effect that the trial had been designed to detect, but one that emerged from data dredging. Subset analysis is a valid methodology, but the statistical tests that are applied to it have to be more stringent. We cannot accept that P<0.05 is significant. After all if you dredge through 20 subsets of data you are bound to find something with a 5% chance of being significant. For example, you have 20 schoolboys. Your hypothesis is that Peter is taller than the others. You have a 1 in 20 chance of being right. However if your hypothesis is one boy is taller than the others, you are almost bound to be right. In the recent British CLL trial subset analysis suggests that overall survival for patients with mutated IgVH genes is better if they are treated with chlorambucil than if they are treated with fludarabine. But that comparison is invalid, because it wasn't one of the things that the trial was designed to detect. It would have needed many more patients to be randomized. It was just this sort of analysis that the manufacturer (not of chlorambucil, I hasten to add) attempted to swing on the FDA. To their credit, the FDA spotted what was going on and refused to license the drug.
Another trick is to use the comparator drug at a lower than optimal dose. For years I have been using chlorambucil at a dose of 10mg a day for two weeks in every four. That's 140 mg per month. The average person is 1.72 sq meters in surface area, so on average I was giving 81 mg/sq m/month. Why am I not surprised when I turn to the pivotal trial for fludarabine and find that patients in the chlorambucil arm received only 40 mg/sq m/month. When I examine the Campath trial which has just shown Campath to be better than chlorambucil as first line therapy, I find that the same rather low dose of chlorambucil has been used. It's not a wrong dose of chlorambucil, but it sets the winning post a little easier to reach.
In the UK we have an organization called NICE that I have referred to before. Its job is to inform the government which drugs are cost-effective and should therefore be paid for by the NHS. It is not perfect, but it tries hard. Not every drug is examined by NICE, but when drugs are not examined, the local health purchaser has to make a decision, and it is likely to be a deal more arbitrary than the one NICE makes. In the US once a drug is licensed it can be prescribed by any doctor as long as the patient can find someone to pay for it. Very often the third party funder will look at the decision that NICE has made in the UK.
Of course the licensing does not cover every possible use a particular drug. Doctors will experiment. For example, Daunorubicin, which has been the mainstay of treatment for acute myeloid leukemia since the 1960s, but for a long period it did not have a license for this use in the UK. In India, a cardiologist who knew a bit about physiology reasoned that sildenafil would be a very useful drug for the treatment of congenital pulmonary hypertension. You can imagine the outrage at a doctor giving Viagra off-license to new-born babies. But he was right and the lives of many babies were saved by his courage.
However, pharmaceutical companies are not allowed to promote their drug for unlicensed conditions. You can imagine why the FDA was outraged to discover that 70% of prescriptions for one popular monoclonal antibody were for conditions outside the licensed indications.
Which brings me to a warning letter sent to a certain pharmaceutical company by the FDA. This is an old letter dating from 7 years ago so I shan’t name the company who no doubt have put their house in order by now. The point of the warning letter was to suggest that the company had violated the terms of the license: “statements or implications by you that this product may indeed be safe and efficacious in the treatment of diseases or patient populations beyond that approved in your application may be considered a violation of the promotional provisions of the Act.” In particular the company was accused of promoting the drug for indications beyond its license. As it happens we now know that that particular drug was useful for that particular indication, and it has become the standard treatment. Nonetheless, it was a transgression.
Pharmaceutical companies are naturally keen to get their product to market and they often have very large sums of money tied up in the success of any particular product. In the past when I have asked drug company reps about a particular unlicensed use of their product, they will say straight away, I am not allowed to promote that use. But if I press them for information they will have the documentation favoring that use handy. It’s just a question of pushing the right buttons. If challenged would say that they were just being helpful in my quest for knowledge. All very well if the doctor reads and judges the paper himself, rather than relying on the company’s interpretation of it.
In my previous post I reviewed the clinical trials of treatments for CLL. You may have noticed that there was nothing about Revlimid there. This is because I don’t want to encourage its use outside its license. This is what I have written previously about Revlimid:
Revlimid has not been licensed for use in CLL and neither has thalidomide. However in small phase II trials both have been shown to have some activity in CLL. Do not be persuaded to take either of these drugs unlicensed, except in the context of a clinical trial. Clinical trials have to be assessed by ethical committees. They will regard any trial as unethical if the risk to the patient is greater for taking the drug rather than avoiding it. Therefore there will be strict entry criteria for these trials, and patients entered into the trials will be closely monitored. Ideally these trials should be randomized phase III trials.
This is still true.
At ASH last year there were two abstracts on the use of Revlimid in CLL. In the first, from MD Anderson the abstract was accompanied by a statement that Revlimid had been approved for use in 5q- MDS and myeloma, and that its use in CLL should be considered off-label. Among 22 relapsed and refractory patients 7 had a response and one a CR. The major toxicity was bone marrow suppression and one patient died of a fungal infection. Tumor flare (sudden tender enlargement of lymph nodes, liver or spleen, rash and fever) occurred in 6, fatigue in 13, nausea in 10, itching in 7 and diarrhea in 5. In the other trial which was from Roswell Park, 45 relapsed and refractory patients were treated, the overall response rate was 42% with 9% CR. Similar side effects were seen as in the Houston experience, but in addition tumor lysis syndrome occurred in two.
My conclusion is that this treatment is no picnic, but because it acts in different ways to most anti-CLL treatment, it may have a role in CLL. We need more information on whether it is able to help patients with p53 deletions and whether it might synergise with existing therapies.