Monday, June 19, 2006

Volunteering for a phase 1 trial.

One of the interesting questions about the TeGenero trial was why it was conducted in normal volunteers. In fact why are any trials conducted in normal volunteers? Increasingly new medicines are targeted towards specific abnormalities that are often only present in a particular group of patients; it would be folly to use the agent in people who did not have the target lesion.

However, there are some agents that are aimed to be used in everybody - flu vaccines, for example, and normal volunteers could be expected to benefit.

But if there is no possible benefit, why would a normal person vulunteer?

It was a great suprise that after the Northwick Park incident, far from our seeing a reduction in volunteers, there was actually an increase. The reason is very clear; people became aware of how much money there was to be made from volunteering.

If money is the motive, or if there is some coercion (such as PhD students in the lab being asked to 'volunteer') then I think the trial is unethical. Patients who might have some small chance of benefiting from a phase 1 trial might well volunteer and those whose relatives or friends have suffered from the targeted condition might reasonably volunteer. Those who claim to be altruistically motivated should have their expenses reimbursed, but nothing that resembles a bribe must be given. It should be remembered that to impecuneous students a bribe doesn't have to be very great.

In my experience cancer drugs are never given to normal volunteers. Although the TeGenero antibody was possibly targeted at CLL, the company was mainly interested in rheumatoid arthritis, hoping that it would switch on regulatory T cells and so switch off the autoimmune process. Boosting regulatory T cells might not have been a good idea in cancer. On the other hand boosting normal T cells in normals turns out not to have been a good idea either. Had rheumatoid arthritis patients been used the effect might have been worse.

Clearly, testing 6 volunteers together was a mistake, but it is exactly how phase 1 trials of small molecules are usually done. The likelihood of serious toxicity is so small that the lower doses are hurried through. The problem here was unexpectedly the dose was very wrong. Whether this was a Siglec5 effect remains to be determined. I think a general lesson is that the first time a new molecule goes into man it should be into a man (or woman).

When we calculate the dose to be used, we estimate the number of target molecules on the cell and the number of target cells in the body, and calculate a dose necessary to saturate them. This rule of thumb methode can be substantially and unexpectedly awry.


Judy Dean said...

I'm consering a Phase I immunotherapy trial at MD Anderson (Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35]) as first-line treatment. One CLL doc enthusiastically pointed me to it, another told me I'd be crazy to do it. (Actually, he said something like, "I eat lunch with those gene therapy guys [NOT the ones at MD Anderson, mind you] and frankly, they're not sure how this stuff works." I'd be curious to know if you think phase 1 trials are ever appropriate for first-line therapy.

Terry Hamblin said...

Obviously there are some situations where phase 1 trials might be appropriate in early stage patients. Vaccines depend on their being an intect immune response, so that there will be neither effects nor side effects in end stage patients. In my experience hene therapy trials like this are the ones that are most carefully scrutinized before they are started.

Anonymous said...

And now TeGenero have gone bankrupt, and the wonderfully corrupt Medicines and Healthcare Regulatory Agency (MHRA) whitewashed their role in the problem as usual.

Just great.