Dotting the I's and Crossing the T's: The Risks of Rushing a Clinical Trial or the FDA Approval Process

I have looped around the issue of clinical trials and the understandable burning desire to get as much early access to these wonder meds in and out of trials ASAP.

Today I am arguing for some painful patience and prudent caution in this rush to judgement.  I am going to point out some of the dangers of trying to speed up trials or cut corners to get drugs to market.

Times are changing fast in the treatment of CLL and we are all looking forward to the promised end of the era of chemotherapy as we have known it for years.

My blog has been filled with top CLL researchers forecasting this brave new world and additional similar interviews from ASH are on their way.

But this brave new world is still at least a year and half and more likely two or three years away, so we are forced to continue to wait for the day when we will be able to simply pick up these magic pills at our local pharmacy.

In the meantime, the only access to ibrutinib or idelalisib or ABT-199 or AVL-292 is through an FDA approved clinical trial.

Not surprisingly, some might want to take shortcuts, and race these drugs through trials and to the market to get wider and earlier access.

Major CLL researchers and patient advocates are also anxious to see these drugs available to as many as possible as soon as possible. Some have spoke powerfully on the need to quickly move the agenda forward and their mounting frustration with the IRB's and the FDA's slow methodical processes. They point out the preventable deaths of those that might have been helped by these new medications, but because many of needy subjects don't exactly fit the inclusion/exclusion criteria for a trial, they are left out in the cold, in a world filled with last years's drugs and treatments.

I get it. I feel it. There are those who need treatment now, but are cut off from the trials and don't want or can't risk chemo.  I have corresponded with many caught in that limbo.  But there are non-chemo options for most. Phase 1 trials are often more forgiving and open.  Also non-trial non-chemo options include HDMP+ R or O, O on its own, or lenalidomide + R,  lenalidomide + thalidomide. Look for something gentle to buy a year or two until the new batch of drugs are available. It may not be ideal, but it is possible and does keep you in the game.

More that one CLL expert has told me that the sure way to ruin a good drug is to skip a step in the process and find out down the line about a foreseeable and preventable adverse event. That is deal breaker for the FDA that will almost certainly send the drug back to square one and will guarantee to make the trip to market slower and more costly. And too often, the parent pharmaceutical company may decide that the hurdle is too high and the expense too great and the potentially beneficial drug dies of a self-inflicted wound long before reaching the finish line. Or if the medication is already on the market, the delayed discovery of a clinical problem is a hanging curveball for the trial lawyers and we all know that when they swing their bats, the ball is headed out of the park and the game is generally over, for better or for worse for the patients left stranded in the field.

Methodical, boring, transparent progress is the only way to go.

Another issue. A common approach used in phase 1 trials has been dose escalation to toxicity. This standard puts pressure on investigators to rapidly keep pushing up doses until something happens. Those somethings are treatment limiting toxicities and include  mild adverse events, but can cross the threshold into a potentially fatal event such as tumor lysis syndrome or a cytokine storm.

Slow and easy does it every time.

Here's a wild idea that might safely speed things up, but it too needs some diligent review.

Some of these new meds might warrant a different approach to phase 1 trials due to their much wider therapeutic margin than traditional chemotherapy where the margin between safe and sick is often razor thin. Do we need to keep escalating dosages until something bad finally forces a full stop?  Could a dose escalation trial be stopped when we see a strong therapeutic signal, but before we get into trouble?

Remember Paracelsus said the difference between a drug and a poison is the dose.

As I write this, I recognize some possible problems with my suggestion. Which new drugs get treated in this proposed new way and which in the old? How do we tease the groups apart ? My modest proposal still needs some careful noodling by those in the trial design business.

But my bigger issues are clearer.

I talked to a woman today whom I encourage to enroll in a CLL ibrutinib versus ofatumumab trial in Madrid because I believe it to be her best option. I was surprised and dismayed to discover that she would be the first to enroll.


I remain convinced that the shortest and easiest way to get these drugs available to all those who need them is to quickly fill the existing trials and to reach the primary outcomes as soon as possible. Sure, we still need to encourage researchers and pharmaceutical companies to design and open new trials that are as inclusive as possible and that best serve the patients while still getting the necessary data, but those two needs can be in conflict. None of this is simple. We need to start with what we have.

When the data is ready and the time is right, when appropriate, we must support the FDA to broadly approve the new medication and then pressure the insurers to cover it for the full range of indications.

Finally, we need to educate the community oncologists and our fellow patients about the changes that been wrought by the courage of those who jumped into trials and the researchers who supported them.

Painful as it might be, there can be no shortcuts and no diversions to getting these drugs approved. All the i's must be dotted and the t's crossed.

For now, check out clinical trials.gov