Is the FDA Too Conservative or Too Aggressive? Analysis of Clinical Trial Design

A case study on FDA from my father, a cardiologist: A recent advancement in replacement heart valves reduces mortality rates from 10% in high risk patients (old and very unhealthy) to 0.9%, from 5% in medium risk patients to 0.4%. This studies were confirmed through clinical trials run by very well respected doctors. Nevertheless, the FDA still required their own set of trials to confirm the safety of the procedure. This was 5 years ago. The FDA first ran a set of trials, not on standard patients but only those that were deemed "inoperable". They spent a few years working that out and found that the device succeeded, but the approval was only given for patients that were inoperable. Then the FDA covered patients that were high risk, spent a few years and found again that the device was hugely beneficial in mortality rates and the device was approved for high risk patients. We are currently in the waiting for the FDA to approve the device for medium risk patients. In the mean time, my father had a medium risk patient who needed a valve replacement. He could not use the new device, so he sent the man to surgery for a standard valve replacement with 5% mortality risk. The man died on the table, becoming part of the 5%, and my father insists that he would have survived if they had been able to use the new procedure. In Germany there are less regulations, and so they have been using the new technique for 5 years with great success. Because of things like this, you'll commonly see medical procedures in Europe that are 5 years ahead of their counterparts in America, all because the FDA insists on using such plodding methods to verify safety.

My experience with the FDA:

I'm "congenitally limb deficient" below the elbow. Grew up in the 90s using horrible myo electric prosthetic limbs that had 2 hour battery life and were in all practicality a glorified claw machine. I ditched that as soon as I realized they were actually a hindrance.

In 2006, there was a TED talk with Dean Kamen about a prosthetic arm developed by DARPA. It blew my mind and got me finally interested in wearing a prosthetic again. So much promise in a field that had been in a coma for the last 20 years.

That arm never happened. Why? Because it took the FDA 7 years to approve it. The project now is dead in water and the group responsible for building it is trying to literally give away their designs. Why did the FDA have to approve a prosthetic limb? Well, because it touches your skin. Yes, the silicon on the back had to be tested because of skin contact.

I'm now the lucky recipient of BeBionic 3 arm, which is great. Worst part about it? It uses radio frequency to control the hand and has a tendency to go haywire. I asked why they didn't just use Bluetooth and he said that would require another 2 years to get FAA approval. Ugh.

Anecdotal, I know.

I've been on the science side of a number of FDA clinical trials for a few years now.

The FDA is too conservative with many metrics, and too aggressive with others. The clinical trial pipeline is tortuously slow for everyone involved-- the EU equivalent agency has done a lot to accelerate the process fruitfully. Eclipsing these FDA malregulations is the problem of transparency; if the FDA forced clinical trials to publish 100% of their data rather than only the positive results, we'd have a better medicine producing industry.

A family member of mine has tried to participate in a clinical trial. The trial also forces him to forgo any existing medication, basically making his illness intolerable. There is no indication in the trial if he is being served with real medication or a placebo, but his life has been extremely affected just by participation. Naturally he quit the trial. How would this statistical analysis address these common behaviors where ill people would just not participate in trials when certain illnesses are involved?

A good summary and commentary here

http://www.marginalrevolution.com/marginalrevolution/2015/08...

TriCorder X-Prize? FDA has done nothing but hobbled it's development. DNA screening for the masses? FDA shut down 23andMe. Terminally ill and willing to try an experimental drug? FDA says, "too bad" (and the Supreme Court agrees).

So the FDA is too conservative for life-threatening conditions, and not conservative enough for relatively mild conditions. That probably fits pretty well with most people's intuitive sense of things; it's interesting to see the math works out that way.

Here's another example:

There's oragenics, which developed a vaccine against dental carries - a disease that affects 5 billion people. Something that i'm sure everybody would really like to have.

And this is why we don't have it ? In their own words:

" Regulatory Status:

We initiated our first Phase 1 clinical trial in April 2005, but we found it difficult to find subjects who fit the trial’s highly cautious inclusion and exclusion criteria, particularly with respect to the subjects’ lack of dentition. We concluded this trial early after enrolling only two of the 15 planned subjects. The FDA then recommended that we revise the protocol for the evaluation of ten healthy male subjects, ranging from 18 to 30 years old and with normal dentition, in an institutionalized setting. After we submitted additional information, the FDA issued a clinical hold letter in June 2007 for the proposed trial with the attenuated strain, citing the need for a plan with respect to serious adverse effects; a plan for the eradication of the attenuated strain in trial subjects’ offspring; and a required pregnancy test for female partners of subjects. We submitted additional protocols in response to the FDA’s concerns. In August 2007, the FDA issued a clinical hold letter with required revisions to the protocol for offspring of subjects. We submitted a response to the clinical hold letter in September 2007, and the FDA removed the clinical hold for our Phase 1 trial in the attenuated strain in October 2007.

While we commenced a Phase 1b clinical trial for SMaRT Replacement Therapy during the first quarter of 2011, the very restrictive study enrollment criteria required by the FDA made the enrollment of candidates meeting the restrictive criteria difficult. Due to the enrollment difficulty we encountered with our initial our Phase 1a clinical trial and now with our phase 1b clinical trial, we determined to discontinue pursuit of our Phase 1b clinical trial."

Such a shame.

http://www.oragenics.com/?q=cavity-prevention

Also: http://fdareview.org/

"Medical drugs and devices cannot be marketed in the United States unless the U. S. Food and Drug Administration (FDA) grants specific approval. We argue that FDA control over drugs and devices has large and often overlooked costs that almost certainly exceed the benefits. We believe that FDA regulation of the medical industry has suppressed and delayed new drugs and devices, and has increased costs, with a net result of more morbidity and mortality. A large body of academic research has investigated the FDA and with unusual consensus has reached the same conclusion. Drawing on this body of research, we evaluate the costs and benefits of FDA policy. We also present a detailed history of the FDA, a review of the major plans for FDA reform, a glossary of terms, a collection of quotes from economists who have studied the FDA, and a reference section with many webbed links. A more detailed table of contents follows. We are happy to receive comments and criticisms."

My small sample size of experience with the FDA: they seem to be very receptive to novel therapies for terminal illness and it's surprisingly straight-forward to get a Phase I trial approved.

There's no static rule uniformly enforcing the initiation of trials, rather your IND (investigational new drug) application is reviewed by experts in the relevant field to determine whether (1) is there a plausible reason to believe your new therapy helps and (2) is it unlikely to kill or severely injure patients.

I can't think of a better way for things to work for late-stage cancer or other untreatable terminal illnesses.

This is not an easy problem. If the FDA is too conservative, people will die who could have lived. If the FDA is too aggressive, a different group of people will die who could have lived. And no matter where the FDA is on the spectrum (insane extremes excluded), there are people in both groups who die. And there are people who cared for those in both groups, who scream about how the FDA is doing it all wrong, and who have diametrically opposed views on how the FDA should change.

Maybe the test should be whether the screaming is equally loud from both sides...

There's so much conflict within the FDA that their opinion should carry no real weight.