“Vision in One Eye Leads the Colony of the Blind… Every Time”

November 8, 2016 rist 1 comment

by Dr. Maurice Cary

Some years ago, while having dinner with a colleague, I asked “why do I feel like I am giving the same advice over and over?” His reply was “because the same things keep happening over and over”- and frustratingly so, that seems to be case. I’ve been in the pharmaceutical industry for going on 31 years now, the last 16 as a consultant helping companies develop their compounds or medical devices. My focus has been on nonclinical safety. All too often I’ve witnessed companies falling for the fact that just because the people they are interacting with know more about the subject or issue at hand, interpret that to mean that they have access to the requisite knowledge to get them safely to where they want to go. Wrong.

 

Just because someone knows more than you, does not mean at all they know enough. This year alone our industry has witnessed major failures because in one case a company and the other, investors, made this erroneous assumption. This time I will focus on the company that failed in development. Not letting investors off the hook: they will be the focus of a later blog.

 

In the ANSM report, “Report by the Temporary Specialist Scientific Committee (TSSC), FAAH (Fatty Acid Amide Hydrolase), on the Causes of the Accident during a Phase 1 Clinical Trial in Rennes in January 2016”, in which the authorities are basically (and rightfully so) trying to get to the bottom of why some healthy volunteers died. These cases are always painful and avoiding such tragedies is why I am staying around this business, when some of my colleagues of similar age are retired or close to it. For details I refer you to the actual report, which is publicly available.

 

For the sake of brevity, here are a couple of things I spotted. How about this one? The report indicated there were “critical errors” in translation and transcription in the Investigator’s Brochure (IB), which ultimately led to poor experimental design, precluding accurate determination of the effective dose when extrapolating animal data to humans. Come on! Really? Could it be that the company decided to save on spending top dollar for perfect translations and preparation of the perfect IB. Could it be that someone internal thought that the translations and transcriptions were fine because it was better than they could do? I don’t know? I do know this was low hanging fruit that should have been executed perfectly.

 

I guess as an attempt to be fair, the regulatory body indicated that “Interpreting toxicology study data is always complex”. True. But it is not impossible and a company should be relentless about obtaining the highest quality data and access to the best interpretive skills, period. I believe the obvious question should be “how can they know?” Fair enough. Here is a simple (perhaps even too simple) answer: if you sense there is a “hole” in the data or interpretation, don’t settle. Delay the entry into the clinic. A delay is a hell of lot better than killing someone. And ultimately when erring: err on the side of caution.

 

Look around; be honest and ask, “Do I really have the experts I need?” If you are not sure, ask around. Ask challenging questions to people who claim they are experts. If they cannot explain it to you in simple terms to your satisfaction, they probably are not the ones you need. Most experts will talk with you for free. I know I will.

 

Here’s a no-brainer I picked up in the ANSM report in reference to a CNS histopathology finding in a primate study: “It is difficult to comment on the precise histological nature of the damage due to the fact that the two pathologists who interpreted the slice slides on behalf of (the company) did not use the same terminology.” Yeah, I can imagine. It happens all the time. That’s why companies try to locate experts, most often external to the CRO, to solve such “mysteries”. But it seems no one spotted this as an issue before the compound got to the clinic. Call me crazy, but one would think if you are working with a CNS active compound, then one would want to resolve to 100% satisfaction any CNS pathology observed in any nonclinical study. Of course this could be a “show-stopper”, but that is the point of nonclinical safety.

 

There was an unexplained early death in one of the nonclinical studies in one species. NO early death should go unexplained. There were CNS signs in another species, albeit at only the high dose, which seemed to have been clarified by…changing species. There is more to be learned about what to do and not to do in the ANSM report, but I will stop here.

 

My bottom-line for this case is: no company developing drugs to be given to humans should depend on the regulatory body to have the total all-encompassing view that it should have to ensure safety of its compound and to protect the public. It is the   company’s (perhaps not legal, but moral) obligation to turn over every stone to make sure their compound is safe…period. Be keenly aware of what you do not know and be relentless in finding the best answers possible to admittedly complicated problems. And to be honest with you, I don’t see that enough.

 

1 Comment on ““Vision in One Eye Leads the Colony of the Blind… Every Time”

  1. Excellent article. I agree this is quite shocking. Of course there is always a small risk in first-in-man studies, but this case highlights that the reason the risk is usually small is due to diligent assessment of preclinical data and knowledge of the mechanism of action of the test drug. Once people fail to understand the magnitude of their decisions and are satisfied with less than 100% care and checking of data and decisions, the historically very low rate of Phase I healthy volunteer mortality and morbidity may be exactly that – history. Of course nobody is infallable and the retrospectoscope is the perfect tool, and I have no wish to criticise the individuals involved – there but for the grace of God go any of us working in this area. However, in the course of my work, I have sometimes been surprised to find people without the necessary expertise assuming they have the skills to make decisions which can be very far-reaching. I know on occasions I have been considered to be picky when I challenge this. Of course most of the time, things go well despite this, and sadly this reinforces belief that it is OK to work like this. The point of checking everything carefully and using the experts is to avoid missing the rare but important warning signs which can lead to tragedy. We must always be vigilant.

Leave a Reply

Your email address will not be published. Required fields are marked *