Counterfeit Drugs in Clinical Trials?

This morning I ran across a bit of a coffee-spitter: in the middle of an otherwise opaquely underinformative press release fromTranscelerate Biopharma about the launch of their

Counterfeits flooding
the market? Really?

"Comparator Network" - which will perhaps streamline member companies' ability to obtain drugs from each other for clinical trials using active comparator arms -  the CEO of the consortium, Dalvir Gill, drops a rather remarkable quote:

"Locating and accessing these comparators at the right time, in the right quantities and with the accompanying drug stability and regulatory information we need, doesn't always happen efficiently. This is further complicated by infiltration of the commercial drug supply chain by counterfeit drugs.  With the activation of our Comparator Network the participating TransCelerate companies will be able to source these comparator drugs directly from each other, be able to secure supply when they need it in the quantities they need, have access to drug data and totally mitigate the risk of counterfeit drugs in that clinical trial."

[Emphasis added.]

I have to admit to being a little floored by the idea that there is any sort of risk, in industry-run clinical trials, of counterfeit medication "infiltration".

Does Gill know something that the rest of us don't? Or is this just an awkward slap at perceived competition – innuendo against the companies that currently manage clinical trial comparator drug supply? Or an attempt at depicting the trials of non-Transcelerate members as risky and prone to fraud?

Either way, it could use some explaining. Thinking I might have missed something, I did do a quick literature search to see if I could come across any references to counterfeits in trials. Google Scholar and PubMed produced no useful results, but Wikipedia helpfully noted in its entry on counterfeit medications:

Counterfeit drugs have even been known to have been involved in clinical drug trials.^{[citation needed]}

And on that point, I think we can agree: Citation needed. I hope the folks at Transcelerate will oblige.

TransCelerate and CDISC: The Relationship Explained

Updating my post from last month about the launch announcement for TransCelerate BioPharma, a nonprofit entity funded by 10 large pharmaceutical companies to “bring new medicines to patients faster”: one of the areas I had some concern about was in the new company's move into the “development of clinical data standards”.

How about we transcelerate
this website a bit?

Some much-needed clarification has come by way of Wayne Kubick, the CTO of CDISC. In an article in Applied Clinical Trials, he lays out the relationship in a bit more detail:

TransCelerate has been working closely with CDISC for several months to see how they can help us move more quickly in the development of therapeutic area data standards.  Specifically, they are working to provide CDISC with knowledgeable staff to help us plan for and develop data standards for more than 55 therapeutic areas over the next five years.

And then again:

But the important thing to realize is that TransCelerate intends to help CDISC achieve its mission to develop therapeutic area data standards more rapidly by giving us greater access to skilled volunteers to contribute to standards development projects.   

So we have clarification on at least one point: TransCelerate will donate some level of additional skilled manpower to CDISC-led initiatives.

That’s a good thing, I assume. Kubick doesn't mention it, but I would venture to guess that “more skilled volunteers” is at or near the top of CDISC's wish list.

But it raises the question: why TransCelerate? Couldn't the 10 member companies have contributed this employee time already? Did we really need a new entity to organize a group of fresh volunteers? And if we did somehow need a coordinating entity to make this happen, why not use an existing group – one with, say, a broader level of support across the industry, such as PhRMA?

The promise of a group like TransCelerate is intriguing. The executional challenges, however, are enormous: I think it will be under constant pressure to move away from meaningful but very difficult work towards supporting more symbolic and easy victories.

What We Can Anticipate from TransCelerate

TransCelerate: Pharma's great kumbaya moment?

Last week, 10 of the largest pharmaceutical companies caused quite a hullaballoo in the research world with their announcement that they were anteing up to form a new nonprofit entity “to identify and solve common drug development challenges with the end goals of improving the quality of clinical studies and bringing new medicines to patients faster”. The somewhat-awkwardly-named TransCelerate BioPharma immediately got an enthusiastic reception from industry watchers and participants, mainly due to the perception that it was well poised to attack some of the systemic causes of delays and cost overruns that plague clinical trials today.

I myself was caught up in the breathless excitement of the moment, immediately tweeting after reading the initial report:

If TransCelerate hits even half its goals, its launch is the biggest #ClinicalTrials event of the past few years. pharmalive.com/News/index.cfm…
— Paul Ivsin (@ivsin) September 19, 2012

 Over the past few days, though, I've had time to re-read and think more about the launch announcement, and dial down my enthusiasm considerably.  I still think it’s a worthwhile effort, but it’s probably not fair to expect anything that fundamentally changes much in the way of current trial execution.

Mostly, I’m surprised by the specific goals selected, which seem for the most part either tangential to the real issues in modern drug development or stepping into areas where an all-big-pharma committee isn’t the best tool for the job. I’m also very concerned that a consortium like this would launch without a clearly-articulated vision of how it fits in with, and adds to, the ongoing work of other key players – the press release is loaded with positive, but extremely vague, wording about how TransCelerate will work with, but be different from, groups such as the CTTI and CDISC. The new organization also appears to have no formal relationship with any CRO organizations.  Given the crucial and deeply embedded nature of CROs in today’s research, this is not a detail to be worked out later; it is a vital necessity if any worthwhile progress is to be made.

Regarding the group’s goals, here is what their PR had to say:

Five projects have been selected by the group for funding and development, including: development of a shared user interface for investigator site portals, mutual recognition of study site qualification and training, development of risk-based site monitoring approach and standards, development of clinical data standards, and establishment of a comparator drug supply model.

Let’s take these five projects one by one, to try to get a better picture of TransCelerate’s potential impact:

1. Development of a shared user interface for investigator site portals

Depending on how it’s implemented, the impact of this could range from “mildly useful” to “mildly irksome”. Sure, I hear investigators and coordinators complain frequently about all the different accounts they have to keep track of, so having a single front door to multiple sponsor sites would be a relief. However, I don’t think that the problem of too many usernames cracks anyone’s “top 20 things wrong with clinical trial execution” list – it’s a trivial detail. Aggravating, but trivial.

Worse, if you do it wrong and develop a clunky interface, you’ll get a lot more grumbling about making life harder at the research site. And I think there’s a high risk of that, given that this is in effect software development by committee – and the committee is a bunch of companies that do not actually specialize in software development.

In reality, the best answer to this is probably a lot simpler than we imagine: if we had a neutral, independent body (such as the ACRP) set up a single sign-on (SSO) registry for investigators and coordinators, then all sponsors, CROs, and IVRS/IWRS/CDMS can simply set themselves up as service providers. (This works in the same way that many people today can log into disparate websites using their existing Google or Facebook accounts.)  TransCelerate might do better sponsoring and promoting an external standard than trying to develop an entirely new platform of its own.

2. Mutual recognition of study site qualification and training

This is an excellent step forward. It’s also squarely in the realm of “ideas so obvious we could have done them 10 years ago”. Forcing site personnel to attend multiple iterations of the same training seminars simply to ensure that you’ve collected enough binders full of completion certificates is a sad CYA exercise with no practical benefit to anyone.

This will hopefully re-establish some goodwill with investigators. However, it’s important to note that it’s pretty much a symbolic act in terms of efficiency and cost savings. Nothing wrong with that – heaven knows we need some relationship wins with our increasingly-disillusioned sites – but let’s not go crazy thinking that the represents a real cause of wasted time or money. In fact, it’s pretty clear that one of the reasons we’ve lived with the current site-unfriendly system for so long is that it didn’t really cost us anything to do so.

(It’s also worth pointing out that more than a few biotechs have already figured out, usually with CRO help, how to ensure that site personnel are properly trained and qualified without subjecting them to additional rounds of training.)

3. Development of risk-based site monitoring approach and standards

The consensus belief and hope is that risk-based monitoring is the future of clinical trials. Ever since FDA’s draft guidance on the topic hit the street last year, it’s been front and center at every industry event. It will, unquestionably, lead to cost savings (although some of those savings will hopefully be reinvested into more extensive centralized monitoring).  It will not necessarily shave a significant amount of time off the trials, since in many trials getting monitors out to sites to do SDV is not a rate-limiting factor, but it should still at the very least result in better data at lower cost, and that’s clearly a good thing.

So, the big question for me is: if we’re all moving in this direction already, do we need a new, pharma-only consortium to develop an “approach” to risk-based monitoring?

 First and foremost, this is a senseless conversation to have without the active involvement and leadership of CROs: in many cases, they understand the front-line issues in data verification and management far better than their pharma clients.  The fact that TransCelerate launched without a clear relationship with CROs and database management vendors is a troubling sign that it isn’t poised to make a true contribution to this area.

In a worst-case scenario, TransCelerate may actually delay adoption of risk-based monitoring among its member companies, as they may decide to hold off on implementation until standards have been drafted, circulated, vetted, re-drafted, and (presumably, eventually) approved by all 10 companies. And it will probably turn out that the approaches used will need to vary by patient risk and therapeutic area anyway, making a common, generic approach less than useful.

Finally, the notion that monitoring approaches require some kind of industry-wide “standardization” is extremely debatable. Normally, we work to standardize processes when we run into a lot of practical interoperability issues – that’s why we all have the same electric outlets in our homes, but not necessarily the same AC adaptors for our small devices.  It would be nice if all cell phone manufacturers could agree on a common standard plug, but the total savings from that standard would be small compared to the costs of defining and implementing it.  That’s the same with monitoring: each sponsor and each CRO have a slightly different flavor of monitoring, but the costs of adapting to any one approach for any given trial are really quite small.

Risk-based monitoring is great. If TransCelerate gets some of the credit for its eventual adoption, that’s fine, but I think the adoption is happening anyway, and TransCelerate may not be much help in reality.

4. Development of clinical data standards

This is by far the most baffling inclusion in this list. What happened to CDISC? What is CDISC not doing right that TransCelerate could possibly improve?

In an interview with Matthew Herper at Forbes, TransCelerate’s Interim CEO expands a bit on this point:

“Why do some [companies] record that male is a 0 and female is a 1, and others use 1 and 0, and others use M and F. Where is there any competitive advantage to doing that?” says Neil. “We do 38% of the clinical trials but 70% of the [spending on them]. IF we were to come together and try to define some of these standards it would be an enabler for efficiencies for everyone.”

It’s really worth noting that the first part of that quote has nothing to do with the second part. If I could wave a magic wand and instantly standardize all companies’ gender reporting, I would not have reduced clinical trial expenditures by 0.01%. Even if we extend this to lots of other data elements, we’re still not talking about a significant source of costs or time.

Here’s another way of looking at it: those companies that are conducting the other 62% of trials but are only responsible for 30% of the spending – how did they do it, since they certainly haven’t gotten together to agree on a standard format for gender coding?

But the main problem here is that TransCelerate is encroaching on the work of a respected, popular, and useful initiative – CDISC – without clearly explaining how it will complement and assist that initiative. Neil’s quote almost seems to suggest that he plans on supplanting CDISC altogether.  I don’t think that was the intent, but there’s no rational reason to expect TransCelerate to offer substantive improvement in this area, either.

5. Establishment of a comparator drug supply model

This is an area that I don’t have much direct experience in, so it’s difficult to estimate what impact TransCelerate will have. I can say, anecdotally, that over the past 10 years, exactly zero clinical trials I’ve been involved with have had significant issues with comparator drug supply. But, admittedly, that’s quite possibly a very unrepresentative sample of pharmaceutical clinical trials.

I would certainly be curious to hear some opinions about this project. I assume it’s a somewhat larger problem in Europe than in the US, given both their multiple jurisdictions and their stronger aversion to placebo control. I really can’t imagine that inefficiencies in acquiring comparator drugs (most of which are generic, and so not directly produced by TransCelerate’s members) represent a major opportunity to save time and money.

Conclusion

It’s important to note that everything above is based on very limited information at this point. The transcelerate.com website is still “under construction”, so I am only reacting to the press release and accompanying quotes. However, it is difficult to imagine at this point that TransCelerate’s current agenda will have more than an extremely modest impact on current clinical trials.  At best, it appears that it may identify some areas to cut some costs, though this is mostly through the adoption of risk-based monitoring, which should happen whether TransCelerate exists or not.

I’ll remain a fan of TransCelerate, and will follow its progress with great interest in the hopes that it outperforms my expectations. However, it would do us all well to recognize that TransCelerate probably isn’t going to change things very dramatically -- the many systemic problems that add to the time and cost of clinical trials today will still be with us, and we need to continue to work hard to find better paths forward.

[Update 10-Oct-2012: Wayne Kubick, the CTO of CDISC, has posted a response with some additional details around cooperation between TransCelerate and CDISC around point 4 above.]

Mayday! Mayday! Photo credit: "Wheatley Maypole Dance 2008" from flikr user net_efekt.