Showing posts with label drug safety. Show all posts
Showing posts with label drug safety. Show all posts

Wednesday, August 7, 2013

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.

Tuesday, June 4, 2013

Can FDA's New Transparency Survive Avandia?

PDUFA V commitments signal a strong commitment to tolerance of open debate in the face of uncertainty.

I can admit to a rather powerful lack of enthusiasm when reading about interpersonal squabbles. It’s even worse in the scientific world: when I read about debates getting mired in personal attacks I tend to simply stop reading and move on to something else.

However, the really interesting part of this week’s meeting of an FDA joint Advisory Committee to discuss the controversial diabetes drug Avandia – at least in the sense of likely long-term impact – is not the scientific question under discussion, but the surfacing and handling of the raging interpersonal battle going on right now inside the Division of Cardiovascular and Renal Products. So I'll have to swallow my distaste and follow along with the drama.
Two words that make us mistrust Duke:
 Anil Potti Christian Laettner

Not that the scientific question at hand – does Avandia pose significant heart risks? – isn't interesting. It is. But if there’s one thing that everyone seems to agree on, it’s that we don’t have good data on the topic. Despite the re-adjudication of RECORD, no one trusts its design (and, ironically, the one trial with a design to rigorously answer the question was halted after intense pressure, despite an AdComm recommendation that it continue).  And no one seems particularly enthused about changing the current status of Avandia: in all likelihood it will continue to be permitted to be marketed under heavy restrictions. Rather than changing the future of diabetes, I suspect the committee will be content to let us slog along the same mucky trail.

The really interesting question, that will potentially impact CDER for years to come, is how it can function with frothing, open dissent among its staffers. As has been widely reported, FDA reviewer Tom Marciniak has written a rather wild and vitriolic assessment of the RECORD trial, excoriating most everyone involved. In a particularly stunning passage, Marciniak appears to claim that the entire output of anyone working at Duke University cannot be trusted because of the fraud committed by Duke cancer researcher Anil Potti:
I would have thought that the two words “Anil Potti” are sufficient for convincing anyone that Duke University is a poor choice for a contractor whose task it is to confirm the integrity of scientific research. 
(One wonders how far Marciniak is willing to take his guilt-by-association theme. Are the words “Cheng Yi Liang” sufficient to convince us that all FDA employees, including Marciniak, are poor choices for deciding matter relating to publicly-traded companies? Should I not comment on government activities because I’m a resident of Illinois (my two words: “Rod Blagojevich”)?)

Rather than censoring or reprimanding Marciniak, his supervisors have taken the extraordinary step of letting him publicly air his criticisms, and then they have in turn publicly criticized his methods and approach.

I have been unable to think of a similar situation at any regulatory agency. The tolerance for dissent being displayed by FDA is, I believe, completely unprecedented.

And that’s the cliffhanger for me: can the FDA’s commitment to transparency extend so far as to accommodate public disagreements about its own approval decisions? Can it do so even when the disagreements take an extremely nasty and inappropriate tone?

  • Rather than considering that open debate is a good thing, will journalists jump on the drama and portray agency leadership as weak and indecisive?
  • Will the usual suspects in Congress be able to exploit this disagreement for their own political gain? How many House subcommittees will be summoning Janet Woodcock in the coming weeks?

I think what Bob Temple and Norman Stockbridge are doing is a tremendous experiment in open government. If they can pull it off, it could force other agencies to radically rethink how they go about crafting and implementing regulations. However, I also worry that it is politically simply not a viable approach, and that the agency will ultimately be seriously hurt by attacks from the media and legislators.

Where is this coming from?

As part of its recent PDUFA V commitment, the FDA put out a fascinating draft document, Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making. It didn't get a lot of attention when first published back in February (few FDA documents do). However, it lays out a rather bold vision for how the FDA can acknowledge the existence of uncertainty in its evaluation of new drugs. Its proposed structure even envisions an open and honest accounting of divergent interpretations of data:
When they're frothing at the mouth, even Atticus
doesn't let them publish a review
A framework for benefit-risk decision-making that summarizes the relevant facts, uncertainties, and key areas of judgment, and clearly explains how these factors influence a regulatory decision, can greatly inform and clarify the regulatory discussion. Such a framework can provide transparency regarding the basis of conflicting recommendations made by different parties using the same information.
(Emphasis mine.)

Of course, the structured framework here is designed to reflect rational disagreement. Marciniak’s scattershot insults are in many ways a terrible first case for trying out a new level of transparency.

The draft framework notes that safety issues, like Avandia, are some of the major areas of uncertainty in the regulatory process. Contrast this vision of coolly and systematically addressing uncertainties with the sad reality of Marciniak’s attack:
In contrast to the prospective and highly planned studies of effectiveness, safety findings emerge from a wide range of sources, including spontaneous adverse event reports, epidemiology studies, meta-analyses of controlled trials, or in some cases from randomized, controlled trials. However, even controlled trials, where the evidence of an effect is generally most persuasive, can sometimes provide contradictory and inconsistent findings on safety as the analyses are in many cases not planned and often reflect multiple testing. A systematic approach that specifies the sources of evidence, the strength of each piece of evidence, and draws conclusions that explain how the uncertainty weighed on the decision, can lead to more explicit communication of regulatory decisions. We anticipate that this work will continue beyond FY 2013.
I hope that work will continue beyond 2013. Thoughtful, open discussions of real uncertainties are one of the most worthwhile goals FDA can aspire to, even if it means having to learn how to do so without letting the Marciniaks of the world scuttle the whole endeavor.

[Update June 6: Further bolstering the idea that the AdCom is just as much about FDA's ability to transparently manage differences of expert opinion in the face of uncertain data, CDER Director Janet Woodcock posted this note on the FDA's blog. She's pretty explicit about the bigger picture:
There have been, and continue to be, differences of opinion and scientific disputes, which is not uncommon within the agency, stemming from varied conclusions about the existing data, not only with Avandia, but with other FDA-regulated products. 
At FDA, we actively encourage and welcome robust scientific debate on the complex matters we deal with — as such a transparent approach ensures the scientific input we need, enriches the discussions, and enhances our decision-making.
I agree, and hope she can pull it off.]

Wednesday, April 17, 2013

But WHY is There an App for That?


FDA should get out of the data entry business.

There’s an app for that!

We've all heard that more than enough times. It started as a line in an ad and has exploded into one of the top meme-mantras of our time: if your organization doesn't have an app, it would seem, you'd better get busy developing one.

Submitting your coffee shop review? Yes!
Submitting a serious med device problem? Less so!
So the fact that the FDA is promising to release a mobile app for physicians to report adverse events with devices is hardly shocking. But it is disappointing.

The current process for physicians and consumers to voluntarily submit adverse even information about drugs or medical devices is a bit cumbersome. The FDA's form 3500 requests quite a lot of contextual data: patient demographics, specifics of the problem, any lab tests or diagnostics that were run, and the eventual outcome. That makes sense, because it helps them to better understand the nature of the issue, and more data should provide a better ability spotting trends over time.

The drawback, of course, is that this makes data entry slower and more involved, which probably reduces the total number of adverse events reported – and, by most estimates, the number of reports is far lower than the total amount of actual events.

And that’s the problem: converting a data-entry-intensive paper or online activity into a data-entry-intensive mobile app activity just modernizes the hassle. In fact, it probably makes it worse, as entering large amounts of free-form text is not, shall we say, a strong point of mobile apps.

The solution here is for FDA to get itself out of the data entry business. Adverse event information – and the critical contextual data to go with it – already exist in a variety of data streams. Rather than asking physicians and patients to re-enter this data, FDA should be working on interfaces for them to transfer the data that’s already there. That means developing a robust set of Application Programming Interfaces (APIs) that can be used by the teams who are developing medical data apps – everything from hospital EMR systems, to physician reference apps, to patient medication and symptom tracking apps. Those applications are likely to have far more data inside them than FDA currently receives, so enabling more seamless transmission of that data should be a top priority.

(A simple analogy might be helpful here: when an application on your computer or phone crashes, the operating system generally bundles any diagnostic information together, then asks if you want to submit the error data to the manufacturer. FDA should be working with external developers on this type of “1-click” system rather that providing user-unfriendly forms to fill out.)

A couple other programs would seem to support this approach:

  • The congressionally-mandated Sentinel Initiative, which requires FDA to set up programs to tap into active data streams, such as insurance claims databases, to detect potential safety signals
  • A 2012 White House directive for all Federal agencies pursue the development of APIs as part of a broader "digital government" program

(Thanks to RF's Alec Gaffney for pointing out the White House directive.)

Perhaps FDA is already working on APIs for seamless adverse event reporting, but I could not find any evidence of their plans in this area. And even if they are, building a mobile app is still a waste of time and resources.

Sometimes being tech savvy means not jumping on the current tech trend: this is clearly one of those times. Let’s not have an app for that.

(Smartphone image via flikr user DigiEnable.)