The FDA’s Magic Meeting

Can you shed three years of pipeline flab with this one simple trick?

"There’s no trick to it ... it’s just a simple trick!" -Brad Goodman

Getting a drug to market is hard. It is hard in every way a thing can be hard: it takes a long time, it's expensive, it involves a process that is opaque and frustrating, and failure is a much more likely outcome than success. Boston pioneers pointing their wagons west in 1820 had far better prospects for seeing the Pacific Ocean than a new drug, freshly launched into human trials, will ever have for earning a single dollar in sales.

Exact numbers are hard to come by, but the semi-official industry estimates are: about 6-8 years, a couple billion dollars, and more than 80% chance of ultimate failure.

Is there a secret handshake? Should we bring doughnuts?
(We should probably bring doughnuts.)

Finding ways to reduce any of those numbers is one of the premier obsessions of the pharma R&D world. We explore new technologies and standards, consider moving our trials to sites in other countries, consider skipping the sites altogether and going straight to the patient, and hire patient recruitment firms* to speed up trial enrollment. We even invent words to describe our latest and awesomest attempts at making development faster, better, and cheaper.

But perhaps all we needed was another meeting.

A recent blog post from Anne Pariser, an Associate Director at FDA's Center for Drug Evaluation and Research suggests that attending a pre-IND meeting can shave a whopping 3 years off your clinical development timeline:

For instance, for all new drugs approved between 2010 and 2012, the average clinical development time was more than 3 years faster when a pre-IND meeting was held than it was for drugs approved without a pre-IND meeting. 

For orphan drugs used to treat rare diseases, the development time for products with a pre-IND meeting was 6 years shorter on average or about half of what it was for those orphan drugs that did not have such a meeting.

That's it? A meeting? Cancel the massive CTMS integration – all we need are a couple tickets to DC?

Pariser's post appears to be an extension of an FDA presentation made at a joint NORD/DIA meeting last October. As far as I can tell, that presentation's not public, but it was covered by the Pink Sheet's Derrick Gingery on November 1.  That presentation covered just 2010 and 2011, and actually showed a 5 year benefit for drugs with pre-IND meetings (Pariser references 2010-2012).

Consider the fact that one VC-funded vendor** was recently spotted aggressively hyping the fact that its software reduced one trial’s timeline by 6 weeks. And here the FDA is telling us that a single sit-down saves an additional 150 weeks.

In addition, a second meeting – the End of Phase II meeting – saves another year, according to the NORD presentation.  Pariser does not include EOP2 data in her blog post.

So, time to charter a bus, load up the clinical and regulatory teams, and hit the road to Silver Spring?

Well, maybe. It probably couldn't hurt, and I'm sure it would be a great bonding experience, but there are some reasons to not take the numbers at face value.

• We’re dealing with really small numbers here. The NORD presentation covers 54 drugs, and Pariser's appears to add 39 to that total. The fact that the time-savings data shifted so dramatically – from 5 years to 3 – tips us off to the fact that we probably have a lot of variance in the data. We also have no idea how many pre-IND meetings there were, so we don't know the relative sizes of the comparison groups.
  
• It's a survivor-only data set. It doesn't include drugs that were terminated or rejected. FDA would never approve a clinical trial that only looked at patients who responded, then retroactively determined differences between them.  That approach is clearly susceptible to survivorship bias.
  
• It reports means. This is especially a problem given the small numbers being studied. It's entirely plausible that just one or two drugs that took a really long time are badly skewing the results. Medians with quartile ranges would have been a lot more enlightening here.

All of the above make me question how big an impact this one meeting can really have. I'm sure it's a good thing, but it can't be quite this amazing, can it?

However, it would be great to see more of these metrics, produced in more detail, by the FDA. The agency does a pretty good job of reporting on its own performance – the PDUFA performance reports are a worthwhile read – but it doesn't publish much in the way of sponsor metrics. Given the constant clamor for new pathways and concessions from the FDA, it would be truly enlightening to see how well the industry is actually taking advantage of the tools it currently has.

As Gingery wrote in his article, "Data showing that the existing FDA processes, if used, can reduce development time is interesting given the strong effort by industry to create new methods to streamline the approval process." Gingery also notes that two new official sponsor-FDA meeting points have been added in the recently-passed FDASIA, so it would seem extremely worthwhile to have some ongoing, rigorous measurement of the usage of, and benefit from, these meetings.

Of course, even if these meetings are strongly associated with faster pipeline times, don’t be so sure that simply adding the meeting will cut your development so dramatically. Goodhart's Law tells us that performance metrics, when turned into targets, have a tendency to fail: in this case, whatever it was about the drug, or the drug company leadership, that prevented the meeting from happening in the first place may still prove to be the real factor in the delay.

I suppose the ultimate lesson here might be: If your drug doesn't have a pre-IND meeting because your executive management has the hubris to believe it doesn't need FDA input, then you probably need new executives more than you need a meeting.

[Image: Meeting pictured may not contain actual magic. Photo from FDA's Flikr stream.]

*  Disclosure: the author works for one of those.
** Under the theory that there is no such thing as bad publicity, no link will be provided.

Changing the Rules, Ever So Slightly, For Rare Diseases

At the end of last year, US Reps Cliff Stearns (R-FL) and Ed Towns (D-NY) introduced the Unlocking Lifesaving Treatments for Rare-Diseases Act (ULTRA for short). Despite what its bold name might imply (and unlike many recent congressional healthcare bills), ULTRA is actually a modest and carefully-though-out piece of legislation.

The main thrust of ULTRA is to enable developers of drugs for rare diseases to take advantage of the FDA’s existing Accelerated Approval pathway. Accelerated Approval reduces the initial burden of proof for manufacturers to bring a drug to market by conducting smaller clinical trials that measure a drug’s efficacy against “surrogate” endpoints – that is, endpoints that do not directly measure the disease, but rather other factors that are associated with the disease. This can greatly reduce the time and cost of clinical trials.

To qualify for Accelerated Approval, however, trials for a new drug needs to meet two conditions:

• The drug must be studied for treatment of a serious disease, with unmet medical need


• There must be clinical evidence that improving the surrogate endpoint is reasonably likely to predict real benefit for those with the disease

ULTRA does not change the first criterion, only the second. For rare diseases, there is often not robust clinical evidence to support surrogate endpoints, so the bill alters the language slightly to permit the FDA to accept “reasonable scientific data that support and qualify the relevance of the surrogate endpoint”. In essence, the burden to prove the validity of the surrogate has been relaxed, permitting their use in pivotal trials, and using a surrogate may reduce the number of patients needed for a trial by as much as 50-75%.

Accelerated Approval still requires the drug manufacturer to complete full trials to more firmly establish the drug’s efficacy – it just allows the drug to be available on the market while those full trials are being conducted. ULTRA does not change this requirement for drugs of rare diseases, so in the end it is not lowering the standard for these drugs at all.

Obviously, anything can happen to a bill as it wends its way through congress. But as it is currently written, ULTRA is a highly rational, well-targeted adjustment to current law that should quickly show benefits for patients with rare diseases, and deserves quick action and passage.

(Further reading: the FDA Law Blog has an excellent review of the proposed act.)

People Who Disagree with Me Tend to End Up Being Investigated by the Federal Government

I don’t think this qualifies yet as a trend, but two disturbing announcements came right back to back last week:

First: As you’ve probably heard, KV Pharmaceutical caused quite a stir when they announced the pricing for their old-yet-new drug Makena. In response, Senators Sherrod Brown (D-OH) and Amy Klobuchar (D-MN) sent a letter to the FTC demanding they “initiate a formal investigation into any potential anticompetitive conduct” by KV. In explaining his call for the investigation, Brown notes:

Since KV Pharmaceuticals announced the intended price hike, I called on KV Pharmaceuticals to immediately reconsider their decision, but to this date the company continues to defend this astronomical price increase.

Second: One week after an FDA Advisory Committee voted 13 to 4 to recommend approving Novartis’s COPD drug indacaterol, Public Citizen wrote a letter to the US Office of Human Research Protections requesting the Novartis be investigated for conducting the very trials that supplied the evidence for that vote. The reason? Despite the fact that the FDA requested the trials be placebo controlled, Public Citizen feels that Novartis should not have allowed patients to be on placebo. The letter shows no apparent consideration for the idea that a large number of thoughtful, well-informed people considered the design of these trials and came to the conclusion that they were ethical (not only the FDA, but the independent Institutional Review Boards and Ethics Committees that oversaw each trial). Instead, Public Citizen blithely “look[s] forward to OHRP’s thorough and careful investigation of our allegations.”

The upshot of these two announcements seems to be: “we don’t like what you’re doing, and since we can’t get you to stop, we’ll try to initiate a federal investigation.” Even if neither of these efforts succeed they will still cause the companies involved to spend a significant amount of time and money defending themselves. In fact, maybe that’s the point: neither effort seems like a serious claim that actual laws were broken, but rather just an attempt at intimidation.