Did a scrappy little start-up just embarrass the FDA?

Adverse Events is a heath-tech start-up so new, they barely exist. Despite that, they’re getting some major results. Today they announced that they found from their early analysis – of the FDA’s own data – that two epilepsy drugs may be more dangerous in pregnancy than their FDA labeling might suggest. They used the FDA’s adverse event reporting data to compare the adverse events of commonly prescribed epilepsy drugs in pregnancy. What they found was that the FDA’s own labeling wasn’t consistent with their data.

Currently, the FDA classifies drugs used during pregnancy as being anywhere on a scale of safety from class A (“no known risk”), through levels of increasing risk labelled B, C, D, and then one final class X (“danger – do not use”). Specifically, Adverse Events found that two drugs, Lamictal and Keppra, which are Class C, may be “as dangerous to a fetus as drugs currently listed” in a more risky category (D).

In fact, Adverse Events’ analysis showed that an average birth defect rate comparison between the two groups, C and D, revealed no meaningful differences between the two. This scrappy little start-up’s analysis of the FDA’s own data may indicate that the FDA’s current categorization of pregnancy risks for epilepsy drugs may need revision. Or may be subject to bias.

I got a chance to talk to Adverse Events’ CEO, Brian Overstreet, at Health 2.0. We touched on some interesting controversies and future directions for this company.

Their provocative premise: Anyone should be able to report a side effect

Adverse Events has taken a new, e-patient approach to adverse events reporting by building in a feature that allows anyone to report their own experiences with side effects from their drugs. That process alone – allowing patients to report problems directly without being filtered through a doctor or drug company – already has some healthcare professionals feeling nervous. Overstreet thinks empowering patients is a huge issue in healthcare, and an important mission for their company. As he put it, “Disease groups have shown that people need a forum and want to share things with other people. Patients are coming to understand that they need to take it into their own hands to manage their conditions. When it comes to side effects, there is both a reluctance to report, and a sense that it will go into a void – if they report it to the FDA, they [the FDA] don’t do anything with it. Even what exists in the FDA’s database is only approximately 10% of what is happening each year. If we can improve that number even a bit – say 30% or 40% – that will be a big benefit to everyone.”

Adverse Events Interactions?

As a doctor, I wanted to know if there is going to be an adverse events “drug interaction” database? I think being able to plug drugs into an app, and find out if their adverse events are compounding each other, would be a great patient care tool. Overstreet explained that such a function “will be version 2.0. It’s a whole new level of math. Just getting and cleaning up the FDA database, we thought would take six months. It took 18 – that kind of adverse events interaction tool is definitely a stage II process.”

A Placebo Side Effects Profile

Every clinical trial ever done against placebo shows the reported placebo side effects. Surprisingly, there is not just a placebo benefit to people, there are also placebo side effects, such as headache and nausea. Sometimes the trials show that the difference between those reported side effects, and the ones for the drug, aren’t that different. I wanted to know if Adverse Events plans to include a placebo tab? Overstreet said no. Since their site is devoted to post-clinical trials experiences (where there is no placebo), they don’t have any plans to include reported placebo side effects for comparison.

Where Do They Go From Here

When it comes to post marketing drug side effect experiences, Overstreet said their first priority is bolstering the patient data beyond the FDA’s reporting, and grabbing the free-form data that is out there in patient chat rooms and groups. That is the most immediate stuff in the pipeline. The second is their approach to areas where the FDA has dropped the ball – as in epilepsy drugs in pregnancy, and statins, where the adverse events for one drug are clearly as common in others, but have prompted no label change. The second big pipeline issue is getting at the number of prescriptions written nationwide. They are currently getting their data from IMS, who get their data from pharmaceutical companies.

Post marketing trials are huge issue that the FDA and pharmaceutical companies are hashing out. Overstreet feels drug companies have to react strongly to any adverse event and the drug companies feel any type of reporting on their part becomes a regulatory issue. But, as he put it, “With our site, they can no longer bury their heads in the sand about this issue. Patients and providers and healthplans are going to now have this data, so they need to start dealing with this data.”

Trolling The Web For Adverse Events

Overstreet explained that one of the innovative approaches they plan to take toward getting adverse events information is by going to patient communities online, and trolling for mentions. He explains that the company is planning on refining this approach, and that, as a task, it is technically very feasible. “There are a lot of resources out there that provide the ability to go out there and look, and give you a dashboard of comments. The question becomes, if you have 1 million records to look at, how do you standardize that process?” Adverse Events plan on tackling that monumental task, and feel it is an important advance in patient safety over the current method, which, as Overstreet explained, “waits for a pharmaceutical company to have received a certain number of completed, full reports, at which point they are required to report it to the FDA. We believe those standards are too high. You don’t need to have the ‘end date’ of someone’s medication [to have a valid report].” According to Overstreet, the primary question they will need to tackle in going out to the web and looking for side effects boils down to “how do you take data that has an unstructured format and turn it into a structured format?”

What They’re Not Planning On Doing

I asked about the touchy issue of vaccines and autism, in terms of where this company stands on the issue of reporting associations that actually may not have any cause at all. In terms of deciphering out the difference between causation versus correlation, Adverse Event’s approach is to deal with this complex issue by a) the sheer scope of the data they have, and b) if a report comes into their database with a higher-than-normal reporting frequency, then it raises a red flag, which they then make public. As Overstreet put it, they don’t want to be arbiters of data, and if they see an issue raised, then they want it investigated.

Similarly, post-marketing trials of open-label drugs is also a scope of work that Adverse Events doesn’t plan on tackling in the immediate future. While there may be some therapeutic potential found for drugs buried in the data that they’ve cleaned and presented, Adverse Events doesn’t, at this time, see pursuing those possibilities as part of their mission.

Overstreet believes that their wealth of data “mutes out some outlier issues.” While they might be willing to work with researchers, and regulatory agencies to investigate issues, they do not plan on going to those groups first and waiting years for it to be sorted out. Like they’re showing with their reporting of pregnancy adverse events rates and anti-epilepsy drug inconsistencies, they instead plan on going straight to the press.

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