BioMarin Advisory Committee Outcome - Canary in the Coal Mine?

December 9, 2015 Brian Daniels, M.D., Peter J. Pitts


iStock_000001785888_Medium.jpgThe FDA recently held an Advisory Committee meeting to consider BioMarin’s investigatory treatment for Duchenne’s muscular dystrophy.  The outcome caught many by surprise - and many were watching this AdComm as a "canary in the coal mine" for broader patient group involvement.       

The Duchenne’s community has been at the forefront of working with the FDA on drafting guidance on how to bring new therapies to market for Duchenne’s, a deadly disease that has no approved treatments.

The outcome was not entirely expected.  The FDA Division provided the Advisory Committee with evidence that showed an imbalance between efficacy and safety and, despite well-prepared and delivered testimony on the part of patient groups, the science under discussion pointed to ambiguous review options inside the FDA.

How does this outcome impact and inform future rare disease development and  patient group involvement?  YourEncore Executive Partner, Peter J. Pitts, sat down with Brian Daniels, former SVP of Global Development and Medical Affairs at Bristol-Myers Squibb, to share their thoughts.

PITTS (Q):       When the FDA document package came out for BioMarin, people were surprised that the Division was relatively negative from an evidentiary standpoint. Do you think that the input from the patient community had an impact at all on how the Division presented its evidence to the Advisory Committee?

DANIELS (A): Most surprising was the charge that was given to the AdComm. The lack of voting question indicated that the Division was concerned about the benefit/risk profile. Did the patient advocacy groups contribute to the development pathway for the drug? I believe they did, particularly in validating the importance of the six-minute walk test to the patient and the family.

PITTS (Q):       What messages does this send to developers?

DANIELS (A): The FDA has listened to the advice of not just the Duchenne’s muscular dystrophy community, but also other communities about how to think about patient-driven outcomes for their diseases. Don’t view this one episode as a step backwards in that approach. It reflects the chronic nature of Duchenne’s muscular dystrophy and the fact that you’re looking at years of therapy.

PITTS (Q):       What you think about the fact that people are now realizing that just because patients have voice in clinical design trials and endpoint selections and, more broadly speaking, risk/benefit analyses patient-focused drug development means automatic approval?

DANIELS (A): I think it reflects that nothing is monolithic in its nature. Even in patient advocacy, you have multiple patient advocates for a disease and they have divergent opinions. I think patient reported outcomes, or at least patient-driven drug development will continue to be important. I think the FDA will listen, but at the end of the day the evidentiary standards for benefit and risk will remain the same. I think patient-reported outcomes will help widen the field of what are important endpoints to make as your primary endpoints or important secondary endpoints. It’s a totality of evidence argument.

PITTS (Q):       Do you think there is a potential for the agency to look at the evidence and say, “We can approve this drug but with significant post-market obligations, specifically real outcomes collection and timely reporting?

DANIELS (A): Yes. This would give the FDA the flexibility to take almost any type of action that they feel is appropriate and represents their best understanding of the potential benefits and risks of the drug.

PITTS (Q):       People seem to have some faith that the process actually is moving forward and that it will ultimately change the weight of certain types of evidence in the review process.

DANIELS (A): I do believe the FDA is seriously listening to patient groups and physicians who have treated these patients as to how to think about more innovative endpoints in trial design. My expectation is that this will continue to show its benefit in helping companies develop novel therapies for diseases in which there aren’t necessarily today well-validated and tested endpoints. So I remain optimistic.

PITTS (Q):       As to the issue of totality of evidence, what we’re doing now is appropriately broadening what “totality” includes. And that’s not binary; it requires significant philosophical work inside the agency and that’s going to make their job tougher.

DANIELS (A): I agree and, as I said, the FDA isn’t going to change their standard for approval, which is in general robust evidence of efficacy and a good understanding of what to expect on the safety side and how to describe the safety aspects in the label. This does open up a greater range of potential endpoints, but at the end of the day, you need to be able to demonstrate with a high degree of certainty that the endpoints you have chosen demonstrate a clinically meaningful change.

PITTS (Q):       It also speaks to the need of better thinking about collection of post-marketing evidence and a more 21st century view of pharmacovigilance and pharmacoepidemiology.

DANIELS (A): Indeed, like we were mentioning before -- the ability for the agency to take positive action will require the commitment to continually develop the medicine in the marketed space and provide the FDA with timely updates about the efficacy and safety of the molecule. Risk/benefit constantly evolves both during the investigational phase of a drug and once the drug is on the market. And I think using what you can learn in the real world as a way to continue to evolve a better understanding of your benefit/risk and how to express that in the label to physicians and patients is the role of the sponsor.

PITTS (Q):       That’s a good point, patient focused drug development isn’t just about getting a drug through the FDA; it’s following it up once it’s on the market to make sure the real world evidence can impact appropriate prescribing and regulatory actions as required.

DANIELS (A): It is worth recognizing the inherent limitations of registrational clinical studies. One of which is that the duration of one or two years usually do not capture the molecular effects on long-term clinical endpoints or safety. There are cases where outcome studies as part of approval; generally the cardiovascular and metabolic and sometimes in oncology. But in general most of the important clinical outcomes, did the patient live longer or have a better quality of life, need the post-marketing studies because they require more time under observation.

PITTS (Q):       So maybe a good way to wrap up is to say that the BioMarin AdComm is to say that patient-focused drug development doesn’t mean drugs are going to be approved quicker or more easily, but it’s going to require more work both on the pre-licensing front and on the post-marketing front as well by developer, by patient groups and by regulators.

DANIELS (A): I agree. The regime hasn’t changed. It remains the same as far as the robustness of clinical evidence needed. And I think we should continue to look forward to innovation within patient directed outcomes.

PITTS (Q):       And that a totality of evidence doesn’t mean that all evidence is equal.

DANIELS (A): That’s clearly the case.

PITTS (Q):       Thanks, Brian. Good conversation.

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