Accelerated Approval Great For “Me-Too” Products, FDA Says

CDER’s Bob Temple explains how competitors could actually help speed up a drug approval but also hold a product to a higher standard.

FDA might consider approving a product under the accelerated approval intermediate clinical endpoint pathway if the drug has only shown an effect on one clinical endpoint but already approved products have an effect on an additional endpoint as well.

Center for Drug Evaluation and Research Deputy Director for Clinical Science Robert Temple offered “The Pink Sheet” an example using a hypothetical new drug for multiple sclerosis that has shown an effect on exacerbations but not on long-term disability:

“We haven’t necessarily taken this [route] but in multiple sclerosis, the drugs do two things – one is they keep you from having flares and exacerbations, but they also have an effect on long-term disability. Well, we have generally approved drugs if they prevented flares but at this point with most of the drugs preventing disability also, it wouldn’t be crazy to say, I want to see that you have an effect both on occurrence rates and on disability. So that’s something where you can imagine if we only had data on one part of that and the drug looked otherwise promising we might ask for both” but grant accelerated approval based on the data in hand.

Of course, Temple said FDA might also decide not to approve the drug until data on both endpoints were available. Or if the drug “looks very promising” he said the agency might grant full approval just on the basis of recurrence and ask for disability data later as a traditional post-marketing requirement.

“This all has to be worked out,” he said, but illustrates the flexibility afforded by intermediate clinical endpoints (ICEs), an often forgotten and rarely used approach to accelerated approval. “Where it was clinically urgent to know this additional thing, then you might say we’re going to use the accelerated approval pathway.”

For instance, Temple explained it might be important to know the effect on the other endpoint to make a decision as to which patients or at what point in the course of treatment that therapy might be used.

While the accelerated approval pathway has always included the intermediate clinical endpoint option, the codification of the pathway in the 2012 FDA Safety and Innovation Act “strengthened” it and made clear that FDA has the “authority if we think it’s needed and there are important questions remaining about whether there is an effect on this outcome, we can ask for that,” Temple said.

“But most of the time as the expedited review document says, we usually [fully] approve drugs if they have an effect on real symptoms,” he added.

Temple acknowledged – as does FDA’s final guidance on expedited programs released in late May – that the agency does not have a lot of experience with accelerated approval based on intermediate endpoints.

And while some have advocated that using intermediate clinical endpoints could provide sponsors and FDA a smoother and faster path to accelerated approval, Temple said industry is probably happier FDA’s focus is elsewhere (Also see "Accelerated Approval Could Be Even Faster With Intermediate Clinical Endpoints" - Pink Sheet, 20 May, 2014.).

For the purposes of accelerated approval, FDA defines an intermediate clinical endpoint as a measurement of a therapeutic effect that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) and is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit (Also see "Accelerated Approval May Support Smaller Trials In Acute Diseases – FDA" - Pink Sheet, 2 Jun, 2014.).

Intermediate Endpoints Good For Short-Term Effects

“If we were to emphasize [intermediate clinical endpoints] more, I can’t believe that the industry would be really happy. That would be to say, that a lot of times you have a clinical endpoint, but we’re not going to approve you, we are going to give you an accelerated approval and make you do other stuff. That doesn’t seem like the thing they would like most,” Temple said.

“I think there are cases where that’s the right thing to do and we are certainly going to be looking at them but … accelerated approval, the real breakthrough if you like, initially was willingness to rely on a surrogate you weren’t sure about. That was a big step.”

The final expedited pathways guidance says that approvals for products for serious conditions based on clinical endpoints other than IMM will usually be considered under the traditional approval pathway. Accelerated approval using clinical endpoints will be considered “only when it is essential to determine the effects on IMM or other clinical benefit in order to confirm the predicted benefit that led to approval.”

“In most situations when somebody has an effect on a bona fide clinical endpoint we approve the drug,” Temple said. “And we gave some examples of why we might not … in the expedited review document.”

Situations in which an intermediate clinical endpoint could be used include:

• If the drug “doesn’t work long enough and other drugs that treat that disease do work longer” and
• “If all the other drugs in the class improve survival and you think you’ve got a drug here that improves symptoms,” Temple said.

“But most of the time if you have an effect we approve it,” Temple said.

The guidance alludes to Biogen Inc.’s Tysabri (natalizumab) as one example of a product that underwent accelerated approval based on a clinical endpoint because the effect seen was short-term in a chronic disease setting (Also see "Elan/Biogen Idec's Tysabri, Formerly Antegren, Approved For MS Based On One-Year Data" - Pink Sheet, 23 Nov, 2004.).

Though the document doesn’t explicitly name the multiple sclerosis drug, Temple noted Tysabri “had an effect over the course of the year of decreasing recurrences or exacerbations but the other available therapies worked for at least two years and we weren’t sure this was going to work long enough.” The accelerated approval asked for two-year data for full approval.

Temple also made reference to Chelsea Therapeutics International Ltd.’s Northera (droxidopa) for symptomatic neurogenic orthostatic hypotension, which was given accelerated approval for a short-term effect on dizziness with a requirement to establish durable or long-term benefit (Also see "Chelsea’s Northera Clears FDA But With A Confirmatory Trial Requirement" - Pink Sheet, 19 Feb, 2014.).

“So that’s a pretty good example because orthostatic hypotension is a long-term illness and most of us thought getting a benefit for a week isn’t really good enough. So we wanted to see that it worked longer and we thought it was reasonably likely that it would.”

No Big Advantage To ICE Accelerated Approvals

Temple doesn’t necessarily see the Northera trend happening often, however, noting most of the time “there is really no big advantage to a company to do a one-week study instead of a 10-week study. It’s not that much easier and sometimes drugs don’t work right away. I mean if you did that in depression your drug would fail because they don’t start working for five or six weeks.”

Plus Temple noted companies may not want accelerated approval if they can avoid it because of the labeling qualifications that might come with the designation (Also see "Accelerated Approval Labeling Caveat Draws Industry Ire" - Pink Sheet, 6 Jun, 2014.).

Still, FDA is curious if people will use intermediate clinical endpoints – or “accelerated approval type B” as Temple called it – more now that the expedited pathways guidance provides more detail on the topic.

Focusing on genetic issues is likely to be more useful in terms of achieving accelerated approval, Temple suggested (see related story, (Also see "Genetic Diseases Could See Indication Expansions Through Accelerated Approval" - Pink Sheet, 16 Jun, 2014.)).

Competitor Data Could Aid Single-Trial Approvals

While having other drugs in a class can sometimes make things more challenging for potential subsequent entrants, Temple noted an example where a competitor’s data set can actually speed approval, and allow a drug to rely on only a single Phase III study.

FDA’s guidance on when a sponsor could get approval on a single trial currently does not discuss the option to consider what other drugs in the class have done, but the agency has done exactly that, Temple said, although not for new molecular entities.

Data from the angiotensin 2 receptor blockers: Sanofi’s Avapro (irbesartan) and Merck & Co. Inc.’s Cozaar (losartan), each helped the other get expanded approval for delaying detrition of kidney function in diabetes patients, he said (Also see "Merck Cozaar Nephropathy Label Should Include Cardioprotection Uncertainty" - Pink Sheet, 22 Apr, 2002.).

“Each study showed an effect but it was nominally significant at .03, not what we would ordinarily say is good enough for single study approval. But there was one study with irbesartan and right at the same time there was another study with losartan and we told both companies we could approve both drugs if we were allowed to rely on data from the other one,” Temple said.

“Amazingly enough they granted us the right to rely on their data for the other party, so both drugs got approved. And that’s clearly because two drugs with identical pharmacology, each had a not overwhelming but significant effect, we thought that was a reasonable basis for approval,” Temple said.

“So what other members of a class have done could be a basis, provide some support for approval. And that really is not explicitly in the evidence document yet.”

FDA is working to see if there are more circumstances that could support single-trial approvals that it hasn’t addressed to add to its evidence document, Temple added.