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Health Affairs


If A Drug Is Good Enough For Europeans, It's Good Enough For Us

February 14, 2014

By Paul Howard, Yevgeniy Feyman

Meningitis is a terrible disease that can kill its victims in a single day. About 4,100 new cases are diagnosed annually in the U.S., with a mortality rate of more than 10 percent. Even with treatment, survivors are often left with serious side effects that can include brain damage and limb loss.

A recent meningitis outbreak at Princeton University was unique, however, because the vaccines typically required by universities don’t protect against the particular strain (serogroup B or �MenB�) of the outbreak. Luckily, Swiss drug manufacturer Novartis has developed a vaccine � Bexsero � that specifically targets this strain of meningitis; the drug has already been approved for use by the European Medicines Agency (EMA), the European Union’s equivalent of the Food and Drug Administration (FDA). And within about nine months the FDA allowed Princeton University to offer the vaccine on campus to its students.

Problem solved, right? Not so fast.

Another MenB outbreak occurred at University of California, Santa Barbara, prompting the dean of U.C. Riverside medical school to request the same deal from the FDA. The FDA has decided to also permit the use of Bexsero in California, after an extended delay likely due to negotiations between the FDA, Novartis, and the university. But it shouldn’t so hard to approve products that have already been vetted by other trusted regulators abroad.

Multiple clinical trials show the Bexsero vaccine is effective and safe in infants and adults. After a full course of therapy (involving three doses), infants and toddlers had complete antibody protection against two vaccine components, and 84 percent against the remaining two. These results led to the drug’s approval in Europe, Australia and Canada. Novartis’ first Phase II trial for Bexsero finished in 2007; about 5 years later, it was approved in Europe, with Australia and Canada following suit a few months later.

Where does the FDA stand? While Phase I and II trials have been completed (these trials establish safety and preliminary efficacy), the FDA has yet to approve a design for Novartis’ �confirmatory� Phase III trials, the largest, most complex trials. Even after they are approved, they may cost millions of dollars and take years to complete � just so Novartis can submit a new drug application to the FDA, let alone have it approved.

The natural question to ask is why the FDA shouldn’t just approve a product already approved for the European Union, Canada, and Australia, while monitoring the vaccine (as all vaccines are already monitored � Bexsero is being actively monitored in the E.U.) through postmarket surveillance records? (Indeed, the more than 5,000 patients vaccinated at Princeton are close to the total number of patients tested in the EMA required trials.)

The Case For Reciprocity

The FDA could argue that the EMA and the FDA have significantly different approval standards. Or that the populations tested in E.U. trials are significantly different than those required for U.S. trials. In some cases, this may be true. But many commonly used drugs � like those routinely used for hypertension, painkillers, and gastric discomfort � are widely available here and in the E.U. There’s also a net loss for society by requiring manufacturers to essentially jump through the same hoops over and over, expending scarce R&D dollars and human resources (i.e., patients) running multiple trials of the same medicines for different regulatory jurisdictions.

If the FDA, EMA, and other advanced regulators have (largely) the same safety standards, there should at least be reciprocal approval for vaccines (and likely many drug classes as well) where the biological understanding of the underlying mechanisms of action are well understood, and where robust postmarket surveillance tools are already in place. The FDA already works, to some extent, with international regulators to harmonize regulations, so this wouldn’t be a heavy lift for the agency.

But while the FDA and EMA engage in high level discussion and collaboration, true reciprocity of approvals has never really been on the table. Why? Regulators may fear losing clout, and application review fees � about $672 million in 2012 � that come with submitting new drug approvals to the FDA. After all, if access to the large and lucrative U.S. market could be obtained by going to the EMA rather than the FDA, there might be a mass exodus of drug applications to the E.U.

A Race To The Bottom? Not Likely.

Skeptics might say that competing on regulatory authority could cause a �race to the bottom� as agencies slash regulations to be most competitive in the global regulatory �marketplace� and attract the most applications. This argument isn’t terribly convincing.

Limited and optional reciprocity. First, reciprocity could be limited to our highly developed trading partners, and to well-understood drug classes or products where there is a high unmet need, like cystic fibrosis or the myriad cancers that don’t respond well to available therapies. Starting with a few classes as a prototype program and using robust surveillance of patient records would rule out the likelihood of another Vioxx-type debacle, where a new and widely used NSAID (a pain-reliever) was linked to as many as 140,000 potential cases of heart disease. Reciprocity could also be optional: Companies could apply for reciprocity, and if either the FDA/EMA declined, they would have to respond, publicly in writing, explaining exactly which regulatory standards the approved application didn’t meet. The drugmaker could also be required to list the regulatory approval standard for the product � EMA or FDA � on the product’s label, so doctors and patients could make informed decisions about whether to use products approved abroad.

Tort and regulatory system protections. Second, developed countries tend to have well-established tort and regulatory systems. In the United States, a company with a shoddy drug would face devastating financial penalties and a tarnished reputation. Regulators’ structural incentives to protect their own populations (and reputations for scientific probity) also wouldn’t change. (In fact, there’s a substantive body of evidence suggesting that FDA regulations are too risk averse, rather than too lax.)

The AIDS precedent. Lastly, we’ve already seen what loosening the FDA’s reins can mean for deadly diseases. Perhaps the best lesson is the war on AIDS in the 1990s, chronicled in films like the Dallas Buyers Club. Desperate patients with no good alternatives imported unapproved medicines into the United States, forcing the FDA to change its regulations and accelerate access to medicines in preliminary testing. AIDS activists deserve credit for pioneering the Accelerated Approval pathway (which essentially cuts out the long and costly Phase III trials), and setting the stage for subsequent FDA reforms. Fast forward two decades and HIV/AIDS has become a manageable, chronic condition rather than a death sentence.

In the long run, reciprocity would encourage beneficial regulatory and scientific competition between advanced regulatory agencies, forcing the FDA and its sister agencies in advanced economies to compete on the efficiency and rationality of their regulations. Economists Alex Tabarrok and Daniel Klein even suggest that reciprocity could also allow the FDA to narrow its focus to the most complex, novel products and technologies that didn’t have any other predicate, and review those more thoroughly.

International regulatory competition would mainly benefit consumers who would gain faster access to new medicines, and (potentially) lower prices if development costs and times fell as well. Most importantly, it would save lives.

Given the FDA’s waiver for Princeton, it’s a good time to ask why reciprocity for EMA approvals shouldn’t be more routine. What’s good enough for the Princeton Tigers, after all, should be good enough for the rest of us too.

Original Source:



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