Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

A major area of concern is the lower number of drugs that get the go-ahead after first review.

Four recently released reports paint a decidedly mixed picture of FDA’s ability to bring drugs to market. Bringing more safe, effective medicines to market for more diseases has been the quid pro quo for industry funding the cost of drug reviews since the first Prescription Drug User Fee Act (PDUFA) was authorized in 1992. The user fee act’s fifth authorization, or PDUFA V, is sailing through Congress and widely expected to be enacted by President Barack Obama well ahead of the current PDUFA’s September 30 expiration.

Not surprisingly, then, groups supportive of the biopharma industry as well as government have used the occasion to review FDA’s progress as well as shortcomings. On May 16, The New England Journal of Medicine published a study concluding that between 2001 and 2010, FDA approved more new medicines more quickly than the EMA or Health Canada.

The median first-review time was 303 days for the 225 new drugs approved by FDA, versus 352 for 99 new drugs by Health Canada and 366 for 186 new drugs by EMA, according to the research team led by Joseph S. Ross, M.D., assistant professor of internal medicine at of Yale University School of Medicine, and second-year medical student Nicholas Downing. FDA also recorded the fastest median total-review time of 322 days, compared with 366 by EMA and 393 by Health Canada. And among 72 new drugs approved by all three agencies, FDA had the fastest median review length at 254 days, compared with 346 days by the Canadian agency and 356 by the European agency.

Those numbers show FDA meeting a key benchmark of both the current PDUFA IV and planned PDUFA V, which set among FDA’s performance goals that the agency will review and act on 90% of standard original NDA and BLA submissions within 10 months of receipt and the same percentage of priority original applications within six months.

Along with that good news, however, the survey found some results less likely to reassure industry: FDA approved the lowest percentage, just 61.8%, of new drugs (139) after one cycle, compared with 68.7% (68) by Health Canada and 96.2% (179) by EMA. Industry has complained about new drugs needing to undergo multiple cycles of review as much as they’ve faulted overall speed of the approval process.

Drawbacks of Inconsistency and Expense

An industry-friendly report acknowledged the agency’s recent successes in cutting review time and approving more drugs but also faulted the agency for widely varying performance across therapeutic areas. In Managing Priorities: Therapeutic Area Variation in FDA Drug Regulation, released earlier this month, California Healthcare Institute (CHI) and The Boston Consulting Group (BCG) noted that oncology and anti-infective drugs experienced the fastest review timeframes at 10 to 15 months. For other categories such as cardiovascular, central nervous system, gastrointestinal, and respiratory drugs, reviews took 20 to 30 months.

CHI and BCG correctly attributed the disparity to FDA’s accelerated approval processes, which has benefited AIDS and cancer drugs. Since FDA introduced the accelerated approval process, 81 products were approved through this pathway: 32 targeted AIDS, 29 cancer, and 20 all other disorders.

Another factor impacting the number and types of drugs getting to the market is the cost of conducting Phase III trials. A report issued in April by Manhattan Institute for Policy Research called Stifling New Cures: The True Cost of Lengthy Clinical Drug Trials looked at four disease categories: adult-onset diabetes, obesity, stroke and other heart ailments, and rare diseases. For drugs that eventually did get approved, Phase III trials accounted for 90% or more of the cost of development.

When looping together therapies in development as well as those sanctioned, average Phase III trial costs varied from $5.57 million for the rare disease drugs studied, rising to $186.75 million for diabetes drugs, $253.6 million for antiobesity drugs, and zooming to about $2.855 billion for heart drugs. The low rare-disease number was skewed by the accelerated approval of Adcetris for Hodgkin lymphoma after Phase II studies.

Manhattan Institute suggests an answer: Allowing drugs found safe and promising in Phase I and Phase II trials to win approval for limited marketing to patients. The institute argues this will benefit patients by giving them early access to new therapies, while FDA could still collect more information and revoke marketing authorizations of drugs whose safety and effectiveness raised more questions than they settled.

That won’t satisfy anyone, though. Patient groups can credibly argue this poses too much risk, while industry has shown it will resist efforts by FDA to backtrack on earlier approvals, such as the agency’s revoking its approval in December of Avastin (bevacizumab) with chemo drug paclitaxel for treatment of women with Her2-negative metastatic breast cancer (MBC).

Focus Needed on Operations

What is to be done? Unfortunately, the CHI-BCG report offers no recommendations on a key question it raises: “How the FDA prioritizes drug reviews and when it chooses to use the tools at its disposal for accelerated approvals, does that align well or perfectly or not at all with public health needs? That’s a discussion we’d like to see and engage in,” CHI president and CEO David L. Gollaher, Ph.D., told GEN.

The CHI-BCG report is more valuable, however, in highlighting two FDA issues that it correctly concludes need attention: Its data collection and analysis as well as its review clock, which Dr. Gollaher likened to the stop-and-start clocks of basketball games.

“We think that a general look at the time from submission to approval in real time would be useful. But more, we want to encourage the agency to engage in a sophisticated discussion about what tools are out there, what algorithms and solutions are the most advanced as aids to decision-making,” Dr. Gollaher said.

That discussion should not result in much new legislation: “A lot of what we’re talking about is well within current statutory authority and is more a matter of managerial focus,” Dr. Gollaher noted. “The opportunity is for the agency to do what any great corporation does, which is to look to its best performance, and try to learn from that, and clone those procedures, activities, and techniques onto areas performing not as well.” He did, however, acknowledge that FDA lacks the flexibility that businesses have to hire, reassign, and fire staff.

One example might be improving the agency’s performance-tracking system, FDA-TRACK, to make it better live up to its acronym for “Transparency, Results, Accountability, Credibility, Knowledge-sharing.” And while FDA now requires electronic submissions, the resulting data deluge often doesn’t help the agency answer the key questions it must address in making drug decisions.

Not All Bad for the FDA

CHI and BCG did, however, acknowledge FDA’s progress toward faster drug decisions. The agency finished the 2011 federal fiscal year with 35 drug approvals. All but one was approved on or before their target dates set under PDUFA and most within their first review cycle.

More encouraging for FDA, a report issued in March by the U.S. Government Accountability Office (GAO) concluded that the agency met most of its performance goals for priority and standard original NDAs and BLAs between FY 2000 and FY 2010. FDA only missed the 90% review-completion benchmark in FY 2008, with 87.6% of standard submissions being reviewed in 10 months, and only 77.8% of priority submissions reviewed within six months.

FY 2008, though, was when FDA implemented the new rules under the Food and Drug Administration Amendments Act (FDAAA) of 2007. Since 2008, the percentage of priority NDAs and BLAs advancing to approval after first review has dropped. A dip was not seen with standard submissions, whose percentage generally rose from FY 2002–10. However, average FDA review time rose slightly between FY 2000–2010 for both priority and standard NDAs and BLAs.

In prepublication comments submitted to GAO, FDA’s parent agency, the U.S. Department of Health and Human Services (HHS), took a largely self-congratulatory stance, citing performance improvements FDA proposed as part of PDUFA V. If PDUFA V succeeds as swimmingly as HHS has forecast, it will largely reflect industry insistence that FDA couple higher user fees with more incentives rather than more rules.

Yet even the industry-friendlier PDUFA V won’t mean as much unless FDA gets more funding to speed up reviews and start catching up on biosimilars. Industry’s share of funding will rise under PDUFA V to 44% from 35% this fiscal year and remain there for five years.

Once the election ends, if history is a guide, Washington is likely to switch gears from talking about bigger FDA budgets to steady or reduced agency spending, especially if the threat of sequestration isn’t resolved by then. And FDA will need all the friends—and especially all the budget money—it can get to address its various shortcomings.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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