Will PDUFA V be a 'damned if it does, damned if it doesn't' scenario for US FDA?
This article was originally published in SRA
Instead of being praised for speeding new treatments to patients or advancing medical innovation, the US Food and Drug Administration has come in for sharp criticism for failing to do enough to ensure patient safety, and this has resulted in the agency shifting to a more cautious, risk-averse posture in recent years, asserted Jonathan Leff, managing director of New York-based equity investment firm Warburg Pincus1,2.
As US regulators have become more cautious – demanding more and more data – the cost, time and risk of investment in medical innovation have gone up, driving capital away from US life sciences and toward other industries and countries, Mr Leff claimed during a 7 July House Energy & Commerce Health Subcommittee hearing, convened to examine reauthorisation of the Prescription Drug User Fee Act.
PDUFA, which was first authorised in 1992, permits the FDA to collect application, review and establishment fees from pharmaceutical companies to help expedite the drug approval process, in exchange for the agency meeting certain performance goals, including reviewing 90% of priority new drug applications within six months and standard applications within ten months.
The FDA and industry recently completed negotiations on the size and scope of user fees for fiscal years 2013 to 2017, or PDUFA V3. The agency is expected to publish the agreed-on details of those negotiations on its website on 1 September, with a public meeting anticipated in October, said Representative Joseph Pitts (Republican – Pennsylvania), chairman of the health subcommittee.
Mr Pitts noted that the FDA must send its final recommendations to the House Energy & Commerce Committee and the Senate Health, Education, Labor and Pensions Committee by 15 January 2012. He said it was his intention to have legislation passed and on the president's desk three months in advance of the 30 September 2012 PDUFA expiry date. "PDUFA is too important to leave to the last minute," Mr Pitts said.
In considering reauthorisation of PDUFA, the Republican leaders on the energy and commerce committee plan to examine the "lack of predictability and certainty at FDA," said Representative Fred Upton (Republican – Michigan), the panel chairman. "These problems at FDA appear to be stifling American innovation, costing American jobs and hurting American patients," Mr Upton claimed. He said the committee would also scrutinise the FDA's risk-benefit analysis for approving drugs and "whether the agency is striking the right balance on this delicate issue".
Mr Upton said the committee would take another look at provisions enacted under the FDA Amendments Act (FDAAA) of 2007 – the law PDUFA IV was enacted under – to see if they have caused delays in the drug approval process, such as the powers granted to the agency to require risk evaluation and mitigation strategy (REMS) plans. He also plans to take aim at advisory committee conflict-of-interest rules implemented under FDAAA, which Mr Upton called "rigid and unrealistic," charging that they have prevented the FDA from using "some of science's best minds and left advisory committee slots unfilled".
In contrast, Representative Henry Waxman (Democrat - California), energy and commerce committee ranking member, said he would be "strongly opposed" to any legislative proposals that may weaken the FDA's authority. "It is in no one's interest to have a weak FDA," Mr Waxman insisted. "If Americans lose confidence in the FDA, they will lose confidence in the pharmaceutical industry as well," Mr Waxman warned, cautioning against viewing the FDA's decisions "through the prism of whether it is good for the pharmaceutical industry".
"That's not the right perspective. The question we should be asking is, 'What is the right decision for patients?'" Mr Waxman said.
Without question, said Warburg Pincus's Mr Leff, protecting patients from harmful drugs is an essential element of what the public expects from the FDA. "But so too is enabling the timely development and availability of new therapies for those in need," he added.
The FDA's current risk-averse posture, where it has demanded more and larger trials, with longer follow-up and greater statistical certainty, has had the unintended consequence of reducing investment in life sciences innovation, Mr Leff argued. He acknowledged that many factors have contributed to the escalating cost, time and risk of new drug development, but insisted that "a changing regulatory environment at the FDA is the most significant".
Regulatory uncertainty, longer drug development timelines and an increasing focus on risk has deterred venture capitalists from investing in biotechnology firms, argued Paul Hastings, president and CEO of OncoMed Pharmaceuticals.
"It is imperative that the FDA be an agency that recognizes its national role in advancing innovation, maintains the ability to effectively review innovative products in a timely manner and promotes a consistent and science-based decision making process that is reflective of patient needs," Mr Hastings said, speaking on behalf of the Biotechnology Industry Organization.
"The US is in danger of losing its position as a global leader in medical innovation and its ability to keep private investment dollars and jobs at home as Europe, China and India continue to develop aggressive strategies to entice companies to take their research and development enterprises abroad," Mr Hastings insisted.
Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said the agency did not consider itself in competition with any other regulatory body. Dr Woodcock insisted, however, that the FDA was not running behind the rest of the world in approvals. She noted that of the cancer drugs approved in the US and Europe between October 2003 and December 2010, the FDA approved 32 in an average of 261 days, while the European Medicines Agency approved only 26 in 373 days. Of the 23 cancer medicines approved by both agencies during that period, all entered the US market first, Dr Woodcock said.
The CDER head contended that the FDA does not take a broad-swath approach to approving drugs, but instead reviews new medicines on a "case-by-case basis, considering the degree of unmet medical need and the severity and morbidity of the condition the drug is intended to treat". "This approach has been critical to increasing patient access to new drugs for cancer and rare and other serious diseases, where existing therapies have been few and limited in their effectiveness," Dr Woodcock said.
The FDA used that case-by-case approach in approving Bristol-Myers Squibb's metastatic melanoma drug Yervoy (ipilimumab) in March, Dr Woodcock said.
While Yervoy was the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment, the drug poses risks for serious adverse effects, including a high risk of fatal autoimmune reactions. But the FDA decided that the benefits of Yervoy outweighed its risk, Dr Woodcock said, especially in light of the fact that no other melanoma treatment had been shown to prolong a patient's life.
As for the REMS, Dr Woodcock noted that those requirements are not necessarily impediments. Indeed, she said, without a REMS requirement for AstraZeneca's medullary thyroid cancer drug Caprelsa (vandetanib), the medicine's benefits would not have been considered to outweigh its risks of adverse cardiovascular events and sudden death, "and the drug could not have been approved".
References
1. House Energy & Commerce Committee Subcommittee on Health press release, 7 July 2011, http://energycommerce.house.gov/news/PRArticle.aspx?NewsID=8782
2. PDUFA V: Medical Innovation, Jobs, and Patients, 7 July 2011, http://energycommerce.house.gov/hearings/hearingdetail.aspx?NewsID=8765
3. US FDA reveals some PDUFA meeting details, Regulatory Affairs Pharma, 6 May 2011