Califf, Nissen, And Others Agree And Disagree About Regulatory Standards

Everyone agrees. A panel of US and European cardiologists, regulators, and industry executives agreed broadly that regulatory standards for drugs and devices need to be rigorous enough to prevent harm to patients. And, they also agreed, the standards shouldn’t be so strict that they stifle innovation.

The problem, of course, is how to find the right balance. So panel members at a European Society of Cardiology roundtable session were unable to agree on whether current regulations in the US and Europe were too easy or too restrictive or in which direction these regulations should move.

Discussing the differences between the US and European regulatory systems, Rob Califf, who is now the FDA’s Deputy Commissioner for Medical Products and Tobacco, tried to strike a balance. He said that the basic principles underlying the  evaluation of drugs is similar in the US and Europe but that “cultural variation could understandably lead to differences in the valuation of risks and benefits and the balance or risks and benefits.”

Califf responded to the criticism of the FDA requirement that the makers of diet and diabetes drugs have to perform cardiovascular outcomes trials. He said that the FDA has taken the position that “we need to understand the long term risk of these drugs that people may need to take for a lifetime.” Drugs that can be taken for shorter periods may have less stringent requirements.

Alan Fraser, of Cardiff University, said that the European system is characterized by earlier access, greater choice, less evidence, greater exposure to risks, expanded use before proof, and different treatment for drugs and devices. By contrast, the US system is characterized by delayed access, restricted range, demonstration of efficacy, avoidance of unexpected risks, evidence-based practice, and transparency.

Fraser also was highly critical of the European decentralized approach to device approval, which leaves evaluation in the hands of individual countries. He said that the central European device office employs only 7 full time equivalent employees, compared with over 300 in the US FDA’s CDRH.

Christian Hamm, of the Kerckhoff Heart and Thorax Centre in Germany, discussed the lag time between the US and Europe in the approval of devices. He pointed out that Europe has had the latest version of the Sapien TAVR valves years ahead of the US. “We are proud that we have these valves available here in Europe that seem to be safer.”

The Cleveland Clinic’s Steve Nissen said he agreed that regulations should encourage innovation but said that the more pressing problem, particularly in Europe, is the lax approval of devices.

But Nissen first acknowledged that the regulatory burden can be too high. He used the example of metformin, which is widely accepted as the most effective diabetes drug. It was introduced in the UK in 1958 and Canada in 1972.After initial approval in the US it was withdrawn from the market in 1977 over concerns about lactic acidosis and did not regain approval until 1995. “European patients had access to a beneficial drug for decades prior to US patients,” Nissen stated.

As a counter-example, Nissen cited niacin-laropiprant, which was approved in Europe in 2008 but did not gain approval in the US. After a large outcomes study showed a serious increase in adverse advents the drug was withdrawn in 2013. “European patients received an ineffective and potentially harmful drug,” he said.

Nissen was especially critical of lax European regulation of devices. Along with other panel members he pointed out that renal denervation devices remain on the market in Europe. 10-20,000 European patients “unnecessarily received a costly, worthless and risky procedure,” he said.  “Believe it or not, there was even another renal denervation device approved in Europe” after the spectacular failure of the Simplicity 3-HTN trial, Nissen said.

In response to proposals that new versions of devices are generally safer than previous versions and do not require a great degree of regulatory scrutiny, Nissen said that “what seems like a good improvement can be a catastrophe.” He cited the case of the Bjork Shiley valve, in which a small change in the shape of the device had disastrous consequences.

Industry representative R.A. D. Scott, of Amgen, was highly critical of tough regulations. He said that because of strict conflict of interest rules the FDA has difficulties finding qualified experts to serve on panels and that public advisory panels exert an undue burden on companies. In addition, he said, the public aspect of the panels “encourages grandstanding.” He said panels should meet outside the public glare and that the need for transparency could be handled through the web.