By Angela Woodall, Healthcare and Environmental Reporter.

Mortalities are rare during a clinical trial, especially during the initial stages. But in January, six men in France who had enrolled in a phase I trial of a pain relief drug  suffered brain damage. One man died.

France’s health minister Marisol Touraine called the incident unprecedented. “I have no knowledge of a comparable event,” she told reporters.

There have been no clinical trials of the drug in the United States, according to the FDA. That does not mean, however, that the U.S. industry won’t feel blowback from the events that happened thousands of miles away. Indeed, judging from past experiences, the scandal could prompt the FDA to tighten regulations here, complicating efforts to make the nation’s cautious approval process more nimble.

In the meantime, FDA regulators began working with their French counterparts in the Agence Francaise De Sécurité du Médicament et des Produits de Santé to understand what happened to the six men who signed up to test the drug, which goes by the name BIA 10-2474.


A History of Scandals

The last major phase I clinical trial catastrophe in Europe happened a decade ago in London when six men suffered permanent organ damage, and the loss of fingers, from severe immune reactions during the testing of an arthritis and cancer drug, the Chemical and Engineering News reported.

The whole point of a clinical trial is to provide proof to authorities that a drug is safe and effective when used as recommended. In fact, many experimental drugs never make it past the first stage despite years of testing, millions of dollars and desperate patients.

The FDA gives authorization to start a trial and will revoke this authorization if they feel the patients have been exposed to unnecessary risks, said Bruno Gagnon, a clinical operations executive who teaches clinical trial design at SanPRC Clinical CRO Francisco State University. “They rule with absolute supremacy about the conduct of clinical trials.”

Likewise, the French equivalent, the Agence Francaise De Sécurité du Médicament et des Produits de Santé, abbreviated as ANSM, is a very serious and sophisticated regulatory body, Gagnon said. French clinical trial organizations have to follow the country’s domestic rules and inspection programs as well as international and European Union regulations. Otherwise, Gagnon said, France and other EU countries are no different from the United States in requiring organizations to conduct proper clinical trials that will be safe for participants.  The FDA typically conducts more inspections of sites, manufacturing facilities, labs and sponsor companies, mainly because FDA regulators have more resources to do so, he said.

Such agencies see their mission as patient safety but the very scandals that have driven them to tighten regulations show that the regulators don’t always live up to their mandate. Injuries and deaths during trials have led to ever stricter regulatory measures.

The approach, according to bioethicist Carol Levine, was “born in scandal and reared in protectionism.” []

One of the most influential scandals happened half a century ago and involved a sedative, thalidomide, which caused severe malformations among children whose mothers took the drug to relieve morning sickness.

Thalidomide, synthesized by a West German company and marketed in 46 countries, never made it to U.S. consumers. But it had a profound impact on the nation’s process for evaluating and regulating new drugs. “In next to no time the fighting over the new drug laws that had been going on for five or six years suddenly melted away,” said Frances Kelsey, a FDA drug reviewer who fought successfully to keep thalidomide from getting U.S. approval.

That scandal added another dimension to the review process, according to an account by FDA historian Suzanne White Junod. After thalidomide, drug manufacturers not only had to prove that a drug was safe, they also had to show “substantial evidence” that the drug was effective based on “adequate and well-controlled studies.”


Balancing Risk and Rigor

Today the wall manufacturers have to scale in search of approval of new therapies has never been higher. The FDA holds patient safety as foremost in their review decisions, said Donna Kato, head of Regulatory Professionals, which helps pharmaceutical and medical device companies meet safety regulations. “The ultimate consideration is weighing the benefits versus the risk of a particular therapy in the subject population.”


Some argue that risk aversion has too much weight in the evaluations, a complaint that has long come from AIDS activists. Oncologist Razelle Kurzrock joined that group, arguing in the Nature Biotechnology journal that fallout from a 2011 scandal at Duke University, where cancer researchers falsified data in a clinical trial there, was “exacting an unjustifiable toll not only on health economics but also on patient lives.”

It’s a delicate balancing act that the FDA is grappling with, especially now that researchers are making digital technology central to the design of clinical trials.

FDA Commissioner Margaret Hamburg sees regulations as an opportunity rather than a roadblock. For example, the regulations resulting from the thalidomide scandal, Hamburg said, raised scientific standards that eventually ushered in today’s sophisticated, science-based life sciences industry.

Angela Woodall | Healthcare and Environmental Reporter


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