Industry in need of major improvements

Best solution? More clinical trials

At the very least, pharmaceutical companies and other sponsors who rely on the clinical trial industry need to evaluate how they conduct post-marketing studies and make improvements that will increase public safety, a health law expert says.

For instance, there is a need for an increase in post-marketing studies to be conducted in a manner that is more consistent with the level of regulatory oversight given to Phase III-B studies, says LaDale George, JD, senior counsel in the health law department/health care business counseling practicing group of Chicago-based Foley & Lardner.

"I believe there’s going to be an increase in Phase IV studies and an expansion of the requirement for diversity of subjects in participating trials," he says.

"We’ve seen two connecting regulatory events lately," George explains. "One is the post-market rejection of products, which is Vioxx."

The other is a heavy enforcement by the FDA of off-label marketing of products, he notes.

Off-label marketing by pharmaceutical companies is the result of pharmaceutical companies learning about positive results from the use of their product in a manner that is different from how it was labeled, George explains.

"But the company has never gone back to test or run a trial to validate that information that would support a change in the labeling," he says. "If they would have run a trial to support a change in the labeling it would be considered a Phase IV trial because of post-regulatory approval, and it would likely support the off-label activity that is being marketed by the company inappropriately."

Instead, the companies at times have spread the word to physicians that an off-label use might work, and the FDA has cracked down heavily on this activity as illegal marketing, charging some drug companies with millions of dollars in fines, George says.

"So what I see is the industry is getting two simultaneous messages: if you’re going to market off-label, you will be punished; so therefore, run a real trial to support what your claims are," he says. "And secondly, I’m seeing the industry being informed that it needs to run stronger, more accurate, and appropriate Phase IV trials in order to not have products pulled from the marketplace."

The FDA should refocus its energies on safety as opposed to effectiveness, George suggests.

"The marketplace will determine whether or not a product is more effective than another," he says. "The FDA’s concern should be on safety because the marketplace is not the testing ground for safety."

While many in the clinical trial industry fear that further FDA scrutiny for safety could result in even more expensive clinical trials and longer delays in getting a new product to market, George disputes that contention.

If the FDA would spend its time looking at safety and not at whether or not it’s putting another me-too product on the marketplace, it won’t take longer, he says.

Let the marketplace and corporate advertising determine which of the hundreds of statin drugs will be used by consumers, but have the FDA charged with the responsibility of putting safety first, George says.

With regard to the ongoing issue of whether selective serotonin reuptake inhibitors (SSRIs) should be prescribed for children and teenagers, he says that is a problem with a lack of diversity in clinical trials.

"To some extent with SSRIs, there was limited testing on suicidality in adolescents, and that’s where things went awry," George says. "That’s an issue of diversity and special population testing."

Diversity and special populations

The need for greater diversity in clinical trials also was highlighted in 2003 by the safety alert issued by GlaxoSmithKline, based in Middlesex, England, regarding the use of salmeterol xinafoate (Serevent), George notes.

GlaxoSmithKline’s letter to the health care community says one study [post-regulatory approval] found that among African Americans taking salmeterol xinafoate, an asthma inhalant medication, there was a statistically significant greater number of primary events and asthma-related events, including death, compared with those taking placebo.1

"As a result, there has been some re-labeling and indication changes for the product to address the impact on a special population," George says.

The same problems have been found in pediatrics medicine where drugs approved for adults have proved problematic for children, he notes.

These issues likely will result in an expansion of trials and a push for greater diversity among clinical trial subjects, George reports.

"You will need to learn if the pharmacokinetics of your product are the same or different based on ethnicity, and that’s significant," he says.

Although this issue is treated as new, it’s based on old facts and common knowledge of health-related differences between people of different ethnic groups, he says.

"For example, Native Americans don’t metabolize grain alcohol the way many non-native American populations do," George says. "And for Hispanics, some diabetes medications on the market are not as effective in many Hispanic populations."

The FDA does not mandate proportionality testing, even in areas of high prevalence, and that’s a mistake, he says.

"If you know that African Americans have a higher incidence of high blood pressure, then before you bring a blood pressure medication to that market, you need to test a higher proportion of that population," George explains.

This philosophy seems to be catching on with pharmaceutical companies, who are increasing their level of diversity, he adds.

One special population for which there are no easy solutions is children, George notes.

Testing children is a public policy problem because it will continue to be difficult to convince parents to have a healthy child used as a volunteer to test a product that would provide a minor health solution, he says.

"This is something we as a community of patients and providers need to come to terms with how we’re going to test better in those populations to assure more accurate and effective treatment of our patients," George says. "Until patient-specific targeted therapies are developed, all medicine still is trial and error."


1. 2003 Safety Alert — Serevent (salmeterol xinafoate). Letter to health care professionals by GlaxoSmithKline. Available on-line at