FDA says off-the-shelf should be on the record

More should be filing IND applications

Too many research studies in this country are using experimental substances in human subjects without the oversight required by federal law and now can expect to undergo heavier scrutiny, say authorities with the U.S. Food and Drug Administration (FDA).

"Any substance that is not already marketed and is used in such a way as to affect the structure or function of the body is an investigational drug, and should have an application filed with us. That includes a lot of stuff that we know now we are absolutely not getting," advises Robert Temple, MD, associate director of the Center for Drug Evaluation and Research (CDER) at the FDA.

"We realize there is a lot of confusion in this area, and we are in the process of writing guidelines to clarify and make the regulations less confusing," he points out.

Following the death of a study subject at Johns Hopkins University in Baltimore, the FDA cited researcher Alkis Togias, MD, for ignoring basic safety rules during the trial and for not filing an investigational new drug (IND) application for the substance used.

In June 2001, Ellen Roche, a healthy 24-year-old, died after inhaling the chemical hexamethonium during a study designed to help researchers better understand the underlying causes of asthma attacks.

Roche was told to inhale the chemical — a known lung poison — so that researchers could see how her lungs reacted. Instead, the chemical severely damaged her lungs, leading to her death.

In its March 31, 2003, warning letter to Togias, federal officials said the study’s consent form did not adequately warn Roche of the risks involved — two prior subjects had experienced adverse reactions, and the chemical involved was known to have toxic effects on the lungs, was not an approved medication, and was a chemical grade labeled for laboratory use only.

The agency also cited Togias for failing to notify the IRB and obtain its approval for changing both the dose and method of delivery for the experimental substance. (The full text of the warning letter is available on the web at: www.fda.gov/cder/warn/2003/02-hfd-45-0303.pdf.)

Of interest to many other institutions, however, was the agency’s ruling that Togias and colleagues should have obtained IND approval from the FDA before proceeding.

Currently, many researchers are using unapproved substances in human subjects without such oversight at all, says Adil E. Shamoo, PhD, a professor at the University of Maryland School of Medicine in Baltimore and co-founder of Citizens for Responsible Care and Research, a nonprofit group dedicated to improving protections for human research subjects.

"They are doing it when they think it is required, I don’t doubt, but there are situations where it is not clear what is required and there is a lot of confusion," Shamoo adds.

When you need an IND

Researchers frequently take familiar substances off the shelf — chemicals not previously thought of as drugs — and use them in human research subjects without filing an IND application.

Sometimes, the experimental substances are ones that occur naturally in the human body and are thus thought of as safe, Temple explains.

However, a plain reading of the federal regulations enforced by the FDA stipulates that these substances should be considered experimental drugs when used by researchers to alter the functioning of the human body, Temple says.

These substances are, in fact, covered by the regulations governing experimental drugs, regardless of what researchers inform participants about in consent documents.

Medications already approved by the FDA and marketed are exempt from the rules — but this exemption only applies to the version of the drug that is actually on the market, Temple emphasizes. The same substance, or medication, in a different form, is an investigational drug.

"We know that not everyone realizes that and we know that we haven’t really pushed hard in the past," he adds.

The death at Hopkins convinced the agency the time had come to crack down on this practice.

"We don’t want to disrupt the whole research enterprise, and we know that many academic centers are going to be troubled if it turns out that every one of their studies should have had an IND application," he says.

"But we don’t want to see any more disasters. We really didn’t like what happened at Hopkins. A person died, for goodness sake. That is where we are. That is why we are looking at it," Temple explains.

Shamoo says federal laws governing use of substances in human subjects should be even stricter.

Under current federal law, only studies receiving federal funding or those covered by an IND application are subject to federal rules governing protection of research subjects.

Studies not involving investigational drugs or supported with federal dollars are subject to no federal oversight and do not have to be approved or monitored by an IRB.

"My attitude is that all chemicals introduced in human subjects ought to go to the FDA," he says.

"If I were advising IRBs and research universities, I would say that whenever they are using a chemical in human subjects, they should get FDA approval by filing an IND."

Shamoo notes that the FDA has sufficient authority under current federal law to require this level of compliance, but his opinion is not universal.

The CDER currently is drafting guidance for research institutions about when it is necessary to apply for an IND permit, Temple says.

The agency wants to find a way to offer maximum protections for research subjects without a massive interruption in critical medical research, he adds.

"There are some kinds of things that you don’t worry much about. Already, for example, there is a separate rule that relates to radioactive tracers," he explains.

"There is a whole section of the regulations that allow people to test those, because they are not expected to have any pharmacologic effect on the body at all. You can run those through radioactive drug review committees, and never send it to us.

That is because we have concluded that if the appropriate criteria are met, there is really no risk. One of the things we are thinking about in this instance is, are there various categories of substances that might be treated the same way?" Temple asks.

In the meantime, CDER has a hotline that researchers and institutions may call to inquire whether a proposed protocol requires IND approval. The compliance number at CDER is (301) 594-0054.

The confusion over investigational substances is just one in a long list of dangers faced by human research subjects, Shamoo says.

He says he hopes that the attention generated by the Hopkins case will lead not only to increased IND scrutiny, but also to reform of federal law.

One set of rules should apply to all research studies involving human participants, whether federally funded or not, Shamoo adds.

"This is already the case, believe it or not, with animals. Any research involving animals is regulated by one law, the Animal Welfare Act of 1966, regardless of the source of the funding.

"Whereas, in humans if it is federally supported or if it is an IND application, the rest is unregulated, which doesn’t make any sense. And that is what I would like to see changed," he points out.