Before a new drug can gain approval by the US Food and Drug Administration (FDA), clinical studies must be conducted that document the drug’s safety and effectiveness.  To do so, a very exacting set of criteria are devised and a very select group of people are studied.  The recall or strengthened warnings required of recently released drugs has led a growing list of experts in the medical community to suggest it’s time for a change in the drug evaluation process, from studies conducted in such restrictive circumstances to one where drugs are tested in real world scenarios.

Most drugs are tested in studies where a clearly defined goal is targeted and the people chosen for the study are usually required to have no other medical issues except the one for which the drug under scrutiny is intended.  These studies are usually short-lived and don’t involve very many study participants.

While the findings of these studies are real in a study setting, they don’t seem to always hold true over time or with the growing number of patients who suffer from multiple medical conditions.  Problems ranging from nasty side effects to death sometimes arise once the drug is approved, marketed, and taken by everyday people in the real world.

Advocates for change have called upon Congress to fund a government-sanctioned institution devoted to comparative effectiveness research that would address gaps in evidence that occur somewhere between the clinical trial and the real, or pragmatic, setting.  Even some staunch defenders of the current method, such as Harvard Medical School’s cardiologist Dr. Eugene Braunwald, admit they’ve changed their thinking.

One drug that provides a convincing history is rosiglitazone, marketed as Avandia and used in the treatment of diabetes.  When tested, it did, in fact, lower blood sugar, the desired outcome.  After use in the real world, however, it was discovered that Avandia increases a patient’s risk of heart attack, a risk already heightened by diabetes itself.  Since many diabetics also suffer from heart failure and other cardiological issues associated with the disease, the drug might have been more appropriately tested on people who also tested positive for heart disease as well as diabetes and for effects other than just the lowering of blood sugar.

Dr. Robert Temple, director of medical policy for the FDA Center for Drug Evaluation and Research, says the agency has no “hard and fast rule” for drug evaluations and says much depends on a drug’s known short-term effects and predictions for its long-term outcome.  He suggests extensive pragmatic studies, involving more than 10,000 patients with complicated medical histories, however, would prove impossible to ever finish.

Dr. Kevin Weiss, the American Board of Medical Examiners’ president and chief executive, says there are no good guys or bad guys in this situation, just entities with different agendas.  He says the pharmaceutical companies making the drugs try to do what is expected of them as does the FDA.  The problem that arises is that neither entity is fully connected to public need.

At Johns Hopkins University School of Medicine, Dr. Steven Goodman, a biostatistician and oncologist, would like to see a reality check included in the larger, pragmatic clinical trials, which he describes as most feasible when as simple as possible.

As an example, he suggests a hypothetical surgical procedure which tests well in a trial setting but doesn’t work well at all in the real world.  The pragmatic study, involving real-world circumstances, would show the procedure doesn’t work but it won’t reveal why.  In this particular case, he suggests the surgical procedure under study may be one that requires so much skill and training that it can only be performed in a limited number of medical facilities, rendering it undesirable or unavailable for most surgical candidates.

Funding for such studies is another hurdle, with limited government funds available and large pharmaceutical companies limiting their funding to only the drugs in their line of products.  Most studies determine whether or not a particular drug works but do not compare it against competitive drugs to gauge which drug works better than the rest.

Skeptics of real-world drug studies say it would be impossible to recruit a large enough number of people willing to accept a placebo in lieu of a real drug.  This concern seems to be no issue, however, in an ongoing study of the drug nesiritide, administered to patients suffering from breathing difficulties caused by heart failure.

Nesiritide gained FDA approval in 2001 because studies showed patients breathed easier in the first few hours after taking it.  Nesiritide dilates blood vessels, which makes it easier for the heart to pump blood, which, in turn, leads to easier breathing.  The drug’s early studies involved mostly white men of an average age of 60 who were monitored for only a short time and who had few, if any, other medical complications.

In the real world, heart failure is common in patients older than 65 who have a multitude of medical conditions to complicate treatment.  More than 800,000 such patients in the US were hospitalized for heart failure in 2006 alone.

In an effort to include a large number of study participants, it’s become a common practice to combine data from several smaller studies, a practice known as meta-analysis.  Meta-analyses themselves have skeptics, including Dr. Adrian Hernandez, a Duke University cardiologist, who says these studies are not much more accurate than merely tossing a coin.  Subsequent studies prove meta-analyses accurate only about 60% of the time.

When a 2005 meta-analysis of nesiritide was conducted, an increased risk of kidney damage and death was discovered, a finding which led sales to drop sharply.

This plummeting sales record led Johnson & Johnson (J&J), nesiritide’s manufacturer, to seek the advice of a panel of experts, including Braunwald, which concluded the drug should be reserved for use only on the very sickest, hospitalized patients, a finding that led J&J to launch a pragmatic study of the drug.

This time, real heart failure patients, with all their medical complications, whatever they may be, have been given the opportunity to enroll in a study of nesiritide at any one of 450 medical facilities worldwide, making this study 15 times larger than any other conducted on the drug.  Only two questions are being targeted by the study – are patients still alive a month after treatment and are they hospitalized again.

Each patient enrolls for the study on a voluntary basis, knowing all along he or she will be randomly assigned an infusion of nesiritide to ease breathing or a placebo infusion of saltwater.  While skeptics warned no one in respiratory distress would gamble on getting a placebo when medicine is needed, enrollment is ahead of schedule, with more North American patients enrolled than have ever been included in a study of acute heart failure.

Source: NYT