The MDS Beacon™

This edition of Dr. Steensma’s quarterly column is about participating in clinical trials. It will be published as a two-part series. In Part 1, Dr. Steensma describes the different types of clinical trials and where to find them. In Part 2, he will address concerns that MDS patients may have about participating in clinical trials.

Clinical trials – sometimes called “investigational studies” or “experimental protocols” – are medical research studies that follow a specific, pre-defined plan, called a study protocol.  While some clinical trials just involve observing patients over time to see how their condition behaves or screening groups of people for a health problem they are not yet known to have, most clinical trials are interventional studies.

Interventional studies are designed to assess the effectiveness and safety of a new medication or a combination of medications, in order to prevent or treat a specific medical condition.  When that medical condition is a difficult or uncommon disorder such as myelodysplastic syndromes (MDS), for which effective therapies are limited and where doctors often do not agree on the best treatment approach in specific situations faced by patients, information gained from well-designed clinical trials can be particularly important.

Clinical trial participation offers several direct benefits to patients.  Enrolling in a clinical trial may give patients their only chance to gain access to a promising new therapy before it becomes widely available.  In addition, patients who participate in clinical trials are monitored closely by the study team and usually receive top-notch care at good medical centers.  (Medical centers that go through the effort to run clinical trials often have specialized resources and employ doctors with focused interests and a lot of experience in an uncommon condition like MDS, which other institutions may lack.)  In addition to these direct benefits, the knowledge gained in a clinical study may help future patients, and altruistic motivations are important for some clinical trial participants.

Before a substance – i.e., a new molecule – can be approved by the Food and Drug Administration (FDA) or the equivalent regulatory agency in another country for general use as a drug, that substance must go through several stages of testing, including multiple phases of clinical trials.

First, before it can be used in humans, the new molecule has to undergo rigorous screening in cells in a laboratory and sometimes in animals.  If the new substance still looks like it could be useful for patients after this “pre-clinical” testing phase, the molecule may move into early phase, “first in human” clinical trials, sometimes called Phase 1 trials.

In Phase 1 studies, the main goal is to find out the right dose of the new molecule in humans and to learn what kind of side effects (sometimes called “adverse events”) the molecule can cause.  Sometimes these side effects are predictable based on animal studies or biochemical knowledge, but since human biology is so complex and people are so diverse, clinical trial investigators are also regularly surprised by unexpected effects of the molecule.

Since the likelihood of benefit from a first-in-human trial is low and little is known about the magnitude of risks, early phase trials are most appropriate for patients for whom all the conventional treatments have failed or patients who have a condition for which there is no good treatment.

As a result, Phase 1 trials generally have the broadest entry criteria, sometimes testing the same molecule in people with several different diseases, such as patients with either MDS or leukemia or another bone marrow disorder. Sometimes anyone with any kind of cancer that hasn’t responded to an existing treatment can participate in a Phase 1 trial.  Most Phase 1 trials enroll between 10 and 30 patients and are conducted at one or a small number of medical centers.

Once a safe dose of the new substance is determined, the experimental molecule can be given to a larger group of patients who have a specific condition, such as MDS.  These condition-specific trials are called Phase 2 trials, and they usually enroll between 30 and 200 patients and are conducted at several different medical centers at the same time.  In Phase 2 trials, typically all patients get the study molecule – just as in Phase 1 trials, there is no placebo or non-treatment control.

Finally, if a molecule looks promising in both Phase 1 and Phase 2 studies, it may move forward to a Phase 3 trial – sometimes called a “controlled” or “randomized” trial – in an even larger group of patients, usually at least several hundred (e.g., one of the largest MDS Phase 3 trials conducted to date, the AZA-001 study that established a survival benefit from Vidaza (azacitidine) treatment in patients with higher-risk MDS, enrolled 358 patients).

In a Phase 3 study, the new substance is compared to an existing standard treatment, if there is one, or to supportive care (e.g., just transfusions as needed) or a placebo (i.e., an inert, inactive substance) if there isn’t any standard therapy.  Safety of the new molecule continues to be carefully assessed during the Phase 2 and Phase 3 trials; sometimes uncommon side effects are first seen only when larger groups of patients are exposed to a new drug.

Use of a placebo is considered ethical only when there is no intervention with established benefit for the particular group of patients enrolled in the study, so that the placebo could actually be safer or better than the experimental molecule.  No responsible investigator would ever give a placebo to a patient if a safe and effective therapy were known to be available.

All studies conducted in the United States must first be reviewed by an Institutional Review Board, a group of independent experts who monitor biomedical research studies in order to ensure that the rights and welfare of study participants are protected.

There are many different kinds of clinical studies.  The most common are industry-sponsored studies, in which a for-profit biotechnology or pharmaceutical company provides both the study drug and the funding to conduct the study.

The study protocols for industry-sponsored trials may either be written by researchers and physicians working for the company or may instead be “investigator-initiated,” which means a doctor at an academic institution has written the study and then petitioned a company for both funding and access to the new experimental molecule.

Often a lot of negotiation must occur before the company and the study team come to an agreement on the specific details of the protocol, since the motivations of the company and the motivations of the study team for conducting the trial overlap, but are not identical.

Another common type of clinical studies are Cooperative Group trials, which are sponsored by the National Institutes of Health (NIH) using taxpayer dollars and conducted at dozens of medical centers simultaneously.  Examples of U.S. Cooperative Groups focused on patients with cancer include the Eastern Cooperative Oncology Group (ECOG), the Cancer and Leukemia Group B (CALGB), and the Southwestern Oncology Group (SWOG).

While the Cooperative Group Program of the National Cancer Institute (NCI) has done a lot of good work in the past and more than 25,000 patients with cancer continue to be enrolled in U.S. Cooperative Group studies each year, there has been a great deal of frustration with the Cooperative Group structure in recent years, since the Groups are perceived by many observers as excessively bureaucratic and conservative, stifling innovation.

On average, a newly proposed Cooperative Group trial takes almost three years to begin enrolling patients, and as of this writing, there are no Cooperative Group studies specifically focusing on MDS.  The current director of the NCI, Dr. Harold Varmus (1989 Nobel laureate), has recently mandated a major restructuring of the cancer-focused Cooperative Groups, including reduction of the number of Cooperative Groups from nine to no more than four and revamping the trial approval structure to streamline it.

Not all clinical trials are created equal.  Some are better designed – i.e., more carefully thought out by the researchers – than others.  Some test compounds that are brand new, about which little is known, while other trials study the effectiveness in patients with MDS of drugs that have been widely used for patients with other conditions for some time, where the safety and side effects may already be well established.

And some studies examine more exciting or more innovative therapies than others.  For example, a large study that opened in late 2008 was designed to compare Procrit (epoetin) treatment to placebo in patients with MDS.  The FDA required Johnson & Johnson, the company that sells Procrit, to conduct the study because of safety concerns that have emerged since 2005 with erythropoietin (Procrit and Aranesp (darbepoetin)) use in patients with certain types of tumors such as breast and head and neck cancer; these safety concerns are of unclear applicability to patients with MDS.

But since erythropoietin is the most commonly used drug in MDS and is widely available without participating in a study and doctors have almost 20 years of experience prescribing erythropoietin for patients with MDS, many doctors were unwilling to allow the possibility of having their patients be randomized to a placebo, and many patients also were unwilling to be assigned to receive a placebo.  So only a few people enrolled in that study – 25, rather than 480 as planned – and as a result, the study was discontinued after a year, which was a lot of wasted effort and money.

In contrast, the initial studies of Gleevec (imatinib) for chronic myeloid leukemia were viewed by both doctors and patients as so extremely promising that many medical centers, including mine, had to institute a lottery system to select patients for the limited number of trial slots available.

It may be difficult for patients and family members to make such judgments about which studies are truly the most interesting, and discussion with a trusted physician or a second opinion may be helpful.

The NIH- and FDA-supported website clinicaltrials.gov offers up-to-date information on ongoing clinical studies conducted by federal agencies (including Cooperative Groups) or private companies.  Because many medical journals will no longer accept papers for publication that report results of studies that weren’t first registered with clinicaltrials.gov, almost all ongoing studies are now registered at clinicaltrials.gov.  As of this writing (April 2, 2011), there are 443 trials listed on clinicaltrials.gov that are actively recruiting patients with MDS, testing more than 50 different drugs.  Information available at clinicaltrials.gov includes the location of study sites, as well as which specific criteria patients need to satisfy to be eligible for the trial.

Dr. David Steensma is a physician at the Dana-Farber Cancer Institute in Boston and is an Associate Professor in the Department of Medicine at Harvard Medical School. His primary area of research focuses on myelodysplastic syndromes and related conditions.