Mar. 01, 2013

Access to Care: What is Being Done, and for Whom?

By Joan T. Merrill, M.D., Medical Director, Lupus Foundation of America
Updated June 28, 2013

After more than a half-century of drought, many new treatments are in development for lupus.Each is finely tuned to target immune-system imbalances that are known to occur with lupus flares, heralding a potential sea change in the accuracy and precision ofmedical care.

Although only one biologic drug, belimumab (Benlysta®), has completed the arduous process to full regulatory approval by the Food and Drug Administration (FDA), several other treatments may be close behind. These include treatments similar to belimumab that tackle slightly different features in the same network of immune pathways (BlyS/APRIL pathways), treatments that inhibit the interferon pathway, and treatments that have other ways of dampening the activity of white blood cells that are hyperstimulated in lupus, especially T cells and B cells.

Will some of these additional treatments be approved fairly soon? We can be cautiously optimistic. There has been progress in understanding how to select participants for clinical trials, how to measure whether a treatment works, and how to put observed side effects into context in order to improve our confidence in the scientific assessment of new treatments for lupus.

However, approval of a new treatment does not ensure that all people with lupus will be able to try it. It is important to keep an eye on a problem known as “access to care,” since issues have already arisen with belimumab. By understanding what delays or even restricts access to care, perhaps some of these barriers can be removed in the future.

The Clinical Trial Process

In order for a treatment to be approved, it has to be successful in a minimum of two very large, and very expensive, scientific studies. These studies have to include patients from multiple clinics and are usually done at many centers around the world. The studies must be placebo-controlled, meaning that some participants are not receiving the treatment being studied, and the study must be “double-blind,” meaning that neither the volunteers nor the doctor know who is getting the real treatment and who is not, until the study is over.

The trial environment has to be highly controlled, as well: There are restrictions on when people can come for appointments, what other medications they can take, and sometimes even what and when they eat. This is not exactly like real life—and it means that most treatments approved by the FDA are tested in ways that are quite different from real life.

The trials also have to be monitored, which means outside professionals must visit each of the locations around the world where the clinical trial takes place, to double-check the accuracy of the results that are being reported. In addition, everything that happens to the participants in the studies must be reported to a central databank, so that adverse events—whether a heart attack or pneumonia or a mild cold, even a sprained ankle—can be compared between those receiving the drug treatment and those receiving the placebo.

Finally, follow-up safety studies that last many years must be performed, to ensure that as much as possible is known about side effects of the treatment before final regulatory approval is given. All of this was done for belimumab.

The Drug Approval Process

Most people in the lupus community are aware that belimumab is the first treatment for lupus in more than 50 years that demonstrated effectiveness in clinical trials, and that it was recently approved by the FDA and other government agencies around the world—but for limited use. This limited use is explained more later on.

Before belimumab was studied, the only FDA-approved treatments for lupus were hydroxychloroquine (Plaquenil®), corticosteroids, and aspirin. This means that government regulatory agencies have never approved the standard-of-care immunosuppressant medications most often used for moderate to severe lupus, including treatments that many readers of this article, if you have lupus, may have been taking for many years: azathioprine (Imuran®), methotrexate (Rheumatrex®), mycophenolate mofetil (CellCept®) leflunomide (Arava®), cyclophosphamide (Cytoxan®), cyclosporine (Neoral®), and tacrolimus (Prograf®). None of these are FDA-approved for lupus.

What does it mean to be taking a treatment that has not been approved by the FDA or other regulatory agencies? It means there is less information available to determine just how safe and effective the treatment is. However, because of the lack of approved alternatives they have been used in clinic for decades to treat lupus.The FDA does not think there is enough information to approve these treatments. . Yet the agency still requires that people with lupus try, and fail, those unapproved therapies—considered the standard-of-care therapies—before they can receive the newly approved treatment, belimumab which has been proven to be effective.

Barriers to Access to Care

One explanation for the FDA decision to require failure of standard-of-care medications is that the pivotal belimumab trials made failure of these unproven treatments a requirement for eligibility. For many researchers, the decision doesn’t make sense. For the lupus community, now that belimumab is approved for use, the notion that you have to fail unproven treatments before you can receive this proven treatment raises the first of several access-to-care issues.

Another requirement for entry into the large international belimumab studies was a currently positive antinuclear antibody (ANA) test or a currently positive anti-doublestranded DNA (anti-dsDNA) test. Those who tested negative when they were screened for the trial were not allowed to participate, even if their ANA test had been positive in the recent past at a different laboratory, and even though the ANA test is known not to be dependable or consistent from laboratory to laboratory.

Why? Because it had been suggested in an earlier clinical study that individuals with current positive ANA or anti-dsDNA were the ones for whom the drug effectiveness could be best demonstrated. This suggestion was never definitely proven, and a final conclusion cannot be drawn from this kind of exploratory analysis.

The suggestion of a relationship between ANA, anti-dsDNA, and belimumab efficacy was interesting, however, because it was also found that more than half of the participants with at least one of those positive tests had measurable levels of BlyS, the inflammatory protein that belimumab specifically targets. Only about one-fourth of those who tested negative for both ANA and anti-dsDNA at the time of entry into the trial had high BlyS. If you think it makes sense that those with high BlyS were the best candidates to receive a treatment that targets BlyS, you are certainly being logical, even though none of these relationships have been strictly proven.

But what about the one-quarter of participants who did not have positive ANA or anti-dsDNA and still had high levels of BlyS? They are ignored, because the FDA has restricted the use of belimumab in real-life clinics to those with a positive ANA or anti-dsDNA (called seropositive patients). That is a second important access-to-care barrier.

It is important to recognize that clinical trials are not designed to determine the entire range of individuals for whom a treatment might work. Rather, these studies are specifically designed to find an optimal group of individuals who can demonstrate the greatest differentiation between a treatment and a placebo, with minimal side effects.

Many of the clinical trials now under way for potential lupus treatments have the same entry restrictions that were used in the belimumab program. What will happen in the future to real-life patients with lupus who don’t fit in the narrow channel of people who meet all the entry criteria for clinical trials? Like everyone who was left out of the large, pivotal Phase III belimumab trials, those who do not meet the entry criteria could well be left out of future clinical trials of promising therapies. And this may happen regardless of whether or not the new drugs being tested really work better in that group of seropositive patients the way belimumab did in one, relatively small, exploratory study.

The implications of this are that once the new treatments are improved, people who are not seropositive are also likely to be denied access to these treatments. It needs to be clarified that even if a medication is not FDA-approved to treat a particular condition, it can be legally prescribed. Thus the use of belimumab for a patient who does not meet the letter of the approval limits is allowed, and physicians may prescribe belimumab for anyone they deem an appropriate candidate, regardless of the FDA approval language. But are insurance companies likely to cover the costs of a drug when it is used that way? This is an increasingly crucial access-to-care issue.

Another problem is that in order to see a difference between belimumab and standard of care treatments, a decision was made to only enroll people when they had significant disease activity and to measure improvement. Is there any other way to evaluate the effectiveness of a treatment? Yes. You could choose to enroll people who are not so ill at the beginning and compare how many flares of lupus occur if you get the real drug or the placebo. Both are legitimate trial designs. But because the first type was chosen for the pivotal belimumab studies, it was felt necessary to allow the background treatments to be increased at the beginning of the study. This meant that there were high numbers of people who were in the placebo group who did get better, narrowing the difference between the response rates in the treatment and placebo groups.

In re-analyzing the trial, it was clear that belimumab looked like it was the most effective in the group of people who were most sick of all when they entered the study. Now some countries are only allowing belimumab to be given to that extra sick population. But there are two reasons belimumab appeared to work better in that group that have nothing to do with its effectiveness. First, the way the outcomes are measured, sicker people are more likely to achieve the degree of improvement needed to be called a responder. Second, the placebo group, receiving aggressive standard of care, are of course less likely to respond in a very ill group of patients than a slightly less sick group of patients. Think about what this means to patients now around the world. If you are not terribly sick you can be denied access to belimumab, which has been shown to prevent flares of lupus. To receive this treatment you will have to wait until you are quite ill, after your organs may have already sustained significant damage. What is wrong with this picture?

The Hard Questions

It is worthwhile to question why the appropriateness of trying belimumab for a given patient is not being left to the individuals most intimately involved in the decision: the patient and the physician. Why shouldn’t a person with lupus be allowed to weigh the risks and benefits of medication choices in consultation with an experienced doctor who knows her or him as an individual, and is not just looking at a stack of graphs containing trial results? When did patients lose their right to choose among treatment alternatives, and when did doctors lose their authority to provide these alternatives?

If belimumab were inexpensive, these questions would not have to be asked. It is true that belimumab is much more costly than the unapproved standard of care immune suppressants, many of which are now “off patent” and available in generic forms. Physicians have no trouble prescribing azathioprine, methotrexate, or corticosteroids with minimal official justifications; coincidentally, these are the most inexpensive alternatives available. Of course, it would be wrong to ignore the potential problems of widespread use of very expensive medications in situations where cheaper alternatives would be perfectly safe and effective. To do so indiscriminately could bankrupt the medical care system. Yet, we must ask ourselves: Is having uncontrolled lupus inexpensive?
Either in monetary or human costs?

And we know not everybody gets an optimal result from belimumab. This is not surprising, considering the unpredictable nature of lupus. Yet, from what is known to date, belimumab is, overall, very well tolerated by most people, adding low additional risks when given with standard of care treatments. But think about the cumulative side effects caused by years of steroid treatment: high blood pressure, diabetes, serious weight gain, high cholesterol, increased risk of serious infections, and severe bone damage. Are these effects of “standard of care” steroids inexpensive?

These serious access-to-care issues need to be addressed by the lupus community—and soon. There is hope on the horizon, but this hope must be made available to those who most need it.

The question left open, then, is which is best to try first in a serious illness such as lupus: the expensive proven medication, or the cheaper unproven medications, that, while we think they are somewhat effective, are also known to cause serious side effects—which, over time, can be worse than the disease itself.


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