Joan T. Merrill, MD

More than 20 companies currently are evaluating treatments for lupus in randomized studies – more than ever before. The recent approval of belimumab (Benlysta), the first drug developed specifically for lupus in over 50 years, ended a 2-decade-long drought for lupus treatment development, by finally providing evidence that a drug has benefits when compared to background treatments alone. Until now, this progress was impeded by the heterogeneous nature of the disease, the complex process of selecting volunteers for clinical trials, the imprecision of clinical trial end points, and the highly complex and often confusing instruments used to measure disease activity that comprises these end points.

But even as the causes of lupus are becoming clearer and basic research is beginning to produce multiple, potential, finely tuned molecular targets for treatment, the completion of phase III trials has been proceeding more slowly than one would hope for.

So what are the factors impeding progress?

For one, multiple, competing, international-scale trials require multiple, well-trained, international trial sites. Although training of new investigators at new trial sites around the world is underway, the process has been slow and the results imperfect. Clinical trials also require experienced clinical scientists who can conform to international regulatory practices, but the rules are enormously complex and sometimes arcane. These clinical scientists must also be trained in lupus outcome measures that are even more complex and sometimes even more arcane. What’s more, in both cases the rules are frequently revised.

As understandably risk-adverse companies find themselves conducting international-scale clinical trials for a poorly understood and serious disease, recent phase III trials have become increasingly restrictive in setting limits on volunteers who are allowed to participate. Sometimes there are pages of entry criteria, making it difficult to recruit enough volunteers from real-world clinics.

Clinical studies that limit enrollment to patients who meet the American College of Rheumatology’s (ACR’s) Classification Criteria for systemic lupus erythematosus (SLE) have put trial participation out of reach for many patients with severe lupus syndromes in only one organ, such as primary discoid lupus, antiphospholipid syndrome, and other blood disorders such as immune-mediated microangiopathy. But patients with multiple organs that are mildly involved can often enter these same trials on a technicality.

One consequence of these increasingly formidable issues in entry criteria for trials is that once a drug is approved, only those people with lupus who meet the criteria may be deemed eligible for the drug by regulatory authorities. Therefore, the treatments will not be available for many or even most of the population we are trying to help. Some insurers have gone even further to require that patients exactly match the entry criteria for trials. They demand that a patient to be covered for treatment match the trial eligibility criteria by having certain scores on the disease activity measurement indices used for the studies, usually the SLE Disease Activity Index (SLEDAI) or the British Isles Lupus Assessment Group (BILAG) index. But most practicing physicians are not trained to use these measurement scales.

Because lupus is a serious and potentially life-threatening disorder, there has been resistance to using trial designs that include placebo groups. One approach to this would be to compare a new agent to a standard-of-care medication. However, very few medications are approved for lupus, illustrating another problem: the difficulty in getting a drug approved for lupus because of clinical trial issues specific to the disease.

Right now, for example, the first-line standard of care agent for lupus nephritis is cyclophosphamide. A number of clinical trials found that mycophenolate mofetin (CellCept) is at least equivalent to cyclophosphamide for the treatment of acute lupus nephritis. This included at least one large international registrational trial (the ALMS study) that was designed as a possible approval pathway for mycophenolate. However, the Food and Drug Administration decided not to approve mycophenolate because proving equivalency to cyclophosphamide was not enough – it had to be proved superior. That is because regulatory agencies consider all unapproved treatments to be the same as placebo. For this reason, most clinical trials are being designed as "add on" studies, in which all patients receive standard of care with the addition of either the study agent or placebo.

Added to this is the fact that the regulatory agencies require yearlong studies in order to prove that efficacy can be sustained. No patient would enter a clinical trial for a year and risk receiving a placebo unless some accommodation was made for their safety and comfort by allowing some increases in their current (often fairly effective) background treatments. This increases the likelihood that the placebo group can do well, limiting the differences that can be seen between a given treatment under study and the placebo population.

In the pivotal phase III international trials of Benlysta, all participants in the study received reasonably effective standard of care background medications, which could be increased in the early part of the study for the patients’ safety and comfort. Then either Benlysta or a placebo was added on to that treatment. This study was able to show that the benefits of Benlysta plus background mediations were significantly greater than those seen in patients on background medications alone, but the difference was narrow. When a trial design must allow aggressive treatment of placebo patients, this will inevitably result in a narrower difference, and a much larger trial is then needed to prove efficacy. Furthermore, any lack of training and standardization in evaluating the patients can make the difference between a positive and a negative trial.

What can be done to address these issues, expedite clinical trials, and promote the availability of more effective treatments for lupus approved by the Food and Drug Administration? The Lupus Foundation of America has been addressing these barriers in a systematic fashion:

1. Improve the quality of clinical trial sites and care of patients who participate in trials around the world. This initiative has led to an online program capable of training and certifying clinicians around the world on the most commonly used lupus disease evaluation systems: the BILAG, SLEDAI, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). The Lupus Foundation of America’s Professional Online Instrument Training (POINT) program is now the primary tool used by companies that are conducting studies of lupus treatments. About 2,000 doctors worldwide are conducting clinical trials of lupus treatments, and this interactive educational tool has become their standard of reference.

2. Support work to improve classification criteria for SLE and outcome measures for trials and clinical practice. The Lupus Foundation of America, in conjunction with the National Institutes of Health (NIH), supported the most recent studies of classification criteria for lupus, and is working to expand definitions of diagnosis and suitability for biologic therapy to serious organ-limited lupus, and to limit such access for patients with insignificant illness, whether or not they have multiple organs involved. Additionally, in conjunction with EULAR (the European League Against Rheumatism), the Lupus Foundation of America initiated and has continued to support a large project to refine the measures for flares of lupus disease that have sometimes provided a confusing aspect to outcome measures. This work has been ongoing for more than 2 years, and has resulted in several abstracts/publications; a final validation study is planned for the near future to support an outcome measure that better matches physician opinion than the current rules allow. These studies were performed by international groups of physician experts, primarily, but not exclusively, members of the Systemic Lupus International Collaborating Clinics.

Finally, to address the problem that once treatments are on the market, simpler disease activity and outcome measures are needed for practicing clinicians to use in a real-world clinic to justify expensive biologic treatments for their patients, the Lupus Foundation of America is supporting a project called DIAL (Directed Integrated Assessment of Lupus), which allows rapid and comprehensive scaling of type and degree of illness in these complex patients.

3. Improve the understanding of the impact of background treatments on clinical trial end points, and evaluate which trial end points best differentiate between treatments. The Foundation has developed a central database of clinical trial data from placebo groups (usually patients receiving different standard of care background treatments) from multiple past clinical trials performed at different companies. By pooling this information, it may be possible to determine which background medications are most likely to result in placebo responses that limit serious flares of disease while not being so effective as to defeat the purpose of a clinical trial. Once this is achieved, it will also be possible to have accumulated enough data on patients who are treated similarly to begin to test the most effective end points in some of these clinical trials.

While clinical drug trials are designed to detect significant differences between the group assigned the treatment and the control group, lupus drug trials need to be designed to detect greater differences. Support for basic science grants remains a priority at the Lupus Foundation of America, and it joins other advocacy groups and the NIH in continuing to award grants to outstanding researchers who continue to refine our understanding of the disease process and potential biomarkers. This, in turn, helps us select and guide the new treatments in development.

Efforts to address and overcome barriers inherent in lupus clinical trials are a discussion that needs to be continually engaged in with the FDA, third-party payers, scientists, physicians who study new treatments, and lupus patients. We need to do more to educate regulators and insurance agencies about lupus, and continue the work of bringing down the barriers to treatment development. This should include convening key opinion leaders, the biotechnology sector, and the NIH and regulatory agencies to work on clinical trial design – something that must evolve further to optimize progress.

Dr. Merrill is the head of the clinical pharmacology research program and is a professor in the department of medicine, rheumatology, and immunology at the Oklahoma Medical Research Foundation, Oklahoma City. She has financial relationships with numerous pharmaceutical companies, including Human Genome Sciences/GlaxoSmithKline, maker of Benlysta. Ms. Raymond is president and chief executive officer of the Lupus Foundation of America, Washington, D.C. (www.lupus.org/newsite/index.html). She reports that she has no financial disclosures.

More than 20 companies currently are evaluating treatments for lupus in randomized studies – more than ever before. The recent approval of belimumab (Benlysta), the first drug developed specifically for lupus in over 50 years, ended a 2-decade-long drought for lupus treatment development, by finally providing evidence that a drug has benefits when compared to background treatments alone. Until now, this progress was impeded by the heterogeneous nature of the disease, the complex process of selecting volunteers for clinical trials, the imprecision of clinical trial end points, and the highly complex and often confusing instruments used to measure disease activity that comprises these end points.

But even as the causes of lupus are becoming clearer and basic research is beginning to produce multiple, potential, finely tuned molecular targets for treatment, the completion of phase III trials has been proceeding more slowly than one would hope for.

So what are the factors impeding progress?

For one, multiple, competing, international-scale trials require multiple, well-trained, international trial sites. Although training of new investigators at new trial sites around the world is underway, the process has been slow and the results imperfect. Clinical trials also require experienced clinical scientists who can conform to international regulatory practices, but the rules are enormously complex and sometimes arcane. These clinical scientists must also be trained in lupus outcome measures that are even more complex and sometimes even more arcane. What’s more, in both cases the rules are frequently revised.

As understandably risk-adverse companies find themselves conducting international-scale clinical trials for a poorly understood and serious disease, recent phase III trials have become increasingly restrictive in setting limits on volunteers who are allowed to participate. Sometimes there are pages of entry criteria, making it difficult to recruit enough volunteers from real-world clinics.

Clinical studies that limit enrollment to patients who meet the American College of Rheumatology’s (ACR’s) Classification Criteria for systemic lupus erythematosus (SLE) have put trial participation out of reach for many patients with severe lupus syndromes in only one organ, such as primary discoid lupus, antiphospholipid syndrome, and other blood disorders such as immune-mediated microangiopathy. But patients with multiple organs that are mildly involved can often enter these same trials on a technicality.

One consequence of these increasingly formidable issues in entry criteria for trials is that once a drug is approved, only those people with lupus who meet the criteria may be deemed eligible for the drug by regulatory authorities. Therefore, the treatments will not be available for many or even most of the population we are trying to help. Some insurers have gone even further to require that patients exactly match the entry criteria for trials. They demand that a patient to be covered for treatment match the trial eligibility criteria by having certain scores on the disease activity measurement indices used for the studies, usually the SLE Disease Activity Index (SLEDAI) or the British Isles Lupus Assessment Group (BILAG) index. But most practicing physicians are not trained to use these measurement scales.

Because lupus is a serious and potentially life-threatening disorder, there has been resistance to using trial designs that include placebo groups. One approach to this would be to compare a new agent to a standard-of-care medication. However, very few medications are approved for lupus, illustrating another problem: the difficulty in getting a drug approved for lupus because of clinical trial issues specific to the disease.

Right now, for example, the first-line standard of care agent for lupus nephritis is cyclophosphamide. A number of clinical trials found that mycophenolate mofetin (CellCept) is at least equivalent to cyclophosphamide for the treatment of acute lupus nephritis. This included at least one large international registrational trial (the ALMS study) that was designed as a possible approval pathway for mycophenolate. However, the Food and Drug Administration decided not to approve mycophenolate because proving equivalency to cyclophosphamide was not enough – it had to be proved superior. That is because regulatory agencies consider all unapproved treatments to be the same as placebo. For this reason, most clinical trials are being designed as "add on" studies, in which all patients receive standard of care with the addition of either the study agent or placebo.

Added to this is the fact that the regulatory agencies require yearlong studies in order to prove that efficacy can be sustained. No patient would enter a clinical trial for a year and risk receiving a placebo unless some accommodation was made for their safety and comfort by allowing some increases in their current (often fairly effective) background treatments. This increases the likelihood that the placebo group can do well, limiting the differences that can be seen between a given treatment under study and the placebo population.

In the pivotal phase III international trials of Benlysta, all participants in the study received reasonably effective standard of care background medications, which could be increased in the early part of the study for the patients’ safety and comfort. Then either Benlysta or a placebo was added on to that treatment. This study was able to show that the benefits of Benlysta plus background mediations were significantly greater than those seen in patients on background medications alone, but the difference was narrow. When a trial design must allow aggressive treatment of placebo patients, this will inevitably result in a narrower difference, and a much larger trial is then needed to prove efficacy. Furthermore, any lack of training and standardization in evaluating the patients can make the difference between a positive and a negative trial.

What can be done to address these issues, expedite clinical trials, and promote the availability of more effective treatments for lupus approved by the Food and Drug Administration? The Lupus Foundation of America has been addressing these barriers in a systematic fashion:

1. Improve the quality of clinical trial sites and care of patients who participate in trials around the world. This initiative has led to an online program capable of training and certifying clinicians around the world on the most commonly used lupus disease evaluation systems: the BILAG, SLEDAI, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). The Lupus Foundation of America’s Professional Online Instrument Training (POINT) program is now the primary tool used by companies that are conducting studies of lupus treatments. About 2,000 doctors worldwide are conducting clinical trials of lupus treatments, and this interactive educational tool has become their standard of reference.

2. Support work to improve classification criteria for SLE and outcome measures for trials and clinical practice. The Lupus Foundation of America, in conjunction with the National Institutes of Health (NIH), supported the most recent studies of classification criteria for lupus, and is working to expand definitions of diagnosis and suitability for biologic therapy to serious organ-limited lupus, and to limit such access for patients with insignificant illness, whether or not they have multiple organs involved. Additionally, in conjunction with EULAR (the European League Against Rheumatism), the Lupus Foundation of America initiated and has continued to support a large project to refine the measures for flares of lupus disease that have sometimes provided a confusing aspect to outcome measures. This work has been ongoing for more than 2 years, and has resulted in several abstracts/publications; a final validation study is planned for the near future to support an outcome measure that better matches physician opinion than the current rules allow. These studies were performed by international groups of physician experts, primarily, but not exclusively, members of the Systemic Lupus International Collaborating Clinics.

Finally, to address the problem that once treatments are on the market, simpler disease activity and outcome measures are needed for practicing clinicians to use in a real-world clinic to justify expensive biologic treatments for their patients, the Lupus Foundation of America is supporting a project called DIAL (Directed Integrated Assessment of Lupus), which allows rapid and comprehensive scaling of type and degree of illness in these complex patients.

3. Improve the understanding of the impact of background treatments on clinical trial end points, and evaluate which trial end points best differentiate between treatments. The Foundation has developed a central database of clinical trial data from placebo groups (usually patients receiving different standard of care background treatments) from multiple past clinical trials performed at different companies. By pooling this information, it may be possible to determine which background medications are most likely to result in placebo responses that limit serious flares of disease while not being so effective as to defeat the purpose of a clinical trial. Once this is achieved, it will also be possible to have accumulated enough data on patients who are treated similarly to begin to test the most effective end points in some of these clinical trials.

While clinical drug trials are designed to detect significant differences between the group assigned the treatment and the control group, lupus drug trials need to be designed to detect greater differences. Support for basic science grants remains a priority at the Lupus Foundation of America, and it joins other advocacy groups and the NIH in continuing to award grants to outstanding researchers who continue to refine our understanding of the disease process and potential biomarkers. This, in turn, helps us select and guide the new treatments in development.

Efforts to address and overcome barriers inherent in lupus clinical trials are a discussion that needs to be continually engaged in with the FDA, third-party payers, scientists, physicians who study new treatments, and lupus patients. We need to do more to educate regulators and insurance agencies about lupus, and continue the work of bringing down the barriers to treatment development. This should include convening key opinion leaders, the biotechnology sector, and the NIH and regulatory agencies to work on clinical trial design – something that must evolve further to optimize progress.

Dr. Merrill is the head of the clinical pharmacology research program and is a professor in the department of medicine, rheumatology, and immunology at the Oklahoma Medical Research Foundation, Oklahoma City. She has financial relationships with numerous pharmaceutical companies, including Human Genome Sciences/GlaxoSmithKline, maker of Benlysta. Ms. Raymond is president and chief executive officer of the Lupus Foundation of America, Washington, D.C. (www.lupus.org/newsite/index.html). She reports that she has no financial disclosures.

More than 20 companies currently are evaluating treatments for lupus in randomized studies – more than ever before. The recent approval of belimumab (Benlysta), the first drug developed specifically for lupus in over 50 years, ended a 2-decade-long drought for lupus treatment development, by finally providing evidence that a drug has benefits when compared to background treatments alone. Until now, this progress was impeded by the heterogeneous nature of the disease, the complex process of selecting volunteers for clinical trials, the imprecision of clinical trial end points, and the highly complex and often confusing instruments used to measure disease activity that comprises these end points.

But even as the causes of lupus are becoming clearer and basic research is beginning to produce multiple, potential, finely tuned molecular targets for treatment, the completion of phase III trials has been proceeding more slowly than one would hope for.

So what are the factors impeding progress?

For one, multiple, competing, international-scale trials require multiple, well-trained, international trial sites. Although training of new investigators at new trial sites around the world is underway, the process has been slow and the results imperfect. Clinical trials also require experienced clinical scientists who can conform to international regulatory practices, but the rules are enormously complex and sometimes arcane. These clinical scientists must also be trained in lupus outcome measures that are even more complex and sometimes even more arcane. What’s more, in both cases the rules are frequently revised.

As understandably risk-adverse companies find themselves conducting international-scale clinical trials for a poorly understood and serious disease, recent phase III trials have become increasingly restrictive in setting limits on volunteers who are allowed to participate. Sometimes there are pages of entry criteria, making it difficult to recruit enough volunteers from real-world clinics.

Clinical studies that limit enrollment to patients who meet the American College of Rheumatology’s (ACR’s) Classification Criteria for systemic lupus erythematosus (SLE) have put trial participation out of reach for many patients with severe lupus syndromes in only one organ, such as primary discoid lupus, antiphospholipid syndrome, and other blood disorders such as immune-mediated microangiopathy. But patients with multiple organs that are mildly involved can often enter these same trials on a technicality.

One consequence of these increasingly formidable issues in entry criteria for trials is that once a drug is approved, only those people with lupus who meet the criteria may be deemed eligible for the drug by regulatory authorities. Therefore, the treatments will not be available for many or even most of the population we are trying to help. Some insurers have gone even further to require that patients exactly match the entry criteria for trials. They demand that a patient to be covered for treatment match the trial eligibility criteria by having certain scores on the disease activity measurement indices used for the studies, usually the SLE Disease Activity Index (SLEDAI) or the British Isles Lupus Assessment Group (BILAG) index. But most practicing physicians are not trained to use these measurement scales.

Because lupus is a serious and potentially life-threatening disorder, there has been resistance to using trial designs that include placebo groups. One approach to this would be to compare a new agent to a standard-of-care medication. However, very few medications are approved for lupus, illustrating another problem: the difficulty in getting a drug approved for lupus because of clinical trial issues specific to the disease.

Right now, for example, the first-line standard of care agent for lupus nephritis is cyclophosphamide. A number of clinical trials found that mycophenolate mofetin (CellCept) is at least equivalent to cyclophosphamide for the treatment of acute lupus nephritis. This included at least one large international registrational trial (the ALMS study) that was designed as a possible approval pathway for mycophenolate. However, the Food and Drug Administration decided not to approve mycophenolate because proving equivalency to cyclophosphamide was not enough – it had to be proved superior. That is because regulatory agencies consider all unapproved treatments to be the same as placebo. For this reason, most clinical trials are being designed as "add on" studies, in which all patients receive standard of care with the addition of either the study agent or placebo.

Added to this is the fact that the regulatory agencies require yearlong studies in order to prove that efficacy can be sustained. No patient would enter a clinical trial for a year and risk receiving a placebo unless some accommodation was made for their safety and comfort by allowing some increases in their current (often fairly effective) background treatments. This increases the likelihood that the placebo group can do well, limiting the differences that can be seen between a given treatment under study and the placebo population.

In the pivotal phase III international trials of Benlysta, all participants in the study received reasonably effective standard of care background medications, which could be increased in the early part of the study for the patients’ safety and comfort. Then either Benlysta or a placebo was added on to that treatment. This study was able to show that the benefits of Benlysta plus background mediations were significantly greater than those seen in patients on background medications alone, but the difference was narrow. When a trial design must allow aggressive treatment of placebo patients, this will inevitably result in a narrower difference, and a much larger trial is then needed to prove efficacy. Furthermore, any lack of training and standardization in evaluating the patients can make the difference between a positive and a negative trial.

What can be done to address these issues, expedite clinical trials, and promote the availability of more effective treatments for lupus approved by the Food and Drug Administration? The Lupus Foundation of America has been addressing these barriers in a systematic fashion:

1. Improve the quality of clinical trial sites and care of patients who participate in trials around the world. This initiative has led to an online program capable of training and certifying clinicians around the world on the most commonly used lupus disease evaluation systems: the BILAG, SLEDAI, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). The Lupus Foundation of America’s Professional Online Instrument Training (POINT) program is now the primary tool used by companies that are conducting studies of lupus treatments. About 2,000 doctors worldwide are conducting clinical trials of lupus treatments, and this interactive educational tool has become their standard of reference.

2. Support work to improve classification criteria for SLE and outcome measures for trials and clinical practice. The Lupus Foundation of America, in conjunction with the National Institutes of Health (NIH), supported the most recent studies of classification criteria for lupus, and is working to expand definitions of diagnosis and suitability for biologic therapy to serious organ-limited lupus, and to limit such access for patients with insignificant illness, whether or not they have multiple organs involved. Additionally, in conjunction with EULAR (the European League Against Rheumatism), the Lupus Foundation of America initiated and has continued to support a large project to refine the measures for flares of lupus disease that have sometimes provided a confusing aspect to outcome measures. This work has been ongoing for more than 2 years, and has resulted in several abstracts/publications; a final validation study is planned for the near future to support an outcome measure that better matches physician opinion than the current rules allow. These studies were performed by international groups of physician experts, primarily, but not exclusively, members of the Systemic Lupus International Collaborating Clinics.

Finally, to address the problem that once treatments are on the market, simpler disease activity and outcome measures are needed for practicing clinicians to use in a real-world clinic to justify expensive biologic treatments for their patients, the Lupus Foundation of America is supporting a project called DIAL (Directed Integrated Assessment of Lupus), which allows rapid and comprehensive scaling of type and degree of illness in these complex patients.

3. Improve the understanding of the impact of background treatments on clinical trial end points, and evaluate which trial end points best differentiate between treatments. The Foundation has developed a central database of clinical trial data from placebo groups (usually patients receiving different standard of care background treatments) from multiple past clinical trials performed at different companies. By pooling this information, it may be possible to determine which background medications are most likely to result in placebo responses that limit serious flares of disease while not being so effective as to defeat the purpose of a clinical trial. Once this is achieved, it will also be possible to have accumulated enough data on patients who are treated similarly to begin to test the most effective end points in some of these clinical trials.

While clinical drug trials are designed to detect significant differences between the group assigned the treatment and the control group, lupus drug trials need to be designed to detect greater differences. Support for basic science grants remains a priority at the Lupus Foundation of America, and it joins other advocacy groups and the NIH in continuing to award grants to outstanding researchers who continue to refine our understanding of the disease process and potential biomarkers. This, in turn, helps us select and guide the new treatments in development.

Efforts to address and overcome barriers inherent in lupus clinical trials are a discussion that needs to be continually engaged in with the FDA, third-party payers, scientists, physicians who study new treatments, and lupus patients. We need to do more to educate regulators and insurance agencies about lupus, and continue the work of bringing down the barriers to treatment development. This should include convening key opinion leaders, the biotechnology sector, and the NIH and regulatory agencies to work on clinical trial design – something that must evolve further to optimize progress.

Dr. Merrill is the head of the clinical pharmacology research program and is a professor in the department of medicine, rheumatology, and immunology at the Oklahoma Medical Research Foundation, Oklahoma City. She has financial relationships with numerous pharmaceutical companies, including Human Genome Sciences/GlaxoSmithKline, maker of Benlysta. Ms. Raymond is president and chief executive officer of the Lupus Foundation of America, Washington, D.C. (www.lupus.org/newsite/index.html). She reports that she has no financial disclosures.