What is Clinical Research?
What is clinical research? “A whole doctor and a whole patient in a room at the same time.” This is very different than looking at tissues in a lab. There are several types of clinical research taking place here at Hospital For Special Surgery. These include:
- Treatment trials
- Observations to understand the course of disease
- Interventions to understand the course of disease
- Epidemiology studies that look at how much a population is affected and why
- Psychosocial studies
- Blood or tissue specimens or autopsies
Conducting Clinical Research: Safety and Confidentiality
In order to conduct a clinical research study, a series of regulations that is in the interest of patient safety and confidentiality must be followed. For example, a research project must meet Health Insurance Portability and Accountability Act (HIPAA) regulations that guarantee participants’ privacy. The Institutional Review Board (IRB), which is a hospital based entity, has to approve the process of the study as well as the risks and benefits involved and must grant permission to conduct the study in order to ensure the patient’s safety. This process can take about six months or so. In addition to several other regulatory bodies, an outside monitoring board that is not affiliated with the study must monitor the proceedings (Data and Safety Monitoring Board, DSMB). This board can put a stop to the study if they perceive that a participant’s safety and/or privacy are being compromised.
A substantial amount of time is invested to ensure that participants are safe throughout the research project and that their confidential health information is not compromised.
Treatment Trials
When most people think of clinical research, they usually think of treatment trials. In placebo-controlled studies, treatment is compared to no treatment, and researchers just look to see what happens. These studies usually produce the cleanest and clearest answers. However, an undesirable consequence of this kind of study is that some patients come to realize that they may not receive the treatment under question. More commonly used as a comparison is the standard-therapy controlled approach. In this type of study, a new drug is compared to standard therapy. Although very common and informative, this type of comparison requires more patients to participate than does a placebo-controlled trial because all patients are expected to improve. Lastly, treatment can be compared to how patients did in the past when compared to the new treatment; these comparisons are called historical controls. This involves looking at the history of the treatment of a person over a number of years. This method is not very reliable, however, because the period of time under observation can be influenced by the introduction of other medications in the system, such as antibiotics or blood pressure medications that may also influence a patient’s outcome.
Trial Phases
Clinical research trials fit into one of four different “phases”. These are different ways to help researchers and participants identify what is being tested.
| Phases |
What Researchers are Looking For |
| Phase 1 |
dose range, immediate toxicity, drug metabolism (to determine if this drug can be given to humans) |
| Phase 2 |
treatment dose, immediate toxicity,
evidence of effectiveness |
| Phase 3 |
formal comparison trials
(against placebo or other drug)
(to measure how effective the drug is) |
| Phase 4 |
after release, any new problems when many people take the drug? |
Kinds of Drugs Observed in Clinical Trials
In treatment trials, researchers are usually looking at three types of drugs:
- Single pharmaceuticals - usually pills 2.
- Combination pharmaceuticals 3.
- Biologics
Pharmaceuticals are pure small synthesized chemicals that usually affect a range of body processes, some of which are abnormal in disease. Examples include the common anti-inflammatories (Motrin, Naprosyn, Celebrex), prednisone, and Plaquenil.
Biologics, on the other hand, are proteins or other naturally formed molecules that usually affect a very specific body process that behaves abnormally in disease. This type of specific effect is considered “targeted therapy”. Biologics are often injected. Examples include Enbrel, Remicade, Humira, and Rituxan.
Aims of Lupus Research
When we think about lupus, we like to believe that there is a very specific cause somewhere in the background. It could be a chemical, a bacteria, a virus, or environmental triggers that are inducing the disease. These triggers cause the body to react violently in order to reject them. This cellular reaction is called the immune response. These cells activate chemicals in the liquid part of the body, called cytokines, thereby causing inflammation [swelling and redness]. This inflammation produces symptoms that can show up in a variety of ways such as rashes, arthritis, or a combination of other symptoms.
The drugs that we use today, such as steroids, Plaquenil, and other drugs, work at the level indicated above in the green. These anti-inflammatory and immunosuppressive drugs put a lock on the inflammatory process as well as the reactions that cause it.
Immunosuppressive drugs such as Cytoxan, Cellcept, and Methotrexate have a drastic effect on immune cells. These immunosuppressive drugs can either turn off the immune cells and leave them helpless, or they can kill them. These drugs work at the green level shown above. If the idea is that the immune response is causing the symptoms, the symptoms can be stopped by immunosuppressives.
The new drugs on trial today are the biologics, which allow for much more specific and targeted therapy and which act in many different ways. You can pick out two or three amino acids in a protein that contain thousands of them (amino acids are the building blocks with which proteins are made). As shown by the red dots in the diagram, biologics can work at various levels of the disease. They can work at the root of the cause to stop it from turning on or otherwise interfering with the immune cells. They can also tell the immune cells to turn off what is turned on or to keep from producing cytokines. They can also work at the level of inflammation, so even if the process has accelerated to the inflammation stage, one can still prevent the inflammation and, subsequently, its symptoms.
When focusing on a very narrow spectrum of biology, there is less overall harm to the system in the long run. The anti-inflammatory and the immunosuppressive drugs act like “big sledgehammers” that “whack” the system. What we hope to do with the biologics is target what is identified as the problem and touch it with the targeted therapy so that the rest of the system stays intact.
Lupus Clinical Trial Consortium
At Hospital for Special Surgery, we are very fortunate to be a part of the Lupus Clinical Trials Consortium (LCTC). This organization is supported by private funding from Rheuminations, Inc., which also funds the Mary Kirkland Center for Lupus Research. HSS is one of the founding members of this organization that has 26 centers in the US and Canada. This is the first time in the United States that a group of institutions will combine the information that they have and use the same protocols to do trials together. This is extremely important because no one has an unlimited number of patients with which to conduct trials; this collaborative effort will help to maximize resources.
Three trials have just begun. Ask your doctor to see if you are eligible to participate.
Tips For Patients/Participants
If you enter a trial, be sure you know what it aims to do. You should know what phase of the trial you are participating in, what the researcher is looking for at that phase, and what the benefits and downsides might be for you.
| Phases |
What Researchers are Looking For |
| Phase 1 |
You are the first to get the drug. You likely will not benefit from it. |
| Phase 2 |
You may be the first to benefit from a drug (or see that it doesn’t work). |
| Phase 3 |
You will see if it is better than the usual therapy (or not). |
| Phase 4 |
You are on a new drug - what are its long range effects? |
You should also know that you can always withdraw you consent at anytime. At any phase of the trial, you can opt out for any reason. It’s always your choice whether you’d like to to continue or not.
Important Note:
There is a difference between approval for selling a drug to the public and approval for selling it specifically for the treatment of lupus (the labeling issue). Sometimes the labeling of a drug may specify use for another illness, but it’s prescribed for lupus. When a drug is used in this way, it is called “off-label” use. There are a number of drugs - such as Cellcept - that are used in this way, as few drugs are specifically labeled for use in lupus. However, some other drugs used for other illnesses may work well in treating lupus even though they might not yet be approved for this purpose.
The Good News
The good news in lupus clinical research is that there are many more opportunities than ever before; there are 26 coordinated centers working together, good measurements of disease, and real hope that even more effective treatment for people with lupus will emerge.
The Bad News/Challenges
- The trials are based on mouse models, which are not the best to compare to some human symptoms that occur, such as rashes.
- Most of the trials are looking at very serious disease and not low-grade chronic illness that would allow use of little or no prednisone and prevent long term complications. While the focus is often on finding a “blockbuster” drug for more serious diseases.
- Clinical trials are sometimes very restrictive regarding eligible participants. They often look for people with specific disease parameters. For example, in some cases, participants who havereceived certain drugs or have been pregnant cannot participate. This limits the number of patients eligible for the trials.
- There may not be enough patients eligible for a certain trial, preventing the researchers from staging it successfully.
Types of Studies at HSS
Lupus clinical research at HSS includes:
Registries:
- LCTC to help researchers find patients willing to participate in trials
- SLE Registry of genetics/tissues
- Antiphospholipid antibody (APSCORE)
Biology of disease:
- Blood samples for interferon and others Pregnancy outcome (PROMISSE)
- Atherosclerosis
Treatment Trials:
- LCTC trials
- Cognitive dysfunction trials
- Antiphospholipid syndrome prevention trials (APLASA)
- Ad hoc based on individual patients
- Plasmapheresis
- IVIG
- Rituximab
- TNF alpha inhibitors
Additional Contact information for studies:
Dr. Michael Lockshin (LCTC, APSCORE, APLASA, PROMISSE)
Dr. Melanie Harrison (Cognitive dysfunction studies)
Dr. Doruk Erkan (LCTC< APSCORE, APLASA)
Dr. Jane Salmon (PROMISSE, atherosclerosis, registry)
Dr. Stephen Paget
Dr. Thomas Lehman (Pediatrics)
For LCTC HSS Clinical Lupus Registry, contact Victoria Kaplan or Joann Vega, 212.774.2795, kaplanv@hss.edu or vegaj@hss.edu (supported by LCTC).
For predictors of pregnancy outcome in APS and SLE (investigators Dr. Jane Salmon, HSS and Dr. Jill P. Buyon, Hospital for Joint Diseases), contact S. Heidi Norbis, 212.606.1214, norbisss@hss.edu .
For more information about HSS’ SLE Workshop, a free support and education group held monthly for people with lupus and their families and friends, please visit our web page.
