The Importance of Clinical Research

What is research?

Research is a systematic investigation to establish facts or principles, or to collect information on a subject. For example, The Lupus and APS Center at Hospital for Special Surgery conducts research to learn more about lupus and/or antiphospholipid antibody syndrome (APS).

A clinical study uses research with human participants. These studies add to overall medical knowledge. Sometimes the participants themselves benefit from the study and sometimes the studies benefit patients down the line.

Why does HSS do research?

HSS does research to gain valuable information for the medical community. Research at HSS can help the medical community:

• Learn about the cause of a disease and its effects on the patient
• Find effective treatments to improve quality of life for those affected
• Determine if a medicine used for one condition could benefit another condition

For example, many lupus patients are prescribed Plaquenil. Plaquenil was originally approved for the treatment of malaria, however, many lupus patients are currently benefiting from this medication.

Types of research and research studies

Current studies at HSS fall into observational studies and clinical trials.

Observational studies are studies in which patients are observed and monitored while receiving routine medical care. The patients’ medical treatment is not altered in any way. Patients may be asked to fill out a questionnaire and give blood for use in animal models or to help researchers gain a better understanding of the progression of the disease.

There are several different types of observational studies.

• Cross-sectional study – analyzes data collected from one specific point in time. In these types of studies participants may be asked to fill out surveys, answer questions and/or give blood samples to provide a picture of the state of the disease at one point in time.
• Prospective cohort study – follows participants over a period of time to evaluate disease progression and outcomes.
• Case-control study – compares participants diagnosed with a disease to those who do not have the disease in order to discover or analyze risk factors. These studies can be retrospective which means they look back in time at the progression of the disease or prospective in which participants record information regarding exposure to risk factors of the disease as they move forward in time.
• Nested case-control study – this type of study is the same as the case-control study except a subset of the group is selected for further analysis. For example, if researchers are studying lupus they may choose to examine a subset of lupus patients who have lupus nephritis.

Clinical trials, unlike observational studies, contain an intervention and determines the safety, efficacy and dosing of a drug. Clinical trials may be randomized in which groups of participants are randomly selected to either receive the standard of care (best approved treatment to date) or the drug under study. Clinical trials are generally blinded, meaning the participant’s physician and the study team is unaware of the treatment that the participant is receiving. This protects the integrity of the data by eliminating bias or causing a “placebo effect.”

Clinical trials take place in four “phases.” Before starting Phase I of a clinical trial, there must be extensive knowledge and sound data obtained through animal models. Data and results from the animal models must show that a drug is promising in the treatment of a disease in order to gain approval from the Food and Drug Administration (FDA) for testing in humans. The FDA approves all phases of the clinical trials.

• Phase I: 20-100 participants
• Phase II: Approximately 200 participants
• Phase III: Thousands of patients internationally
• Phase IV: (Pending approval) Continued monitoring with an increased focus on adverse reactions and side effects in patients

Participating in Clinical Research

Each clinical study has a protocol, or a list of guidelines or a research plan. Included in the protocol is the goal or purpose of the study, how many participants will be enrolled, what will be done at every study visit, and the plan for data analysis. The protocol also identifies how researchers will define outcomes. For example, a study may say that if 30% of participants improve by a minimum of 60% then the drug will be considered effective. The protocol will also include the results from animal models and previous phases of the study; eligibility and exclusion criteria for participants; a schedule of the tests and procedures; the number of volunteers needed; what information will be gathered from the volunteers; and the length of the study.

Who conducts clinical studies?

There will be a Principal Investigator who is often a physician but can also be a social worker or someone else involved with the research team. The research team itself can be made up of physicians, nurses, research coordinators, social workers, pharmacists, and other health care professionals.

Who funds clinical studies?

Funding for clinical trials can come from a number of different places. Pharmaceutical companies may fund a clinical trial directly or through organizations and foundations. Clinical trials can also be federally funded by agencies such as the National Institute of Health (NIH). Health care providers and philanthropic individuals may also fund clinical trials.

How do you know if you qualify for a clinical study?

Always speak with your doctor to help determine if you are eligible for a study. Your physician may be asked to fill out the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) to evaluate your current disease activity.  Eligibility may be dependent on:

• Level of disease activity
• Specific manifestations of lupus
• Use of, or lack of use of, certain drugs
• Genetic factors

Risks and benefits of participating in a clinical study

There are always risks and potential benefits to participating in a clinical study. The risks may include:

• Time commitment
• Frequent drawing of blood
• Unknown side effects of the treatment,
• No immediate benefits

Potential benefits may include:

• Additional care and attention from the research team
• Access to experimental and new treatments
• Knowing that the knowledge gained may benefit others in the future.

Protection of research participants

Each participant is asked to sign an informed consent form at the start of a study. Included in this form are the risks and potential benefits as well as the schedule of visits as outlined in the protocol. If there are any changes in the protocol of the study, such as an additional questionnaire, participants will be given a new informed consent form. This is called re-consenting. Consent forms are written in a language that participants can understand and participants will be able to ask the research team any questions they may have. Participants can withdraw from a study at any time, even if the study is not over.

All studies are reviewed and approved by the Institutional Review Board (IRB)/Ethics Committee (EC), a panel of physicians, scientists, researchers, and members of the community, before a study can begin. Studies are continuously monitored to ensure that each study is ethical, and that participants are not being exploited or endangered.

In addition, the Data Safety and Monitoring Boards (DSMB) examine un-blinded data, which means they are aware of which participants are receiving the drug under investigation and which are receiving the standard of care. The board will look at incoming data to evaluate whether a drug is producing overwhelming negative side effects which may prompt a discontinuation of the study. They may also find overwhelming positive results which may prompt the researchers to expedite FDA approval for the drug.

Additional agencies that protect participants are the Office of Human Subjects Research Protection and the FDA. Both agencies have the authority to determine whether a sponsor or pharmaceutical company, is adequately protecting research participants.

Considerations for participation

Clinical trials and your health Participants are encouraged to continue seeing their usual health care providers while enrolled in a clinical study. Participants should share their involvement in the study with their health care providers and discuss whether it would be best for you to stay on your current medication versus joining a clinical trial with your physician. Participants in a clinical trial should note any changes that occur during the course of the study. This may include sleep or appetite changes or any number of positive and negative side effects.

You should take into account that most trials involve some level of risk for the participant but this risk may not be greater than the risks related to routine medical care or disease progression. The IRB/EC will determine that the risks of a trial are minimized for participants and are reasonable in comparison to the potential benefits.

Questions to ask before participating

Below is a list of questions potential participants may want to ask before participating in a clinical trial.

• What is being studied?
• Why do researchers believe the intervention being tested might be effective? Why might it not be effective? Has it been tested before?
• What are the possible interventions that I might receive during the trial?
• How will it be determined which interventions I receive (for example, by chance)?
• Who will know which intervention I receive during the trial? Will I know? Will members of the research team know?
• How do the possible risks, side effects, and benefits of this trial compare with those of my current treatment?
• What will I have to do?
• What tests and procedures are involved?
• How often will I have to visit the hospital or clinic?
• Will hospitalization be required?
• How long will the study last?
• Who will pay for my participation?
• Will I be reimbursed for other expenses?
• What type of long-term follow-up care is part of this trial?
• If I benefit from the intervention, will I be allowed to continue receiving it after the trial ends?
• Will results of the study be provided to me?
• Who will oversee my medical care while I am participating in the trial?
• What are my options if I am injured during the study?

How Research Impacts Patients

Research can establish new drugs and products for the treatment of disease, change how the medical community approaches a disease, and much more.  Dr. Jane Salmon presented the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study to demonstrate how current research has impacted the medical community’s approach to pregnancy in lupus patients.

Case Study: PROMISSE Study for Pregnancy in Lupus

Women with lupus who become pregnant are at risk for a number of pregnancy complications including: miscarriage, premature delivery, fetal growth restriction, preeclampsia (characterized by high blood pressure and protein in the urine), and fetal/newborn death. Doctors do not know how to predict who will suffer these complications, why these complications occur, or how to prevent them. This is where the importance of research comes in. With the PROMISSE study researchers are currently working to understand why women with lupus have pregnancy complications and how those complications can be prevented.

Animal models

Researchers cannot ethically begin their research by studying patients, although their goals are to understand human disease, sothey gathered as much information as possible through the use of pregnant mice. Some of the mice were injected with antibodies from healthy human donors and others with antibodies from lupus donors. Just like humans, mice treated with the healthy antibodies were able to give birth to their pups without any complications, whereas pregnant mice treated with the lupus antibodies had pups that did not survive or were smaller in size. Through studying the mice, researchers found that the pregnant mice with lupus were experiencing inflammation in the placenta, so they worked to identify ways to block inflammation with specific drugs.  Pregnancies in mice where certain pathways of inflammation were blocked were protected from damage by the lupus antibodies.

Observational study

The findings in the mice studies allowed the researchers to move forward, however, they could not yet work with humans. The next step of research was to begin a prospective observational study. They had to identify which pregnant women with lupus were at the highest risk for pregnancy complications and in need of the inflammation blocking drugs. They did not want to administer drugs to women who did not need them. It was clear that some patients with lupus had pregnancy complications and others had perfectly normal pregnancies.

As we learned earlier, an observational study is one where the participants continue with their regular medical care with no intervention. Data is collected through surveys, questionnaires and/or drawing of blood. Researchers gathered information from the beginning to the end of the participants’ pregnancies. The observational study took place for eleven years between 2003 and 2014 in the US and Canada. There were 755 pregnant participants enrolled in the study. Each participant was seen every month of their pregnancy with a total of 233,925 blood samples collected from all of the participants.

What they found was that 80% of women whose lupus was quiescent (inactive or dormant) during their pregnancy were able to give birth without complications. This finding changed the way doctors counsel their female lupus patients regarding pregnancy. A doctor can now safely tell a lupus patient that she will experience less complications during pregnancy if her lupus is inactive. In addition, the data from the study helped researchers to identify certain biomarkers (factors in the blood) early in a pregnancy that predict life-threatening complications to a mother and fetus. This allows doctors to identify patients, very early on in their pregnancies, who are at particularly high risk for complications.

The PROMISSE study is an example of the ways in which research can directly impact lupus patients. The results of the observational study changed the way doctors counsel women with lupus and provided information on ways to identify those at highest risk. These results also help researchers to take the next step in identifying and testing drugs that can be used to help prevent pregnancy complications.

Next step: Clinical trials

Using this information, researchers identified those women who are at the highest risk for complications and invited them to participate in the next phase of study - a clinical trial which will involve an intervention. Participants will be given a drug that does not cross the placenta to block a key inflammatory pathway that was identified in the mouse models. The clinical trial phase that follows the PROMISSE study has been approved and enrollment has been initiated. It is called the IMPACT (IMProve Pregnancy in APS with Certolizumab Therapy) study. The IMPACT study will help doctors to determine whether this approach will prevent poor pregnancy outcomes in lupus patients at a very high risk for such complications. 

Some information from the presentation was provided by clinicaltrials.gov.

For more information on current research at HSS you may contact the Lupus and APS Center of Excellence.
Email: LupusAPSCenter@hss.edu
Phone: 1-877-SLE-CURE
Website: www.hss.edu/lupuscenter

Learn more information about HSS SLE Workshop, a free support and education group held monthly for people with lupus and their families and friends.

Updated: 5/9/2019

Authors

Related articles

Summary by Gwyneth Kirkbride, Social Work Intern, Lupus Programs, Department of Social Work Programs