What are clinical trials?

Clinical trials are structured research experiments used to advance medical knowledge and patient care. This means that there is a very clear and well-formulated process to test something that might be useful in treating a condition.  Trials often investigate new treatments, interventions, therapies and approaches to a disease or symptom.  They might also compare the effectiveness of different treatments, for example, does one drug relieve leg cramping more than another. Clinical trials are the way that we gather evidence to determine whether or not something works and how well it works. 

The participants in clinical trials are sometimes called Heroes because they are testing something that is unknown.  It is important that the drug or therapy is tested in as safe a manner as possible.  The principal investigator of a clinical trial is responsible for human safety and for only conducting a trial when they are sure it is safe. 

The most scientifically sound way to determine safety is by conducting a great deal of testing in cells and in animals before testing on humans.  This testing results in a clear sense of whether a drug is safe in a specific population with a specific disease.  A drug may even already be widely used as treatment for a certain condition, but it must be tested in cells and animals that mimic the issues or disease of the specific population. 

For example, there are three drugs that are under consideration for use in people affected by pseudoxanthoma elasticum (PXE): magnesiumbisphosphonates and sodium 4-phenylbutyrate (4-PBA).  Of these three, only magnesium has been extensively tested in cells and in mice that have the ABCC6 gene knocked out.  There is an approved clinical trial for magnesium underway at Mt. Sinai Hospital in New York.  Bisphosphonates and 4-PBA have not undergone extensive testing in cells and other organisms.  While these treatments are used for other conditions, it is still difficult to determine whether or not the complicated problems that PXE causes will negatively affect human cellular function and other organisms when exposed to these drugs. 

Informed consent is the process in which researchers are required by law to inform potential and enrolled participants with the necessary information about the study. This should not be a one-time event, but a process of keeping you engaged in the on-going status of the study.

In order to ensure your own safety, ask the following questions of your physician or principal investigator before agreeing to participate in a trial:

A1. Testing a drug on animals and before humans is an important step in the drug trial process because it allows researchers to see possible side effects and results they may not have predicted. If there were to be an adverse side effect that had not been predicted and there was no animal trial, humans could be harmed. Asking if there has been an animal trial and what the results were can help you to decide whether or not to participate in the trial.

A2. It is important that you know if the drug was tested on humans. If there is enough data from testing in animals, it might be fine to begin testing on humans – and, in fact, someone has to be the first!

A3. Trials have stages: Phase I, II and III, and sometimes IV. These phases are defined as:

Phase I: Studies test a potential new drug with a small number of volunteers for best dosage and potential side effects.

Phase II: Studies test a drug with known dose and side effects with a larger number of volunteers to learn more about side effects, how the body uses the drug, and how the drug helps the condition.

Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.

Other research may provide only indirect benefit to the patient by giving researchers information that may be an important first step toward developing a treatment. For example, research may show how a disease progresses or how it affects other systems within the body, rather than resulting in a viable treatment or intervention.

A4. In a double blind, placebo-controlled clinical trial, neither the patients nor the researchers know who is getting a placebo and who is getting the treatment. Assignment to each group is randomized; no doctor, patient or researcher may choose the group to which a trial volunteer is assigned. Because patients don’t know what they’re getting, their belief about what will happen doesn’t taint the results. Because the researchers don’t know either, they can’t hint to patients about what they’re getting, and they also won’t taint results through their own biased expectations about what the results will be.

A5. This is a very important issue, not only for PXE but for all conditions. It is important that researchers have a way to clearly measure something concrete to determine whether a treatment is working. PXE is a slowly progressing disease. It seems to speed up and slow down at different times. How can the researcher understand whether the disease has slowed down as a result of its natural course or because of the treatment? For PXE, researchers use things like skin lesions, eye signs, and blood vessel imaging to measure the progression of the disease. These are hard to measure accurately, and even more importantly there is no natural history of the effect of PXE on these organs. In other words, we must observe PXE’s progression in each of these organs in many people over a long period. PXE International has done a great deal of work on this, and continues to assess this through the survey that is part of the new PXE Health Engagement and Lifestyle Program (PXE HELP). However, if we are to ever have very accurate endpoints and/or biomarkers, then we must conduct a careful study of how PXE progresses in humans that includes physical examinations in addition to all of the health information and medical records that we are collecting.

A6. These review boards oversee research performed on human participants. Legitimate research on an intervention is never performed without a certified review board’s approval. In reviewing research protocols, these boards look to protect the safety and rights of people throughout the trial process starting with obtaining consent. All review boards are registered with the regulatory bodies like the United States Food and Drug Administration (FDA), the Medicines and Healthcare Products Regulatory Agency (MHRA), or the European Medicines Agency (EMA) before they can officially begin reviewing research protocols. The principal investigator of the study is not a member of the review board, since this would present a conflict of interest. The review board is made up of researchers, clinicians, and usually a community member. The review board assesses the trial and then approves or rejects it. For more information about review boards, see FDA Regulatory Information and “The ethical review process for clinical trials in the European Union”.

A7. It is important to know who is sponsoring the trial. The sponsor is the company or organization conducting the trial. They are often the funding party(ies) of the trial. If the sponsor of the trial is an academic institution or university, ask what their plans are for seeing the intervention through all of the phases, and particularly to be sure of its availability to patients. Sometimes well-meaning researchers not familiar with the pathways to development inadvertently make a drug unavailable because it has already been used in another condition and cannot be approved for your condition because of omissions in. Also ask about conflicts of interest. Are they doing the trial because they received funding and must do it? Are they doing the trial because they need to publish a paper? If the sponsor is a company, understand their desire to see the drug approved and ask how they have designed the trial to reduce their conflicts of interest.

A8. In the USA, every trial must be registered with ClinicalTrials.gov and supervised by the Food and Drug Administration. In Europe, trials are registered with either the World Health Organization (WHO), Medicines and Healthcare Products Regulatory Agency (MHRA) or the European Medicines Agency (EMA). If the trial is not registered, ask why it is not registered. The sponsor of the trial or the trial’s principal investigator (PI) is responsible for completion of the registration. Once the trial is registered with the FDA, information about it can be found on clinicaltrials.gov. If you do not see the trial on clinicaltrials.gov, the WHO International Clinical Trials Registry Platform or the European Medicines Agency (EMA) EudraCT, it is either still under review or was never submitted for review.

A9. This is a key question, and often one that is not thought through completely. If the drug or treatment happens to be a completely new treatment, then you would be able to receive it, provided the results are positive and the sponsor has created a pathway toward approval. This means that the sponsor will have worked with the FDA and/or EMA to determine what they needed to prove in order to obtain approval. Once they obtain approval, or during the process, they will work with a company to manufacture and sell the drug or treatment in the correct dosage. If they do not do this, then the treatment will not be readily available.

A10. If this is a treatment or drug already on the market, then the researcher will work to understand how to apply the treatment to the new condition or indication.

The first consideration is to answer what formulation of the treatment is right for this condition? Often, a treatment in a metabolic condition like PXE will need to be administered to children so that it prevents the build up of minerals. The researcher will need to determine if the formulation can be scaled (measured) to suit a lower body weight and a child’s metabolism. The next consideration is what dose is optimal and what can someone tolerate. The researcher will do extensive pharmacokinetic and pharmacodynamic studies:

  • Pharmacokinetic: What the body does to a drug and the intensity of the drug’s effect, i.e. movement of the drug into, through, and out of the body; the time course of its absorption, bioavailability (rate of metabolism in circulation to the site of action), distribution, metabolism, and excretion
  • Pharmacodynamic: What the drug does to the body, via chemical interactions

Ultimately the researcher will be working with FDA and/or EMA to apply to have the treatment relabeled. This means that the treatment will be named as appropriate for the new condition. If it is not labeled, then we will be in a similar position we are in with treatments like Avastin/Lucentis/Eylea. These treatments are available to patients whose clinicians are willing to say that they have macular degeneration, but not to those whose clinicians label their eye disease as pseudoxanthoma elasticum. While this is not much of a problem in the USA, it is a very big problem in Europe, South America, Asia and Africa. The various health systems in those regions (most of the world) generally do not approve the use of these treatments and people with PXE needlessly lose their vision. In some countries this is because it is not legal to prescribe something off label, in other countries it is because coverage and reimbursement of the cost of the drug is tied to the treatment being approved by a regulatory agency.

A11. In some ways it is easier because some of the important testing is already done, and some of the toxicity and side effects of the drug are known. In other ways it is hard since it might be difficult to get the company that sells it to relabel it. Without relabeling it will be hard for some people to get access. Furthermore, some studies will still have to be done to determine dosing and other crucial components, such as appropriateness for children. Any drug that can prevent mineralization in PXE would have to be administered to children or young people, and so effects on development and reproduction will have to be considered carefully.

A12. In order for researchers to effectively study the risks, benefits, and side effects of their treatments, they need to prevent unrelated factors from interfering with their results. For example, if someone was participating in two clinical trials at once, it may be impossible to tell which treatment was working or causing adverse effects. For this reason, it is likely that you will not be allowed to sign up for other studies after you begin participating in one. It is also possible that if you have been treated in one clinical trial, you may not be eligible for another one because it may not be possible to determine whether effects are from the first treatment or the new one.

A13. Being fully informed of the risks, side effects, and benefits of the trial you are considering is important when evaluating clinical trials. Not only understanding these factors, but comparing and contrasting the risks, effects, and benefits of the trial to your current treatment can help you realize that while one option may have a greater possible benefit, it could also have a greater risk.

A14. In any trial that PXE International is involved, we strongly encourage the researchers to return your personal data to you. Sometimes they must wait, so that they are not unblinding a trial inadvertently.

A15. Yes, they will save a lot of time and money if they do. There are literally hundreds of under-enrolled and underpowered studies. There are hundreds more that choose wrong endpoints. This is because correctly constructing a clinical trial that will give concrete useful results is difficult and not something with which most academic scientists have experience. The clinical trial must use the drug or biologic in a form able to be administered to humans without it being onerous, and it must be a standardized and stable form of the molecule.

Dealing with Fears

Many protections and safeguards for volunteer patients are built into the clinical research process. It may help alleviate some of your fears about participating in a clinical study to know what some of these are:

The Patient Bill of Rights – All patients who take part in studies at the Clinical Center are protected by the Patient Bill of Rights, which was developed by the American Hospital Association for use in hospitals across the country. The Patient Bill of Rights contains guidelines to ensure privacy and confidentiality of patients and their medical records.

Hospital Accreditation – As in any medical research facility, an institutional review board (IRB) must review and approve every new study before the study can begin. The IRB is made up of medical specialists, statisticians, nurses, social workers, medical ethicists, and members of the community. The IRB reviews protocols to ensure patient safety. In addition, The Joint Commission periodically reviews the Clinical Center hospital to see if stringent standards, leading to Joint Commission accreditation, have been met.

Informed Consent – Before entering a study, it is important that you as the patient fully understand the study and what your involvement would mean. Staff members will help by engaging you in an informed consent process, which has detailed information about the study, including the length of the study, the number of visits required, and medical procedures and medications included. It also provides expected outcomes, potential benefits, and possible risks.  Most critically, it gives you an opportunity to ask as many questions as you wish. 

Staff will review the trial’s process with you and answer your questions. If you decide to participate after reviewing the statement and talking with staff and family members, you will need to sign the informed consent statement. Your signature indicates that you fully understand the study and agree to participate voluntarily.

Patients can take part in clinical studies covering a wide range of medical diseases, conditions, and rare disorders affecting both children and adults, including those relating to AIDS, aging, alcohol abuse and alcoholism, allergy, cancer, digestive and kidney problems, diabetes, eye disorders, infectious diseases, genetics, mental health, neurological disorders, stroke, and others.

Are you being asked to participate in a clinical trial? Make sure to ask these questions.

Download questions.

In order to decide if the study is right for you, you need to understand the study and its components. Here are some questions you should ask before consenting to participate in the study:

  1. What is the purpose of the study?
  2. Has the study received Institutional Review Board (USA)/Ethics Review Board (Canada and Europe) approval?  Can I see a copy of the approval?
  3. Has the researcher consulted the FDA (USA)/ EMA (EU) /MHRA (UK) about the trial so that it is safe and has the best shot at success?
  4. Why do researchers believe the new treatment being tested may be effective?
  5. Has it been tested before?
  6. Has it been tested in animals?  If no, then why not?  If yes, what do the animal results show?
  7. What is the researcher's reason for doing the trial?
  8. Is he/she receiving payment for each research subject's participation?
  9. How long will the trial last?
  10. What tests and treatments does the study involve? Will I be hospitalized?
  11. What are the short-term and long-term risks and benefits of this trial?
  12. What are the possible side effects? How do these compare to my current treatments?
  13. How will the trial affect my daily life?
  14. What type of long-term follow up care is part of the study?
  15. What is likely to happen to me with or without this treatment?
  16. Could my condition become worse during the study? What will happen if it does?
  17. If I am harmed as a result of the research, what treatment would I receive?
  18. What do you do to monitor patient safety throughout the trial?
  19. Who will pay for the treatment and all other expenses related to the study?
  20. Where will information from the study go?
  21. Will I receive my own measurements?
  22. What will be done with the results?  Will I receive a summary of the results?
  23. If the results of the study indicate the drug or intervention is useful, has the researcher planned properly so that it will be available to people with pseudoxanthoma elasticum (PXE)?
  24. How does the researcher ensure that the drug will be approved and further paid for by insurance or socialized medicine programs?
  25. What other options or choices do I have if I decide not to participate?
  26. How can I end my participation in the study if I change my mind?
  27. Who do I contact for questions and information about the study?

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