Rare Disease Report

Symposium Summary: Ethics and Rare Disease Clinical Trials

JULY 18, 2012

This past June, the Angelman syndrome foundation invited six internationally renowned and accomplished panelists to discuss the "Ethical Considerations in Rare Disease Research" at a dinner symposium.

The panelists included: 1) Stormy Chamberlain, PhD, Assistant Professor in the department of  Genetics and Developmental Biology at the University of Connecticut Health Care Center in Farmington CT, 2) Dan Harvey, PhD, chief operating officer at Dart Neuroscience LLC in San Diego CA, 3) Joseph Horrigan, MD, child psychiatrist, Durham NC and head of medical research for the non-profit organization Autism Speaks, 4) Ben Philpot, PhD, Associate Professor in the department of  Cellular and Molecular Biology at University of North Carolina, Chapel Hill NC,5) Michelle Roth-Cline, MD, PhD, pediatric ethicist at the Food and Drug Administration (FDA) in Silver Springs MD, and 6) Wen-Hann Tan, MD, pediatrician and instructor at Boston Children's Hospital in Boston MA. The chairpersons of the symposium were Charles Williams MD, Professor of Pediatrics and Genetics in the Department of Pediatrics, University of Florida in Gainesville FL (and on the Board of Directors at Angelman Syndrome Foundation) and Leigh Sutherland, parent of an adult with Angelman Syndrome.

The discussion centered around 7 questions that the chairpersons asked the panel based on queries they had received. Below are highlights from that discussion. For a full appreciation of the questions and the thoughtful answers the panelists provided, please go to http://www.angelman.org/2012-dinner-debate/.

Question 1. Even with IRB oversight for conformed consent, how can study participants be assured that the researchers conducting clinical trials are doing so in an ethical manner and have the best interests of the study participants in mind?

This question was first addressed by Dr. Michelle Roth-Cline who stated clinical trial ethics requires a team effort. There are numerous checks and balances throughout the development of a study protocol to make sure that a clinical trial is ethically and scientifically sound.  By the time the study begins recruitment it has already been checked/reviewed numerous times to make sure that the study is necessary and will meet an unmet need in a safe manner.

Dr. Joseph Horrigan added a great method to determine if a trial is in the best interests of the participant is to do what their organization does. During the review process for a trial, they will go to the researcher and ask ‘if the roles were reversed, would you allow your child to participate in this study?’ The answer to that question can easily determine if a trial is necessary or not.

Question 2. How can families or individuals affected by a rare disorder protect themselves from undo influence in obtaining accurate information in deciding whether or not to participate in rare disease research?

As a parent, Co-chair Leigh Sutherland told the panel that most parents get their initial information from a variety of internet based sources. Often it is difficult for them to know what information is scientifically accurate.

Dr. Roth-Cline answered the question by reiterating that by the time a clinical trial is recruiting participants, that trial has had multiple levels of review. As such, the participant should feel safe with the data presented in the protocol. Dr. Roth-Cline also noted that the FDA has an extensive library of drug information that can help parents.

Question 3. Who is responsible for educating and informing the trial participants of all aspects of the research process and the potential trial outcomes? Does the informed consent really protect the study participant?

Dr. Wen-Hann Tan started his to answer these questions by pointing out that it is a very challenging issue. However, he is of the opinion that the lead investigator of a trial should be responsible for telling participants what the trial is about and what the trial is not about. The lead investigator should also detail the potential benefits and the risks of the trial. Dr Tan said that if a parent asked about a trial, he provides parents with all the pertinent information for the trial then a week or so later, he asks them questions so that he knows the level of understanding the parent has about the trial. Based on that conversation, he will provide any additional information to help the parent understand the trial their child is about to begin. Dr. Tan also stressed that this review process is repeated several times. But Dr. Tan also stated that it is also up to the parent to get a second opinion on the trial and they should never rely solely on one person to provide them with explanations.

Dr. Stoney Chamberlain, as a basic researcher, stated that is their policy to tell parents to contact their doctor about any concerns the parent may have and it is important that scientist minimize their interaction with the trial participants to avoid confusion. A clinical trial, like medical treatment, is very complex and the medical information should be provided from a medical professional.  With that being said, Dr. Chamberlain noted that parents often ask her scientific questions and she is more than willing to answer those questions. 

Question 4. Should fast-track research be considered in lieu of conducting a more traditional, double-blind, placebo-controlled trial? Discuss the pros and cons of fast-tracking drugs for rare disorders.

Most on the panel agreed that this is a very complex issue. Dr. Ben Philpot noted that parents need to remember that fast tracking means the review process is faster but that the protocol for the study and the reason for the study still need to be well thought out. Furthermore, from a researcher’s perspective, he added that more thought may go into a fast track trial since a rejection of a fast track study may hinder future recruitment and studies simply due to a small item in the protocol not being properly addressed early on.

Dr. Roth-Cline added that even if a drug is fast tracked, every effort is made to make sure the preclinical data is still viable and the protocol still answers the basic questions – will this drug help the patient and is it safe.

Question 5. Is off label use of drugs for rare diseases okay?

Dr. Tan was concerned about off label use because it is usually impossible to answer the question – is that drug safe and effective for that rare disease? And whatever one thinks of the long process of developing a proper clinical trial, clinical trials are the only way to properly answer that question. 

Dr. Dan Harvey added that off label use means you are doing a clinical trial with one participant. As such, if you are doing off label use, you need to ask ‘how are you going to determine if the drug is working? What are you going to measure? What safety concerns are you going to look for? Etc.’

Question 6. What are the ethical implications for assessing the development and comprehension of individuals with neurodevelopmental disorders (ie, Angelman’s Syndrome)?

Dr. Tan stated that a clinical trial is only ethical if the outcomes can be measured in a meaningful way. Therefore, the trial needs to have a vetting process to find and/or create an assessment outcome measure that is applicable to the rare disease patient population being studied. Dr. Tan added that finding such a measure can be a very time consuming process long before the study begins to receruit.  Dr. Tan further argued that if a trial does not develop a measure that is well accepted by the scientific community then it will likely not get approved by the FDA. In other words, the trial with an untested outcome is a waste of everyone’s time and in his view, unethical. Dr. Tan also noted that clinical trials often have numerous developmental measures to obtain a better understanding of whether a drug is safe and effective.

Question 7. What is the responsibility of the pharmaceutical and medical industries for developing treatments for rare disease populations (even when there is not a return on investment)?

Dr. Harvey bluntly stated that those entities are for-profit industries and if they can’t make a profit making a drug, they will not pursue it. However, Dr. Harvey added that those big industries are also involved in research for other ‘profitable’ diseases and some of that research may lead to information that will allow them to develop drugs for rare diseases that are profitable.

Dr. Roth-Cline added that government agencies and foundations have provided many financial incentives (and research) to allow the for-profit companies to pursue rare disease treatments.   


Angelman Syndrome

Angelman syndrome is a neuro-genetic disorder that occurs in approximately 1 in 15,000 live births. It is due to a mutation of a gene UBE3A found on chromosome 15. Characteristics of the disorder include developmental delay, lack of speech, seizures, and walking and balance disorders. Individuals with Angelman syndrome will require life-long care. Symptoms vary with each individual and Angelman syndrome may be misdiagnosed as cerebral palsy or autism.

At present, there is no specific treatment for Angelman syndrome. Most patients with Angelman syndrome will require medication to control seizures. Various forms of physical, occupational, communication, and/or behavior therapies are also common.

Angelman Syndrome Foundation

The Angelman syndrome foundation is a national 501(c)(3) organization dedicated to providing persons with as much helpful information about Angelman syndrome as possible.

The Angelman syndrome foundation sponsors an biennial conference and provides various grants for research. Since 1996, the foundation has funded 66 research grants totaling over $4.6 million.

For more information about this foundation, visit http://www.angelman.org/

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