Earlier this year, Jean Burns—a friend and colleague—shared experiences with me that offer important insights for government and industry funded clinical research sponsors to consider as they look to improve their partnership with study volunteers. Jean has given the gift of her participation to eight clinical trials focusing on Parkinson’s disease treatments since 2003. What follows is a Q&A with Jean to understand her past study volunteer experiences and perceptions, to highlight a major problem encountered in a recent experience, and to raise issues for broader discussion:
Ken: Jean, can you briefly describe your medical condition and your past experience as a study volunteer?
Jean: I am a 63-year-old woman who has Parkinson’s disease (PD). I was diagnosed in January 2003 at the age of 51 shortly after noticing I had an intermittent tremor in one hand. The initial neurologist told me I “either had a brain tumor or PD.” An MRI showed I did not have a brain tumor, so I received a PD diagnosis.
In the summer of 2003, I joined the Parkinson Research Examination of CEP1347 Trial (PRECEPT) as a de novo person with Parkinson’s disease (PWP). Its goal was to determine if CEP-1347 could slow the progression of early PD. I had difficulties with my Primary Investigator. The PI didn’t believe me when I initially told him about side effects I had. The Informed Consent (IC) required that only he could prescribe meds for me. So the trial nurse and I carefully kept a list of the medicines I was taking. During one appointment he added a drug and stopped another. Upon checking with my pharmacist, I learned that two of my meds were contra-indicated with the possible side effects of seizure, stroke, and death. I immediately stopped the meds and called the trial nurse. The doctor’s response was that none of his patients had experienced any of those reactions. Since I didn’t want to be the first, and I stopped the meds. Eventually I wrote five pages about how that doctor treated me and I was eventually allowed to switch study centers.
Ironically, just a few months after I switched study centers, the trial sponsor, Cephalon halted the trial simply by posting on its website that the trial had not met its endpoints and it was over. Participants and researchers alike were caught unaware. In fact, the researchers had just gone to Florida for a meeting to discuss the trial results to that point.
Because CEP-1347 didn’t work, and it didn’t change the course of PD progression, the members of PRECEPT were considered a “control” group of early diagnosed pwp, And about 500 of us were recruited to a follow-on trial named PostCEPT where we would be followed by researchers who hoped to learn more about the natural history of PD as well as to possibly determine early biomarkers of PD.
As part of PostCEPT, I was a part of PROBE, the Coriel Repository, B CIT scans, and FOUND. Later I also participated in a Kinetics trial. My data is part of LABS PD and PD DOC and the NINDS DNA Repository
Ken: Let’s talk specifically about your recent experience with the NINDS Phase I study and some of the unique challenges you’re facing in this clinical trial?
Jean: This NIH-NINDS-funded study is a Phase I clinical trial of experimental gene therapy with convection-enhanced delivery involving MRI-guided placement of one or more catheters directly into the brain to provide distribution of the therapeutic agent to a larger volume of the brain tissue. This provides higher drug concentrations directly to the tissue and uses molecules that do not normally cross the blood-brain barrier. It tests the safety of the gene transfer material delivered directly into a specific region of the brain. No one knows whether this study drug will have any effect on Parkinson’s disease.
But I was not going to miss participating in a GDNF study. Ten years ago I watched in dismay as Amgen halted its GDNF clinical trials. Then I watched as Amgen refused to allow the trial participants to continue to receive GDNF for “compassionate use.” I met several of the original GDNF trial participants at the 1st World Parkinson Congress in Washington DC (October 2004). I heard their stories. I believed them when they said GDNF worked for them. I decided if GDNF ever became available for humans in clinical trials, I would be interested in a new clinical trial.
In this clinical trial there are occasional risks (risks that might happen on up to 10% of study participants) of bleeding, bruising, infection, and postoperative pain at the incision site. There is also a risk of stroke, due to bleeding in the brain that may occur during or within 24 hours of the surgery. The risk of stroke in surgeries similar to this is 12 people out of 100. If a stroke occurs, it may involve the loss of some neurological function (including speech or walking) or death.
The side effects may be permanent but the risks are unknown. Possible risks may include brain hemorrhage; worsening of motor function; allergic reaction that could include fever, rash swelling or difficulty breathing; and theoretically, development of a brain tumor .
All of these things are serious, but what concerned me the most in the IC was the Policy Regarding Research-Related Injuries: “The Clinical Center will provide short-term medical care for any injury resulting from your participation in research here. In general, no long-term medical care or financial compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal Government. However, you have the right to pursue legal remedy if you believe that your injury justifies such action.”
If I were to have a severe adverse event (AE) requiring long term care, I would be on my own. If my family needed financial help for long term care, they would have no recourse but to sue the federal government. In the case of this clinical trial, the NIH is listed as trial sponsor, but there are other entities involved in the study. In June 2012, uniQuire issued a press release that it was collaborating with UCSF and NINDS to start clinical trials in the U.S. using uniQure’s GDNF. Under the terms of the collaboration, uniQure will have the rights to the results of the study in addition to the IND. In exchange, uniQure will manufacture the GDNF-AAV construct using its baculovirus platform for the next phases of the study.” Shouldn’t these organizations have an obligation to provide insurance coverage for study volunteers? I was truly shocked when I learned that a clinical trial sponsored by the NIH would do nothing to pay for long term care needed as a result of serious trial-caused injury or disability.
Ken: How were your concerns handled by study staff, the IRB? By NINDS? By Leaders in the Parkinson community?
Jean: I asked the trial nurse to find out if the Primary Investigator (PI), had patients with any adverse events (AEs)? There were none.
During a meeting with the Primary Investigator via Skype, I told him that I was offended that the IC did not provide catastrophic long term care insurance in the case of injury to the human participants. He laughed and said it was a “boilerplate NIH form.” I repeated that it was offensive to me, but I let the matter drop. I knew that nothing could be done at that point. I would join the trial or not. To my mind, using this boilerplate document shows benign neglect. It didn’t occur to the researchers or the members of the IRB that there was anything amiss with the document. I decided that if I joined the trial (and survived), care for human participants would be a matter that I would take up after the surgery.
In early April, during my 1-month post surgery visit at the NIH, I visited the Office of Human Subjects Research Protections, Office of Intramural Research. I told them my story and they asked if I would be willing to speak to people from the Office of Bioethics. I said yes. I reiterated that there must be some way to fund insurance coverage for Phase I trial participants.
I also took the opportunity to speak to some high level members / leaders of four of the national U.S. Parkinson’s organizations. In casual conversation, I asked them: What did they think about human participants not being offered catastrophic long-term care in case of AE? One representative was appalled. Another representative offered to look into the matter. I later sent a follow-up email to that representative but never received a response. The third and fourth representatives said that it would be very expensive, and that they can understand why it is set up this way (and agreed that they status quo was fine with them).
Ken: What lessons and insights would you like to offer other patients and their families facing similar protocols and situations in the future?
Jean: Do your homework. Search the web for information about your clinical trial, about the sponsors, and about all contributing entities to the study. Ask questions. Read the IC carefully. What are the risks? What will happen to you if you have a severe AE?
In this clinical trial, I am required to spend 60+ days traveling and/or having clinic days; to give 150+ vials of blood; to have 7 MRIs; to have 3 PET scans; to have 3 lumbar punctures; to go through 5 psychological exams, and to keep 5 OFF-ON diaries over a period of 5 years
It’s so important that research sponsors remember that we are VOLUNTEERS. We DONATE our time and our health to participate. Among the people and groups involved with the trials, we are unique in receiving no compensation. Take care of us. Make our travel arrangements. Pay for our hotels and meals. Make participation easy. Ensure we pay no money out of pocket for our expenses. This can be done. I made several trips to the IND for SPECT scans and they set up and prepaid all travel and hotel reservations. We were even given vouchers for meals. Only an occasional taxi or meal out needed to be reimbursed with receipts. It can be done.
Make participation easy and even pleasurable. It’s possible. If the IND can do it, so can others. I shouldn’t have to argue to be reimbursed for a taxi ride.
I’ve been in a number of clinical trials and I am really dismayed that study volunteers in the US are not treated with full respect and dignity. Carl Elliott, MD, PhD, states that“If a subject is permanently disabled and unable to work, sponsors have no obligation to pay compensation for his or her lost income. If a subject dies, sponsors have no financial obligations to his or her family. Not a single academic medical center in the United States makes it a policy to compensate injured subjects or their families for lost wages or suffering. These policies do not change even if a subject is injured in a study that is scientifically worthless, deceptive, or exploitative.” No-fault compensation schemes for medical injuries were adopted in Sweden in 1975, Finland in 1987, Norway in 1988, and Denmark in 1992.
What price do we put on a human life? As a clinical trial volunteer, the scientific community, members of Parkinson's organizations, plus members of my government ask for me and other human volunteers to go in harms way to test a new drug or treatment. It almost seems like a strategy to exploit patients desperate for a cure. Shouldn't they take responsibility for catastrophic care if that is necessary? If they do not, then who should?
It is long past time for a change. Government and industry research sponsors can address this problem: They can create and use no-fault insurance policies; they can require study sponsors to set aside a percentage of their research budget to insure the human research participants; and they can require Parkinson’s organizations to set aside a percentage of their budgets to insure the human research participants.