About Phase 1 Clinical Trials and their Terminally-Ill Volunteers
Phase 1 clinical trials are the gateway to testing new therapies and drugs on humans. In cancer research, the clinical development of new remedies for cancer begins with Phase I studies that use volunteers who have incurable cancer. For these people, all possible avenues for cure or containment of their cancer have been exhausted.
The primary objective of most Phase 1 studies is to determine the toxicity profile of a new agent or new combination of agents. By exposing successive small cohorts of terminally-ill volunteers to a pre-set schedule of escalating dosage amounts, the dose-limiting toxicity (DLT)/ maximum-tolerated dose (MTD) is arrived at. Once the highest dose of the new agent that is demonstrably injurious to approximately a third of the trial volunteers becomes known, the “safe” dose for humans can then be established and Phase 2 studies for efficacy can commence.
Studies show that less than 5% of patients who enroll in Phase I trials benefit medically from participation.
Not all persons terminally ill with cancer can be accepted into a Phase 1 study. The prospective Phase 1 subject’s body must meet a specified level of adequate major organ function before enrolment in the study. In a Phase 1 trial, it doesn’t matter what kind of cancer the person is dying of, just that they possess a human body still capable of processing the investigational drug.
How Informed Is Informed Consent?
Prospective clinical trial volunteers are required to read and sign a lengthy consent form meant to ensure that they fully understand what they are agreeing to when participating in the clinical trial.
However, despite the extensive consent form and face-to-face discussion, studies show that prospective participants may still lack basic comprehension of the concepts that define many trial protocols. In Center for Information & Study on Clinical Research Participation (CISCRP) focus groups, for example, some volunteers did not have a good grasp of study-defining words such as “placebo-controlled,” and many were unclear about the purpose of their particular study.
- Don’t fully read the lengthy consent form.
- Don’t fully understand the legal terminology.
- Have limited understanding of the trial purpose.
- Overestimate the benefits.
- Underestimate the risks.
- Trust in and rely on the integrity of the recruiting medical personnel.
Informed consent in Phase 1 cancer trials is particularly problematic, as the context in which a prospective volunteer must understand and make a decision is complex and emotionally charged. These people, and their families, are coping with the fact that they have a terminal illness and all standard treatments have been exhausted.
Phase 1 cancer trials offer almost no hope of therapeutic benefit and significant potential for serious and even life-threatening side effects. Studies have shown that those cancer patients recruited for Phase 1 cancer trial participation often overestimate the potential for benefit (therapeutic misconception) and their expectations of the treatment’s benefit are significantly different from those of the physicians overseeing the Phase 1 research.
According to participants, the clinical trial recruit often doesn’t know what questions to ask since the whole concept of experimentation using a human being is totally beyond the average person’s range of experiences.
In addition, complete and accurate comprehsions of the Full Disclosure Form can be hampered by a person’s ability to judge or reason. In the case of the terminally-ill person, such factors as high levels of stress (possible PTSD), intoxication, severe sleep deprivation, etc. can impair mental acuity.
The informed consent process runs counter to the way in which most people regard their medical care giver. We typically trust a doctor to advise us about what the best treatment or course of action will be and don’t think of medical treatment as a risk-analysis process. We are inclined to assume a doctor has our best interests in mind and we often don’t see the distinction between a clinical researcher MD and our attending physician.
Palliative Care Alternatives
Another factor in the decision-making process of the end-of-life patient is whether palliative care treatment has been discussed as an option. Studies suggest that "posing comfort care only as a real alternative during the informed consent process and in consent documents might diminish the inclination of some potential participants to enroll because it avoids the misapprehension that that there is no alternative to enrollment." (Sachs G, "Opportunities for Promoting Palliative Care Medicine in Cancer Research," Cancer Invest 16 1998:503-508)
Why Do People Volunteer for Phase 1 Clinical Drug Trials?
The reasons people volunteer are varied and highly personal. The idea of participating in a clinical trial is often initiated by personal contacts, such as friends and family or physicians who have experience with or information about clinical research trials.
Phase 1 clinical trial volunteers may be motivated by a variety of reasons. Some of the most common motives given by volunteers are:
Enhanced care. Trial volunteers may feel that the thorough monitoring of their physical situation – promised to them for the purposes of collecting data for the investigational drug’s approval – will result in superior personal medical attention. They may feel that they will have access to larger, more renowned medical facilities and expertise than is available in their home community.
Want to feel that they are taking control of their medical condition and well-being. Patients who are terminally ill with cancer can feel helpless and cut adrift when they discover there are no further treatment options for them. In addition, they generally suffer from extreme fatigue. An attempt to mitigate the depression often associated with fatigue by using anti-depressants does not eliminate this constant and debilitating cancer symptom. Even if a patient has been given a prognosis of short life-expectancy, time can be a burden as the patient has no energy to do things. A cancer patient may face the conundrum of having little time left to live but finding that time “hanging heavy on their hands.” A Phase 1 drug trial presents the dying cancer patient with a minimally vigorous yet worthwhile “plan of action.”
Want to feel that they are still useful. A terminally-ill cancer patient may be feeling that they are a burden to absolutely everyone, so being told that they are needed as a participant in a medical research endeavour can be a relief from the angst of feeling useless. Additionally, a terminally-ill cancer patient approached to enrol in a clinical trial might feel as one of the few that can provide assistance and thus have a unique contribution to make.
Want to know that their participation will make a difference. Volunteering for a clinical trial is an opportunity for terminally-ill cancer patient to personally be a part of and, possibly contribute significantly to, a cure for cancer; their participation may, ultimately, spare others from the distress that they have suffered. This is one of the most compelling reasons that volunteers cited for participating in a trial and it is extremely important for volunteers to know that the knowledge gained in their trial was readily accessible and put to the best possible use.
Want hope for therapeutic benefit. It is common for Phase 1 clinical trial volunteers to overestimate the miniscule chance that the trial could offer any therapeutic benefit. In addition, researchers recruiting clinical trial volunteers may be imbued with enthusiasm for the eventual acceptance of the drug they are shepherding through the drug approval process and their optimism may influence the prospective volunteer.
How Do Clinical Trial Volunteers Want to Be Regarded?
In a CISCRP focus group, clinical trial volunteers stated that they did not want to be referred to as "guinea pigs” or even “research subjects” but preferred the term “volunteers.” They wanted to be seen not as passive recipients of investigational drugs and procedures but as active participants partnering with the trial investigators to advance medical science.
What Constitutes a Good Experience for a Phase 1 Clinical Trial Volunteer?
Of course most Phase 1 volunteers hope that their cohort has received the “safe dose” of the investigational drug and that the safe dose is an effective remedy for the type of cancer or other disease that the volunteer has and that it will become the proven new weapon in the fight against cancer.
However, the likelihood of any clinical trial volunteer being involved in the testing of a pharmaceutical product that is granted marketing approval is only 10%.
Other factors that volunteers say are important to them are:
- Warm and caring interactions with the medical staff.
- An environment where they feel comfortable asking questions.
- Personal relationships.
- Post-trial feedback about outcomes.
The CISCRP focus group volunteers stated that the information on the side effects or status of their investigative therapy was extremely important to their feeling that the clinical trial experience had been worthwhile.
More than anything else, study volunteers want to know that their participation matters. Regardless of the outcome, people who participated in clinical research want assurance that something was learned from their contribution that will inform medical knowledge about the disease and how to treat it.
Phase 1 Clinical Trial Volunteer Stories
Vancouver Sun Article on Research with Respect
This full-page article was featured in the August 'A' section of The Vancouver Sun. The subsequent 'Letter to the Editor' ended up being posted on the 'Medicine Matters' blog. Months earlier - late March, the reporter, Pamela Fayerman had been apprised of the *RwR* program but she chose to focus on the 'people aspect.' Her editor then asked for a more 'balanced' piece. This was eventually achieved by connecting with another Phase 1 volunteer who was a living, 'satisfied customer' of the cancer agency.
A Female Superhero Loses Her Battle
Andy's Phase 1 Clinical Trial Experience: as told by his wife
For the desperately ill, trials of new drugs offer one last hope. But as this terrifying story shows, if it all goes wrong, you could be on your own:
Dave’s Phase 1 Clinical Trial Experience: as recalled by his wife
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In early August, 2005, during an annual physical exam, our GP noticed that Dave was pale and sent him for blood work. Two days later, Dave received 2 blood transfusions and was scoped to see if the blood loss (detected in tests of his stool) was due to a re-occurrence of esophageal ulcers (’94). We were told that Dave had advanced esophageal cancer that was inoperable. After further tests, we were told that the cancer had metastasized to his liver and lungs. Dave had no pain and no difficulty swallowing – just overwhelming fatigue – but the news that his lungs were cancerous was devastating. Dave had been dealing with COPD for 15 years and so the prospect of even greater difficulty with his breathing was a psychologically crushing event.
During a subsequent visit to the GP, while Dave and the doctor were chatting about a second pathology report that hadn’t come in yet, I asked for a copy of the ultra-sound report. I do not know why that request popped into my head. The GP obliged. The report had the phrase “no pulmonary involvement.” I queried the GP as he had given us the results 2 weeks earlier. “Oh,” he said, “I must have been thinking of another patient.” That was a very good day – Dave had been cured of lung cancer!
In late Aug. 05, Dave was told that he could, possibly, have another 6 months to live.
Dave’s situation was assessed by BCCA oncologists. He was put on dexamethasone. He was given morphine to have on hand to deal with the liver pain that we were assured would strike viciously some day soon. He was put on what Dave called “happy” pills – a month later, the dose was doubled. He signed a “Do Not Resuscitate Order” as Dave opted to die at home.
The oxygen condenser was moved into our home and the schedule for visits from the community nurse was being established. In Oct. 05, Dave had 4 doses of low-radiation to cauterize the esophagus - to minimize the blood loss - but that’s all they could do for Dave.
Dave had seen an article in The Vancouver Sun newspaper, in September of ’05, re gene therapy being developed by a cancer researcher friend of our daughter.
After contacting him, Dave was offered the possibility of joining a Phase 1 clinical trial. However, only a chemotherapy study was being offered. Our nurse daughter and I tried to dissuade Dave from becoming involved with chemotherapy of any kind. Even Dave was convinced that the original oncology specialist’s advice was accurate - that chemotherapy would be ‘a lot of pain for no gain”.
But Dave saw the clinical trial as an opportunity to do something worthwhile with the last days of his life. It took so much out of him – traveling to Vancouver; going through the examinations and tests to see if he qualified to join the Phase 1 study.
The day before his 69th birthday, he was told that he had been accepted. We had a small birthday party and then went back to Vancouver to take up a month-long residency in a room that we had rented as it was a stipulation of the trial that Dave be in close proximity to the research facility for the first 30 days of the trial.
On Monday, November 21/05, Dave had the first infusion of CPX-1, at a dosage being tested on the 6th cohort of a proposed 8 cohort study.
I helped Dave get to the research facility every time a blood test was required - 16 times in the first week. He was so very tired; but he dealt well with the side effects - a couple of bouts of diarrhea; the high doses of Imodium seemed to work.
He had been cautioned that contracting a respiratory infection was a concern, especially as it was ‘flu season’. So, because of fear and fatigue, we became quite isolated.
At the end of the first week, the swelling in Dave's legs completely disappeared – overnight. No more wrestling with elastic stockings! We thought it was a good sign that the +2 edema that he had experienced since September, was gone.
On the Tuesday of the 2nd week of the trial, the diarrhea returned – frequent episodes and violent vomiting and retching incidents. That afternoon, we got in to see the research doctor who ordered a couple of hours of IV hydration with Maxeran at their Ambulatory Daycare.
That day was the last time a doctor from the research facility gave Dave a ‘hands on’ physical assessment and the only time the trial nurse saw Dave that week or ever again. I borrowed a wheelchair to get Dave back to our rented room.
That Tuesday was the last day that he ate food.
Each day for the next four days, I dressed Dave, bundled him up and trundled him over to the research facility by wheelchair for blood tests – shifting in and out of the car was too exhausting for him.
On 3 of those days, I took him to the Ambulatory Daycare for a couple of hours of IV hydration. Every 2 hours I would make sure that he took the high doses of Imodium. Dave was sleeping a lot, so I had to wake him to take the medication.
Every day I phoned the trial nurse to express my concern – that was when the hydration sessions and stool test were arranged. She said that Dave must drink at least 8 oz. of fluid an hour, so I would have to disturb him 2 or 3 times an hour – except at night.
During those last few days, Dave didn’t like me very much. The Imodium just wasn’t working. Dave had diarrhea episodes 7 to 10 times a day.
I moved him from his bed to the bathroom with a walker.
On the Thursday, I told the trial nurse that Dave was too ill; that we didn’t think he could have the second infusion of CPX-1 scheduled for Monday of the next week.
On Friday, again I went to her office, while Dave was having hydration, I was crying when I told her that Dave just could not have another infusion because he was so very sick. I met the trial doctor outside her office and told him Dave was so sick and that the Imodium wasn’t working. He said to stop the Imodium and come in the next morning, Sat., for another mini-hydration. He introduced me to the resident who would cover for him on the weekend.
I stopped the Imodium that afternoon but Dave had a huge vomiting episode and 4 diarrhea incidents in an hour and a half when we got back from the hydration session. I put Dave back on Imodium – it actually was slowing the bowel movements down – but just to Level 4 chemotherapy-induced diarrhea. I found out later that the care guideline for cancer patients with Level 3 / 4 chemotherapy-induced diarrhea recommends that the patient be hospitalized immediately and administered 24 hour hydration until the diarrhea is controlled. Level 5 chemotherapy-induced diarrhea is death.
When we got to the Ambulatory Daycare on the Saturday morning, I asked for the doctor to come and see Dave. The doctor sat in a chair at the bottom of the bed that Dave was in while he was hooked up to the IV. The doctor said that the blood work of that morning showed that Dave’s kidney function had gotten much worse (280 creatinine) but that they didn’t have a bed for him. The doctor told us to continue with the Imodium and to come back on the Sunday morning for more lab tests and another mini-hydration session.
Late Saturday afternoon, I phoned the research facility; spoke to the resident doctor and told him that I was concerned – that Dave was even weaker and that he wasn’t answering my questions correctly. The doctor said to bring him in again on Sunday morning.
The doctor was contacted again, about 10 pm, and was informed that Dave’s breathing was extremely laboured. The doctor said to stick with the plan to bring him into the research facility in the morning. At 3 am on Sunday morning, I woke Dave up to give him the double dose of Imodium. Dave indicated that he needed to go to the toilet. I moved him onto the little seat on the walker but just as I was transferring him onto the toilet, he had a seizure. I couldn’t get him back onto the bed.
I called for help and 911 were phoned. As we were just 2 blocks from VGH, the ambulance was there within minutes.
Dave was breathing and I insisted that everything possible was done for him.
VGH Emergency was so caring of Dave. But the soles of his feet were black; his creatinine level was 505; his breathing was raucous as he had acidosis (blood turned to acid) and he was terribly agitated.
Dave was taken to be X-rayed and after that effort he never made another meaningful sound or gesture. The research facility’s resident oncologist dropped into VGH Emerg twice that day and both times he told me that they could get Dave “over this hump”. The VGH kidney specialist told me that dialysis was not an option as Dave’s capillary system had shut down. He was given morphine to ease his breathing.
At 6 pm, that Sunday, blood poured out of his mouth and nose and he died.
I asked the research facility if the clinical study needed Dave’s body. The doctor sounded appalled that I would ask that question and replied, “No, it wasn’t needed.”
Later, I asked the research facility about the level of care that they provided. They said that they were sorry that the level of care did not meet our expectations - they judged the level of care that they provided to Dave was “reasonable” and “adequate”. I asked the research facility’s Ethics Board if the protocol (plan of action) for the clinical trial was detailed enough. The Ethics Board Chairman wrote, “My finding is that the deficiency in this case was not with the procedures that are in place but rather that those procedures were not always followed.”
The ‘safe’ dose of CPX-1 was determined to be the dosage administered to the 5th cohort of the Phase 1 clinical trial process. The Phase 2 clinical trials of CPX-1 are currently in progress – but not in Vancouver.