Tag Archives: Ethics

Does being unconscious mean you should miss out?

The front page of the Herald this morning questions the participation of unconscious patients in clinical trials.

While I understand Auckland Women’s Health Council co-ordinator Lynda Williams unease, I also detected a failure to understand the process of how progress in medicine is made.

First, all research in such cases is approved by ethics committees which include lay people and patient advocates. That is clear in the article. In my experience they are very very thorough at ensuring the best interests of patients are highest priority. Family or whanau consent is almost always required (especially if the research involves an intervention*). These are the same family or whanau who are talking with medical staff and, at times, providing consent for medical interventions.  When a person is vulnerable it is up to all around them to treat them with respect and care.  Offering them, through their family, the opportunity to participate in research is showing respect for them as a valued member of society who is prepared to give in the interests of others.  Indeed, it is a right of the patient, through their family, to be offered such research.

Second, without such research there can be no progress in medical treatment of unconscious critically ill patients. In order to save lives interventions must be made at critical junctures during the progress of a disease, normally at the earliest possible time. It is in the best interests of us all that such research take place. The alternative is to give up hope and allow current mortality rates to remain as they are. I research a disease (Acute Kidney Injury) which affects 1 in 3 people in the Intensive Care Unit and increases their chances of dying about 4 times. There is no treatment and it is devilishly difficult to detect in the early stages. An estimated 2 million a year die because of Acute Kidney Disease. Without the generosity of family and friends allowing trialling of an intervention (always based on years of prior research and judged to be possibly efficacious) there will be no progress and the death toll will remain high. I salute family and patients around the world who have participated in such studies in the past, and will do so in the future.

Disclaimers: 1. I have no knowledge or understanding of the antiobiotic trial under discussion.  2. I have been involved in an intervention study where participants were unconscious at the time consent was obtained.

*Note, there are some circumstances where when minutes count an intervention is required.  Research in these areas is ethically more difficult, but no less necessary.  I welcome public debate in this area.  While ethics committees can deal with ensuring minimisation of harm in such circumstances, we do need to decide as a society what sacrifices of individual rights we should make for the greater good.

My 10 Commandments of a Data Culture

Thou shalt have no data but ethical data.

Thou shalt protect the identity of thy subjects with all thy heart, soul, mind and body.

Thou shalt back-up.

Thou shalt honour thy data and tell its story, not thy own.

Thou shalt always visualise thy data before testing.

Thou shalt share thy results even if negative.

Thou shalt not torture thy data (but thou may interrogate it).

Thou shalt not bow down to P<0.05 nor claim significance unless it is clinically so.

Thou shalt not present skewed data as mean±SD.

Thou shalt not covet thy neighbour’s P value.

Herceptin: the long and the short of it

If I, or anyone I loved, had breast cancer I’d want to make damned sure they got the best possible treatment. This is at the core of issues surrounding how the drug trastuzumab (trade name Herceptin) is to be used.  This morning Radio New Zealand reported that the Breast Cancer Aotearoa Coalition has made a submission to the Northern B Ethics Committee to stop New Zealand women entering a trial comparing short duration (9 week) and long duration (12 month) Herceptin treatments.

I understand that the submission is based on the results of another study, the PHARE trial.  I will shortly summarise this study.   I will also summarise the SOLD trial which the BCAC want stopped (in NZ).  Before I do so, a disclaimer.  I have no a priori position on whether a short or long duration treatment should be funded, I am not involved or have been involved in any Herceptin studies and I have no links whatsoever to the manufacturers of Herceptin (Roche pharmaceuticals).  I have spoken publically against the process that resulted in the funding of 12 months of treatment.  This was in 2008 when the National political party (not in government at the time) had as an election promise that they would fund 12 months of Herceptin rather than 9 weeks as Pharmac had proposed.  My argument then, as now, was that it was wrong for a political party to make such a call.  The independent entity, Pharmac, has been given the responsibility to make such calls and is required to base them on the best available evidence.  If the politicians believe that those calls are not being made correctly, then they need to improve the funding for Pharmac or its structure so that we can all be confident the best calls are made.  They should not try and override their calls for political gain, which is exactly what happened in 2008.

 What is Herceptin and who benefits?

  • Herceptin (transtuzumab) is a drug marketed by Roche for the treatment of HER-2 positive breast cancer.
  • HER-2 refers to Human Epidermal growth factor Receptor 2 which is a protein that promotes the growth of breast cancer cells.
  • HER-2 is present in only about 1 in 5 breast cancers.
  • Herceptin is, therefore, only an option for up to 1 in 5 people with breast cancer.
  • Herceptin improves survival.  From the Cochrane review* of the efficacy and safety of trastuzumab (I paraphrase): “If 1000 women were given standard therapy alone (with no trastuzumab) then about 900 would survive. If 1000 women were treated with standard chemotherapy and trastuzumab for one year, about 933 would survive (33 more women will have their lives prolonged), about 740 would be free of disease recurrence (95 more women will not experience the disease return).”
  • Herceptin increases heart toxicity: “If 1000 women were given standard therapy alone (with no trastuzumab) then five would have experienced heart toxicities. If 1000 women were treated with standard chemotherapy and trastuzumab for one year 26 would have serious heart toxicity (21 more than the chemotherapy alone group) due to the drug.”

 The SOLD (Synergism Or Long Duration) trial

http://clinicaltrials.gov/show/NCT00593697

In women diagnosed with early breast cancer with high risk of recurrence who are HER2-positive this compares a 9 week course of trastuzumab with a 51 week course.

The study began recruiting in 2008 and is expected to be completed by January 2015.

The primary outcome is a comparison of the Disease-Free-Survival (DFS) at the end of the study in the two groups. DFS for an individual is the length of time they survive without symptoms of cancer after the end of the treatment.  Secondary outcomes look at overall survival and measures of heart function and adverse events.

This is a world wide trial run by the Finnish Cancer Research Group and New Zealand patients may be eligible to enter.  I understand Pharmac is providing  $3.2M to support this trial**.

The Northern B Health and Disabilities Ethics Committee approved the ethics application for this study.  It consists of lay and professional members and judges if a study is meeting a number of specific criteria designed to ensure study participants rights and interests are safeguarded.

The PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure) trial

http://www.clinicaltrials.gov/ct2/show/NCT00381901

This study aimed to compare two treatments: six months and 12 months of Herceptin.  The primary outcome was again Disease-Free-Survival.  The aim was to recruit 7000 people, only 3400 were recruited.

The trial was reported as a non-inferiority trial.  That is it tested if the six months treatment was not worse than the 12 month treatment.  It did not show that six months was equivalent to 12 months. It also failed to show it was inferior.  The trial had enough participants that if the lower bound of the 95% confidence interval of the Hazard Ratio*** had been greater than 1.15 then they could have drawn a positive conclusion about the  difference in the two studies.  It was not, the 95C%CI was 1.09-1.66 (ie the lower bound, 1.06, was not greater than 1.15).  This did not stop Roche and others reporting that the trial showed women receiving six months had a 28% higher risk of dying or having cancer return than those at 12 months (ie 1.28 being halfway between 1.09 and 1.66).

The results have only been presented in abstract form at a conference.  They have not gone through the rigorous peer review process yet, as far as I can tell.  I have not seen any information on the cardiac toxicity outcomes.

Summary of the evidence

The Ethics committee must decide if the PHARE trial and any other relevant information is sufficient that it would be unethical for patients to continue to be offered the opportunity to participate in a 9 week v 1 year SOLD trial.  This is a fair question to ask.  The difficulty they face is that the PHARE trial was not a 9 week vs 1 year trial, the results were inconclusive, the results have not as far as I can tell undergone peer review, and the published results appear not to say anything about differences in the rates of adverse events, especially cardiac ones.

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*Cochrane reviews are independent and adhere to strict quality control.  They are about as “good as it gets” for assessing treatments.

**Under the NZ Public Health and Disability Act s48(c) one of the functions of Pharmac is “to engage as it sees fit, but within its operational budget, in research to meet [its] objectives…”

*** The Hazard Ratio in this case is simply how many times more or less a patient on 6 months compared to 12 months treatment is likely to not survive or still have cancer at the end of the study period.