Clinical Investigator’s Program: Why Research Ethics Matter

Clinical Investigator’s Program:Why Research Ethics Matter Michelle A. Mullen University of Ottawa Departments of Paediatrics & Women’s Studies Bioethicist, CHEO

Clinical Research: an ethical enterprise • Cancer Rx • Transplantation • Infectious Diseases • Cardiovascular Care • Genetics

Goals… • Walk in the hall of ignomy • Lessons to be learned? • Why ethics matters… • Good Science & Good Ethics – take home messages

Dr. Roger Poisson 1994 • Falsified data in ground-breaking lumpectomy vs. mastectomy cohort • Claimed he was trying to do the best for his patients: conflated clinician and researcher roles • FDA ban from any access to U.S. funds and disciplined by his professional college

Lessons…? • FDA disqualified Poisson from grants process after he acknowledged falsifying results of other studies • ORI found “115 well-documented instances of data fabrication” • Investigators must continually remember when they are acting as researchers and when they are acting as clinicians. Investigators need adequate training as scientists. • A colleague described Poisson as a “proud man-proud to say that he puts most of his patients in trials, proud to get grants, proud to get his name on research papers”

Dr. Nancy Olivieri 1998 • Dr. Olivieri wanted to tell research subjects and the scientific community of potential (lethal) risks with the drug (deferiprone) that children in a clinical trial were taking as experimental treatment for thalassaemia • The manufacturer of the drug ordered her not to disclose these findings to participants or researchers • Public and protracted conflict

Lessons…? • Institutions need to adopt AND enforce strict conflict of interest polices • Institutions and REBs need to review contracts • Confidentiality clauses that potentially restrict informing either participants or the scientific community are unacceptable (time-limited notification clause) • Clinician investigators need to understand their obligations, rights, responsibilities prior to undertaking clinical research

Mr. Gabriel Lessard • In 1991 Lessard volunteered to take part in a study to screen for prostate cancer • The next year researchers found a slight abnormality but decided the result wasn't important and chose not to tell Lessard • In 1993, researchers did another test, with abnormal results but it was too late, the cancer too invasive

Lessons…? • Quebec coroner Luc Malouin says researchers put medicine on the back seat • "The doctor has the obligation to give the truth to the patient" • Standards for clinical disclosure (Reibl v Hughes SCC) are higher in the research context • Consent, disclosure of pertinent/unexpected findings, disemmination of research results should be considered a priori

Ryan 2002 • 4 year old child died at the Children's Hospital of Eastern Ontario after he was given a "significant overdose" (25X) of an experimental drug (Interleukin II) for ‘treatment’ of NB • CHEO has been praised for its transparent approach in handling this issue

Lessons…? • FDA inspection; letter to trial physician posted on web site • Previous OD and toxicity reported, not taken account of – safety and monitoring • HC did not undertake separate investigation, but notified research centres, drug companies, REBs and hospitals across Canada that adherence with regulations “is obligatory” • Mistakes happen on clinical trials -

Jesse Gelsinger • 18 yo first patient to die in clinical trials for gene therapy • OTC (ornithine transcabamylase) deficiency, usually fatal at birth -some normal cells enabled him to survive with diet / meds • Sept/99 Jesse injected with adenovirus carrying a corrected gene • died four days later (massive immune response with multiple organ failure and brain death)

Lessons…? • FDA concluded scientists involved in the trial broke several rules of conduct: • Inclusion of Gelsinger as a substitute for another volunteer, despite having high ammonia levels that should have led to his exclusion • Failure by the university to report that two patients had experienced serious side effects from the gene therapy • Failure to disclose the deaths of monkeys given a similar treatment in the informed consent documentation. • The University of Pennsylvania later issued a rebuttal, but paid the parents an undisclosed amount in settlement

Why ethics matters… • Why do patients come to us? • Who benefits from clinical research? • Who pays for research? • Starting research process from ethical viewpoint… • Good Science & Good Ethics needed

Good Science & Good Ethics • Equipoise • Roles/dual agency • Disclosure  risks & benefits  conflict of interest  unexpected results  recruitment (vulnerable populations) • Safety & Monitoring • Regulations

Even if I don't finish, we need others to continue. It's got to keep going without me. Terry Fox

Clinical Investigator’s Program: Why Research Ethics Matter