1. Protection of Human Subjects Case #2
Responsible Conduct in Biomedical Research
Protection of Human Subjects Case #2
Salim Darwiche
Jean-Bernard Nobs
Marco Pisano
Anders Sandholm
Valentina Triacca

2. Philadelphia, September 13th, 1999

3. The Father My Son, Jesse

4. (Ornithine transcarbamylase deficency syndrome)
Jesse Gelsinger
Born 18th of June 1981
Pretty normal infancy
At ~3 years: first signs of metabolic disorder
Final diagnosis: OTC
(Ornithine transcarbamylase deficency syndrome)
High level of ammonia in the blood
Mild (6% enzyme efficiency)
Could be controlled by medication and diet

5. Jesse – the teenager
Jesse grew up, having a normal life, but taking nearly 50 pills a day!!
He was inconsistently taking them.
1998: We were made aware of a clinical trial, in Philly, about OTC.
Christmas 1998: Heavy crisis.
Jesse’s primary medication was not effective enough, and was not taken constantly.
With the new medicine: great results!! Jesse was ordering and eating food like a teenager!

6. 1999 - Clinical trial proposal: Gene Therapy
Technique to be used:
injection of viral vector into the liver.
Danger associated:
8 hours immobility
Flu-like symptoms for a few days
Remote possibility to contract hepatitis
Most dangerous part: needle biopsy to be performed one week after the infusion: 1 to chance of death.
Previous results:
Mice: working temporarily – preventing death
Most recent patient: + 50% efficiency!! Wow!!!
After Jesse, they can show exactly how well this works!
Over people in the US will benefit from this study

7. The Scientist A Treatment for OTC

8. Ornithine transcarbamylase (OTC) deficiency

9. Gene therapy

10. What course of action would your recommend?

11. The Physician Morbidity and Mortality

13. Post-Mortem Evaluation:
Proximate cause of death was acute respiratory distress syndrome.
Systemic inflammation complicated by multi-organ failure.
Cause of systemic inflammatory response syndrome not clear.
OTC 018 vs. OTC 019

14. How would you handle the situation?

15. The Media The Fallout, The Scandal

16. FDA investigates on the way UPenn conducted the trial

17. Dr. Wilson failed to:
Adequately protect the safety and welfare of subjects, enrolling subjects who were not eligible for the study
Ex: Gelsinger’s high ammonia levels should have excluded him from the study
Adequately protect the rights of subjects  disinformation about risks and adverse events that occurred during the study
« How many subjects experienced adverse effects? »
Dr. Wilson’s point of view: 0!

18. Obtain informed consent
Side effects experienced by subjects previously involved in the trial: not mentioned!
2 monkeys given a similar treatment died: not mentioned!
Risk of disseminated intravascular coagulation: not mentioned!
He didn’t inform subjects about his financial interest (holding 30% of GENOVO)
Accurately and completely identify changes in the research activities
He changed inclusion criteria without informing the competent institution
He eliminated the exclusion criterion of history of hepatic or vascular disease

19. Post-hoc Expert Opinion Don’t give up on gene therapy

20. Impact on research Understand risk Gene therapy and stem cell research
No one should be allowed to sign up for a experimental drug and treatment if they don’t clearly understand if its safe or not
Gene therapy and stem cell research
Someone has to go first, this will include risk
In the US, no national insurance program covering drug experiment.

21. New treatment Researchers studied the immune system
1 Case, Leber congential amaursis
Progress loss of vision, lead to blindness
Missing an enzyme (Gene RPE65)
Alessandro Cannata
18 years old
Vision problems since birth

22. Alessandro Cannata University of Pennsylvania School of Medicine
A tiny dose of healthy RPE65 gene was inserted into a “gentle” virus (AAV)
Injected into the retina
(Retinal cells don’t divide)
Only a phase 1 safety trial
(small dosage)

23. Alessandro Cannata
“When I was returning home from Philadelphia and still wore the bandage over my eye, I was at a restaurant and wanted to order but could not see the waiter, so I removed the bandage and it was as if someone had turn on a light”

24. Final Comments