Protection of Human SubjectsCase #2

Salim DarwicheJean-Bernard Nobs

Marco PisanoAnders SandholmValentina Triacca

Responsible Conduct in Biomedical Research

Philadelphia, September 13th, 1999

The Father

My Son, Jesse

• 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

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!

Jesse – the teenager

• 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 10 000 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 500.000 people in the US will benefit from this study

1999 - Clinical trial proposal: Gene Therapy

The Scientist

A Treatment for OTC

Ornithine transcarbamylase (OTC) deficiency

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ucd-overview&rendertype=figure&id=ucd-overview.F1

Gene therapy

What course of action would your recommend?

The Physician

Morbidity and Mortality

0 10 20 30 40 50 60 70 80 90 100

Clinical Summary

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

How would you handle the situation?

The Media

The Fallout, The Scandal

FDA investigates on the way UPenn conducted the trial

Dr. Wilson failed to:

• Adequately protect the safety and welfare of subjects, enrolling subjects who were not eligible for the studyEx: 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!

• Obtain informed consent1) Side effects experienced by subjects previously involved in the trial: not

mentioned!2) 2 monkeys given a similar treatment died: not mentioned!3) Risk of disseminated intravascular coagulation: not mentioned!4) He didn’t inform subjects about his financial interest (holding 30% of GENOVO)

• Accurately and completely identify changes in the research activities

1) He changed inclusion criteria without informing the competent institution2) He eliminated the exclusion criterion of history of hepatic or vascular disease

Post-hoc Expert Opinion

Don’t give up on gene therapy

Impact on research

• Understand riskNo 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.

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

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)

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”

Final Comments