Stringent Compliance Required in Pioneering Biotechnology, says Physician & Human Gene Therapy Researcher
Original Post Date: February 1, 2010
Author: Evan Scullin, MD
A clinical trial conducted at the University of Pennsylvania went horribly awry in 1999 when one of the gene transfer trial subjects, an 18 year old man named Jesse Gelsinger, spiraled into a devastating immune reaction and died as a result. Jesse suffered from ornithine transcarbamylase (OTC) deficiency, a rare genetic disease caused by the inexpression of a functional OTC gene, preventing the normal elimination of ammonia from the body. This deficiency results in a toxic build up of ammonia, a protein metabolite. For the gene transfer trial study, the team at the University of Pennsylvania utilized an engineered strain of the adenovirus, which causes the common cold.
In an April 2009 Article in Molecular Genetics and Metabolism, Dr James M. Wilson, the director of the clinical trial said, “It is clear now that the Clinical and Quality Assurance (QA) groups did not have the resources necessary to assure complete compliance for such a dynamic and complex protocol. They were asked to cover too much territory; each clinical research nurse oversaw as many as three gene therapy protocols at any one time, while the QA group, which numbered seven staff members at its peak, was responsible for most aspects of [Good Manufacturing Practice] GMP, [Good Clinical Practice] GCP, and [Good Licensing Practice] GLP compliance for up to seven active investigational new drugs. Support for these programs was provided primarily from grants and contracts that, individually, did not provide sufficient Clinical and QA resources to fully support specific protocols.”
Wilson said that insufficient Quality Assurance played a major role in the trial’s shortcomings along with a conflict of interest with a biotechnology firm, Genovo that had invested heavily in the treatment. By not rigorously considering the QA aspects of the trial, he said, patient safety had been placed at risk.
In a later interview in September 2009 with the journal Scientific American, the director of the trial, Dr. Wilson posed the question in an interview, “If the worst-case scenario played itself out—not the potential or likely, but the worst—would [going ahead with the study] be acceptable?” His answer to this question was — absolutely not. This central question, he says, would have been an excellent gauge as to whether his team was ready to proceed with the study. It would also serve as a solid cue to the industry as a whole today for evaluating whether all supports for a trial are in place before moving ahead, particularly in regard to Quality Assurance.
This specific case demonstrates the high importance firms must place on GMP, GCP, GLP toward preventing scenarios where patient safety can be compromised amidst powerful forces that often act on those studies. When companies have invested in research, clinical trials become high stakes endeavors. Companies want to develop solid products for the least in cost, but following short-cuts in testing and bringing those products to market threaten the very innovative products themselves, by casting a cloud over the specific technologies when things go wrong.
Aggressively pursuing new therapeutic technologies is important in order to bring effective cutting-edge treatment to patients, but this is only worthwhile when patient lives and interests are fully protected first. In the competitive world of scientific discovery – especially in the life-sciences, the industry must seek safety first before seeking return on investment. Life-sciences firms must consider good compliance practice as “routine” and as part of the cost of doing business in successfully developing and manufacturing new products for patients.
The following are Dr Wilson’s enumerated lessons learned from the failed project, as listed in the April 2009 article:
Lesson #1: The clinical protocol is a contract with the research subjects and regulatory agencies that must be strictly and literally adhered to.
Lesson #2: If you think about reporting – then do so!
Lesson #3: It is very difficult to manage real or perceived financial conflicts of interest in clinical trials.
Lesson #4: Informed consent may require objective third party participation
These lessons could apply to most any clinical study and would certainly serve as part of a helpful roadmap for innovative biotech and pharmaceutical endeavor in the decade ahead.
Molecular Genetics and Metabolism:
Dr. Evan Scullin is the Director of Business and Product Development of PharmaLogika, Inc and is a consultant to the life sciences industry. His work focuses on both domestic and cross-border pharmaceutical ventures and collaboration between medical institutions, governments and private firms.