Califf Airs Concerns About Zolgensma Data Lapse
Former FDA commissioner Robert Califf says the current concern over the inclusion of faulty data in Novartis’ BLA for Zolgensma (onasemnogene abeparvovec-xioi), a novel gene therapy indicated to treat spinal muscular atrophy in children at a cost of $2.1 million for a single, one-time dose, raises questions about the role of application sponsors in alerting FDA to data problems and the role of the agency in resolving such issues. In an online Stat opinion piece, Califf says it is his understanding from news accounts that Novartis followed its internal procedures in not notifying FDA before conducting its own investigation into the use of faulty data. For its part, FDA is concerned that it approved the drug before learning of the data problems but says the data integrity issues did not concern clinical trials with human volunteers and would not have affected the approval decision.
“It’s likely that had Novartis notified FDA about the data integrity issue, the accelerated review would have been delayed,” Califf writes. “…My experience in more than 40 years of developing and evaluating medical products, and two years working at FDA, has convinced me that it’s critical to have a second pair of eyes on every aspect of preclinical development, clinical development, and post-market evaluation….Mistakes, sometimes quite subtle ones, are common in study design and conduct, as well as in the analysis and reporting of findings. Purposeful manipulation or falsification of data and analyses, on the other hand, is much less common. Nevertheless, the complexity and level of detail needed makes it relatively easy for inaccurate work to pass muster among non-experts, and for the small fraction of purposeful data manipulators or fabricators, detecting such malfeasance requires expertise and dedicated effort.”
Califf notes that one of FDA’s core functions is to perform independent reviews of study design, data integrity, and analysis. Being untruthful with FDA carries civil and criminal penalties and risks a loss of trust for the portfolio of an entire company, he says.
“If FDA is to discharge this essential mission on behalf of the public,” Califf writes, “it must have adequate funding in order to maintain a talented workforce with deep knowledge of the relevant medical products, quantitative expertise, and highly specialized clinical and scientific judgment. An important but challenging part of this effort revolves around balancing involvement with industry while at the same time vigilantly guarding the agency’s independence.”
Califf also notes that his concern extends beyond medical products since dietary supplements, cosmetics, and food products all receive much less rigorous scientific oversight.
“As the Zolgensma story unfolds,” he concludes, “I hope it will remind us that we need a well-funded FDA that provides independent oversight on the methods, data analysis, and claims about data. While the current system has served us well, major issues need to be addressed to ensure that we improve oversight to accommodate an increasingly complex, multidimensional scientific environment. I have no special insight into the motivation for FDA’s specific aggressive public statements regarding the Zolgensma case, but I suspect the key issue of trust in the face of overwhelming complexity is driving the stern warning and possible consequences.”