What’s Behind NIH’s Quality Problems?

Operations for producing sterile biopharmaceuticals are so unsafe at the National Institutes of Health (NIH) that the agency should halt efforts to rebuild its troubled operation for producing these products for clinical trials. That’s the advice of an external “red team” working group appointed by NIH Director Francis Collins to evaluate quality and safety and make recommendations for improving patient care and clinical research at the NIH Clinical Center (CC). The panel’s final report, which was unveiled in April 2015, is prompting Collins to overhaul the leadership and organizational structure of this preeminent national center for conducting thousands of NIH clinical trials on cutting edge therapies.

These issues have emerged over the past year following internal complaints about a lack of quality control and basic maintenance at NIH facilities established to produce drugs for clinical trials conducted by NIH staff scientists and investigators. FDA conducted a for-cause inspection at the CC’s Pharmaceutical Development Section (PDS) in May 2015 and issued a scathing report citing fungal contamination of injectables, defective air handling systems, deficient equipment cleaning, and a lack of standard operating procedures (SOPs), among other quality defects. NIH halted production of sterile products last year while it tried to fix the problems, while also seeking commercial sources of needed sterile products. An internal task force conducted an extensive internal investigation, hired outside quality control experts, worked to improve a drug-compounding unit at the CC that produced drugs for individual patients, and brought in new leadership for the CC pharmacy department.

As these efforts uncovered more concerns, Collins appointed the red team external advisory working group to examine how the deficiencies at the CC PDS may reflect broader structural and cultural shortcomings at the NIH clinical research program. In its final report, the panel criticized NIH for a lack of attention to patient safety, fragmented governance of clinical research, and inadequate systems to monitor, report, and enforce safety and quality standards throughout the research enterprise.

The panel further chronicled continuing serious problems at NIH’s sterile drug production operation, starting with its failure to gain FDA certification of the facility in the first place. In addition, the assessment found little systematic monitoring of facility operations and a failure of management to address internally reported maintenance problems.

So instead of spending some $50 million to rebuild the PDS facility to meet quality standards, the advisory panel calls for NIH to rely more on quality commercial sources and other vetted external compounding facilities for sterile clinical supplies. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) in Frederick, MD, appears more capable and may be able to produce some of the products needed by other NIH institutes. NIH needs to continue to work with FDA to ensure that ongoing production of non-sterile products by the PDS and the NIH compounding pharmacy are compliant with quality standards. The PDS needs clear, written SOPs that detail processes for training, production, system monitoring, maintenance, and quality control before releasing any product to the clinic, the report advises.

The advisory group also called for an assessment of the dozen or so other NIH facilities that produce sterile materials for clinical trials on a small scale. That assessment recently led to the closure of an NCI operation engaged in cell therapy production and a facility under the National Institute of Mental Health producing positron emission tomography (PET) materials.

The problems at the NIH pharmacy production unit appear similar to those related to sterile drugs uncovered by FDA at numerous pharmacy compounding operations in the United States, as well as at prescription drug manufacturing sites around the world. Sterile conditions needed to produce safe, high quality injectable products are difficult to establish and maintain, and the nation’s premiere biomedical research operation has to set an example for others.