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Problems in assuring reliable drug quality and supply dampens progress in bringing lifesaving therapies to market.
Pharmaceutical companies developed, and FDA approved, dozens of new drugs and biotech therapies in 2019, as new discoveries in genomics and drug development continue to bear fruit. Even if 2019 approval numbers don’t set new records, the list includes notable breakthroughs, including Novartis’ controversial gene therapy Zolgensma; Vertex’s triple combo for cystic fibrosis; and new treatments for cancer, migraine, light-sensitivity, Parkinson’s disease, pneumonia, rheumatoid arthritis, tuberculosis, and urinary tract infections. The steady rise in applications for investigational therapies has made it difficult for the Center for Biologics Evaluation and Research (CBER) to keep pace, while the Center for Drug Evaluation and Research (CDER) continued to reorganize its Office of New Drugs (OND) to better assess and process a growing volume of submissions requiring special attention.
At the same time, high price tags on transformative therapies heightened challenges for prescription drug reimbursement and payment strategies. Health plans, payers, and policy makers continue to debate multiple proposals for reforming drug coverage and pricing, ranging from wider importing of less costly products from abroad, federal government price negotiations, and specific limits on annual price increases and patient out-of-pocket costs. There’s much talk of “value-based pricing,” but legal and technical difficulties limit this approach. The resulting uncertainties make it difficult for manufacturers to plan research programs, devise pricing and marketing strategies, and commit to upgrades in production operations.
A main cause of delay in bringing cutting-edge therapies to market in recent months has been difficulties in ensuring that production systems can ensure product safety and quality. The transition from pilot-scale to commercial manufacturing of gene and cellular therapies can be challenging and costly, observed CBER Director Peter Marks at the PDA/FDA Joint Regulatory Conference in September 2019. He emphasized the need for high-quality manufacturing of these new products, noting that treatments made from living cells or tissues often are not easily characterized, are susceptible to microbial contamination, and involve complex manufacturing materials and processes.
CBER published several guidances on testing and producing new cellular and gene therapies and has promoted additional assistance for manufacturers of advanced technologies, Marks added. But limited gene therapy manufacturing capacity will continue to be a major problem as multiple new products gain market approval, particularly those for treating chronic conditions in larger patient populations.
Such hurdles have prompted leading manufacturers such as Pfizer and Sanofi to make major investments in new biotech manufacturing sites. In addition, firms of all sizes look to work with contract manufacturing organizations with capacity for quality biotech production. To address these needs, as well as the difficulties of smaller developers of treatments for rare conditions, Marks backs the creation of a public-private consortium that can produce quality materials for preclinical and clinical studies more reliably and at lower cost.
While manufacturing issues delayed access to new breakthrough therapies, such problems also continued to disrupt production of many common, low-cost medicines that are important for treating many serious health conditions. In response to concerns from Congress and the public, FDA issued a report in October 2019 examining the financial, manufacturing, and policy issues underlying short supplies of important prescription medicines in the United States. The analysts found that of 163 drugs that first went into shortage between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality issues; only a few had problems due to increased demand or natural disasters (1).
A lead proposal from FDA officials is that manufacturers able to ensure a reliable supply of high-quality therapies should be able to command higher prices, an approach designed to encourage companies to invest in modern production systems able to avoid shortages, particularly for the low-priced, low-profit sterile injectables that companies often decide to abandon, rather than commit to the long-term upgrades needed to meet standards. To support this approach, FDA Acting Commissioner Ned Sharpless and CDER Director Janet Woodcock called for a system able to measure and rate a facility’s “quality management maturity” that can inform the public about its commitment to reliable quality production (2).
In addition, the report included more common actions to prevent and address ongoing shortages, such as permitting longer expiration dates where justified or increasing penalties on firms that fail to provide timely and adequate notification of a likely interruption in production. FDA also could require manufacturers of certain drugs to conduct periodic risk assessments to identify vulnerabilities in supply chains and plans to mitigate such risks. And new international standards for harmonizing post-approval changes in drug manufacturing and formulation, as proposed in a new guideline (Q12) developed by members of the International Council for Harmonisation (ICH), would make it easier for manufacturers to modernize or alter a production facility that serves multiple markets.
Manufacturers should “sell quality-not just medicine,” Woodcock stated in an FDA “voices” posting (3). Even though industry strongly opposed an earlier CDER effort to establish a system for rating companies on their ability to achieve quality drug manufacturing, Woodcock maintained that a firm’s ability to reliably make a product in sufficient quantities and with sufficient speed to “ensure that supply consistently meets demand over sustained periods of time” should be a strong selling point. This discussion will continue in 2020.
1. FDA, Report–Drug Shortages: Root Causes and Potential Solutions,FDA.gov, Oct. 29, 2019.
2. N. Sharpless and J. Woodcock, “Statement on FDA’s New Report Regarding Root Causes and Potential Solutions to Drug Shortages,” Press Release, Oct. 29, 2019.
3. J. Woodcock, “To Help Reduce Drug Shortages, We Need Manufacturers to Sell Quality-Not Just Medicine," FDA.gov, Oct. 24, 2019.
Vol. 32, No. 12
When referring to this article, please cite it as J. Wechsler, "Quality Issues Offset Biomedical Advances," BioPharm International 32 (12) 2019.