On Monday, June 18th, BIO 2012 was much more subdued than I’d remembered seeing it in the past. However, it was just the first official day, and a number of breakout sessions touched on important topics.
Perhaps the most important of these topics is drug shortages. A panel of professionals from regulatory, manufacturing and patient welfare backgrounds discussed the topic. Kevin Whalen of Pfizer’s worldwide policy group, chaired the session, with:
Lou Di Genero, EVP and CSO for Leukemia and Lymophoma Society
Gerry Migliaccio, SVP Pfizer Global Supply Chain
Nancy Dennis, founder and CEO, National Patient Advocate Foundation and PAF
Jouhayna Saliba, special assistant to the head of FDA's drug shortage program
Peter Pitts, of the Center for Medicine in the Public Interest (CMPI)
As Whalen explained, shortages are a complex issue and there is no “one size fits all” solution. He asked: how do we get constituent groups together to examine root causes of shortatges, and understand why the problem is peaking now, and how do we assure that patients receive their medications? He then showed a local New York news clip profiling a cancer patient who cannot get the chemotherapy drugs he badly needs.
Low costs for the drugs are a major problem, panelists agreed, as manufacturers leave businesses and research and clinical trials are slowed.
But the situation is dire, as Mr. Di Genero noted. He recalled a comment by champion cyclist Lance Armstrong’s physician. Armstrong was treated with medicine developed in the 1960s. Were Lance diagnosed today, his doctor said, the odds would be stacked against him.
Manufacturing is critical issue, De Genero noted, but so is the pricing issue. Could there be a partnership between generics, pharma industry and not for profit patient advocacy groups, to create stockpiles of these drugs?
As Peter Pitts noted, “We have an opportunity, not to fix the blame, but to fix the problem.” He cited from a survey of 1800 physicians that found more than half frequently or always have problems stemming from drug shortages. The top three problems? Little to no information on the potential duration of shortage, lack of warning to FDA, and little or no information on the cause of the shortages.
He mentioned the fact that CDER’s more robust program involves closer coordination with compliance to manage shortages through better communication, facilitation and negotiations.
FDA Commissioner Hamburg says that shortages have fallen by half year to year over the past few years. However, Pitts asked, is this decline due to FDA’s ability to demand information on potential shortages earlier?
Some pieces of the drug shortage puzzle still haven’t fallen into place, he said. For instance, 30% of injectable drug manufacturing capacity is currently offline due to manufacturing problems. Pitts was critical of FDA. “A 30% hole in mamufacturing is more than a hint that something’s amiss at White Oak,” he said, later mentioning the fact that FDA had recruited new inspectors, and questioning the validity of some of their reports.
Among the other sources of blame, Pitts said, are:
• artificially low prices
• group purchasing organizations, which, he said, have created a concentrated market that excludes other would be suppliers or distributors. “It’s no surprise that shortages are in those generic drugs sold to GPOs rather than to consumers. They are sold at next to no profit margins,” he said.
He summarized some of the legislative fixes being proposed, noting that “manufacturers will now have to report anything looking like a shortage, increasing the potential for noise-to-signal problems." Pitts noted that Orrin Hatch’s bill is focusing on the average sales price of the drug, making it the only bill that attempts to deal with the economic causes of the shortages.
Ms. Saliba of FDA discussed the Drug Shortage Program at CDER, which started in 1999 with 11 full-time staffers. Designed to prevent and resolve shortages, she said, it brings together FDA experts, industry and external stakeholders with the goal of informing the public and reaching out to healthcare professional organizations, patient groups and other stakeholders. FDA’s powers to deal with drug shortages are still limited, she said, and manufacturer participation is voluntary. “There’s no penalty for not reporting,” she said.
Summarizing recent statistics, she noted that 2011 was a high point for shortages, with 251 drugs in short supply, all of them important, including treatments for cancer, anesthetics and involving highly specialized manufacturing techniques. These products would pose high risks to patient if manufacturing were handled less than meticulously, she said. 73% of them were for injectables.
As to the reasons for these shortages, 47% were due to quality issues. Capacity constraints were the second biggest problems, with an insufficient number of manufacturers, or too few manufacturing lines to generate the required amount.
For sterile injectables, the major problem was component problems (56%) with 20% due to capacity issues. Currently, she said, seven manufacturers account for most of the market. There has also been increased reliance on CMOs.
Sterile injectables – top reason was component problems (56%), 20% due to capacity issues.
Quality and compliance problems in manufacturing centered around sterility (with bacterial or mold contamination often cited), foreign particle contamination (when glass, metal, or fibers were found in vials of the drugs), crystallization of active ingredient, precipitate formation, with product reacting with raw materials or containers, formation of new impurities or degradants, equipment breakdown problems caused by insufficient plant maintenance, and natural disasters.
Last year, she noted, 195 shortages were prevented, mainly due to early notification by manufacturers.
“Industry must be committed to a culture of quality manufacturing,” she noted. We need better methods and redundancies and manufacturers need to report and correct even small problems, promptly. “We owe it to patients. We need to work together to ensure they get quality medicines they need.” She said. She also noted the need for commitment to quality to come from senior management down.
Pfizer’s Migliaccio boiled the issue down to lack of good robust root cause analysis.
We have a lot of anecdotal info, FDA has its info, but it’s not complete with information from manufacturers on how the root cause came about. Some examples he noted, were cases where demand exceeded capacity due to raw material, API, or packaging component availability, or control systems were inadequate to catch problems before the material was released. “Media fill failure in an aseptic environment can steal months from your capacity. We need to figure out what occurred and how to fix it,” he said.
Generics margins are very low, Migliaccio noted, and for some of these products, there are no profit margins. If you have an unprofitable product and aging facilities, how do you convince management to invest in new equipment and capacity for a product that’s coming offline?” he asked. “When you’re pressured, you look for lower cost suppliers of API’s ingredients, packaging components, but .they’re not usually as reliable.
Whelan asked panelists whether companies should be required to report on shortages as they develop. Increased notification won’t fix the problem, Saliba noted, although it can divert some of those shortages.
Manufacturer notification has been increasing six fold per month, she said. "We started with 10 per month, now we're at 60. Shortages would have been worse without it. But it’s not a fix. We need to continue to work on this, she said, and to discover the root cause."