Fragile Antibiotic Supply Chain Causes Shortages And Is A National Security Threat
As a practicing infectious disease physician, I become acutely aware, on occasion, of shortages of antibiotics or essential medical supplies, such as saline (salt water) solutions. For years, I’ve been concerned that the availability of these medicines should be regarded as a national security issue, but that issue appears to have received little attention.
One problem I’ve encountered is that many pharmaceutical companies seem to hold where their plants are located as a closely held secret. In recent years, it has become clear that much of the outsourcing is to China and India, and in the U.S., to Puerto Rico.
Why is this occurring? Antibiotics are not as profitable to drug companies, as they are only taken for short courses. Pharma prefers drugs for chronic diseases, such as diabetes or hypertension, that need to be taken for years, or oncology drugs with their hefty profit margins. In fact, a number of companies have elected to stop developing and marketing antibiotics. As of 2008, the only big pharmaceuticals with active antibacterial discovery programs were GlaxoSmithKline, Novartis, AstraZeneca, Merck, and Pfizer. Bristol-Myers-Squibb stopped in 2006. In 2011, Pfizer ended antibiotic research at its main center.
Several factors contribute to the looming crisis in antibiotic availability and are nicely discussed in a new white paper from the nonprofit Access to Medicine Foundation. A major problem is the shortage of active pharmaceutical ingredients (APIs), often developed only in Asia. For example, piperacillin-tazobactam is a critically important antibiotic—and the global shortage occurred because of an explosion at a Chinese factory, the sole source. Manufacturing the combination antibiotic occurred primarily in India and Italy. Star anise, the source of the anti-influenza drug Tamiflu, is grown almost solely in China. When I looked into this problem in 2015, Levaquin’s active ingredient was made solely in Japan.
Another example is long-standing shortages of penicillin. Used first as an antibiotic in 1942, penicillin is very inexpensive, so no longer of interest to drug companies. Benzathine penicillin G (BPG) is the first-line treatment for syphilis, and cases of that—and other—sexually transmitted diseases have been on the rise. A global shortage of BPG has caused perinatal deaths and deformities from syphilis, especially in Brazil and Sub-Saharan Africa.
Antibiotic shortages also contribute to antibiotic resistance, when physicians substitute unnecessarily broad-spectrum antibiotics. Growing resistance is a double whammy, occurring at the same time as there are fewer antibiotics in the development pipeline to treat these superbugs. Gonorrhea, for example, is now extremely resistant to treatment in the UK, Japan, France, and Spain. Sexually transmitted diseases and MDR-TB or XDR-TB (multiply or extremely drug resistant) tuberculosis are huge public health threats.
The Access to Medicine Foundation outlines strategies to preserve supply chains. They recommend:
—Pharmaceuticals employ demand planning, sharing data among others, and trying to predict demand for drugs, based on historical epidemiologic patterns. Some companies, such as GlaxoSmithKline (NYSE:GSK), work with the WHO in anticipating supply and demand needs.
—Local manufacturing to contribute stability and help assure an uninterrupted supply of medications.
Jayasree K. Iyer, Ph.D., Executive Director of Access to Medicine Foundation, cites Mylan as a good example of a company making having everything it needs for its HIV/AIDS products in-house, from API to the finished dosed forms nine geographically dispersed sites. Decentralization protects the company from the kind of disaster that occurred with piperacillin-tazobactam.
—Strengthen distribution, which is now fragmented. There are several collaborative supply chain initiatives, including ones focusing on pandemic preparedness and another on neglected tropical diseases. The latter group works with the Gates Foundation and NGOs as well as pharma. Ensuring quality, both by monitoring for substandard drugs and counterfeiting, is a primary focus. Product packaging and stability is a concern, particularly for vaccines and medicines that require being kept cold throughout their handling. Ebola vaccines in Africa, where there is no electricity in some regions, is one example.
What are the consequences when the best drug, or “drug of choice” is not available? A 2015 survey in Europe found 51% of pharmacists reporting that patients received inferior drugs. Rationing was common, and medication errors increased. Too low doses of antibiotics can fuel resistance. More toxic alternatives might also be given. In a U.S. Emerging Infections Network survey in 2016, 73% of physicians noted that drug shortage affected their patients’ outcomes adversely.
Puerto Rico is home to 49 pharmaceutical companies and more than 70 medical device manufacturers. Perhaps this is because, despite an educated workforce, “Puerto Rico offers the lowest labor costs of any region under U.S. jurisdiction – with hourly earnings in manufacturing averaging 65 to 80% of the U.S. average,” as PRIDCO (Puerto Rico Industrial Development Company) boasts. Notably, more than 30 drugs and 10 biologics without good therapeutic alternatives were made primarily or exclusively on the island.
Puerto Rico—a U.S. territory—produces 10% of our drugs, and even more of our IV solutions. There was quite a shortage of IV saline, used routinely for mixing medicines for infusion intravenously or for treating dehydration. Baxter (NYSE:BAX) is the primary producer of IV fluids and supplied 43% of the U.S. market’s needs. Most of that was produced in Puerto Rico, and hospitals were left scrambling. The FDA allowed imports from other countries and extended the expiration date of the fluids.
Last year’s Hurricanes Irma and Maria devastated the island, and more than 11% of homes and businesses are still without power. The pharma and device industries reportedly fared better than individuals because large corporations had back up generators and were able to import diesel and supplies to maintain some function. Erin R. Fox, PharmD, Senior Director, Drug Information and Support Services at University of Utah Health tells me that all of the pharma manufacturers are now back at full capacity.
By relying on few manufacturers and sources of raw materials, the U.S. is making itself very vulnerable. As of 2017, we import 80% of our medicines from India, and China produces 40% of the active components (API). Canada is another major source of our drugs. Germany is the second top source of pharma imports (by value), and is a major source of biologics, drugs derived from living material.
This national security concern is shared by Dr. Amesh Adalja of the Johns Hopkins University Center for Health Security. He notes that we stockpile some drugs and vaccines against bioterrorism agents and as part of (influenza) pandemic preparedness. Concerns remain however as “countries may want to keep the countermeasures for their own population” and may have export restrictions, as Australia and Canada did with the H1N1 swine flu vaccine. Adalja stressed that the bottom line is “Do we have a durable U.S. supply?
Given our reliance on imports of essential medicines, a related concern for some is what the impact of possible trade wars with China, Europe, Canada, and Mexico might be. Dr. Fox told me that, “if China and India decided to simply stop selling raw material to the US – we would not be able to make about 80% of the drugs that we need.” Perhaps this warrants more consideration and discussion.
In the interim, Iyer suggests that there must be “agreements between antibiotic manufacturers and governments that ensure supply can meet global demand,” and that this might require government incentives. She also suggests a more collaborative approach between countries, manufacturers, UNICEF, and the Gates Foundation. This is a very aspirational goal.