SHORTAGES

by stevefredman

On one level we’re talking supply and demand–the quantities of a medication that are required and available at various price levels.

When a drug is needed for a non life-threatening conditions and it costs too much, people who don’t have the money don’t buy it.  In “developed” countries, doctors and patients who are facing a life threatening illness expect the needed drugs to be accessible when they need them. 

Climate is what we expect.  Weather is what we get–  Mark Twain.

“With the proper drugs” 90 percent of the 3.000 children a year who are afflicted by T-cell acute lymphoblastic leukemia are curable. “Between 2009 and 2019, nine of the eleven medications doctors used to treat the disease were intermittently hard to get.5” In 2019 two companies were producing Vincristine and one of them, Teva, stopped. “This is truly a nightmare situation,” one pediatric oncologist complained.  “Vincristine is our water. It’s our bread and butter.”  Another doc added: “You either have to skip a dose or give a lower dose, or beg, borrow or plead.” We will still be able to cure childhood leukemia but it’s harder “with one hand tied behind your back.14” 

Bruce Chapner, an investigator at the National Cancer Institute, wrote about the limited availability of “workhorse cancer drugs”: and the astounding short supply of generic drugs:  antibiotics, blood pressure meds, anesthetic agents and electrolyte solutions.21

56 percent of hospitals surveyed by the FDA reported they had changed patient care or delayed therapy in light of scarcities: 36.6 percent said they had rescheduled non-urgent or emergent procedures. “In Europe, the past five years have seen global shortages of at least ten essential oncology drugs. Two of five European doctors surveyed said the problems occurred on a weekly basis and typically last a few months.”20

After a new pharmaceutical is created it can’t be marketed until it’s shown to be beneficial and relatively safe.  In the U.S. its creator is then given a multiyear monopoly.  When that ends others can fabricate and distribute the medication.  Most of the drugs people take are generics, and many are made by one of the planet’s three top generic manufacturers: 

  • Teva, an Israel based company that has $9 billion in sales, and factories in many countries,
  • Sandoz—a Swiss company that is the generics division of Novartis and has $8.5 billion in sales, 25,000 worldwide employees and 30 manufacturing sites, and
  • Actavis, a $70 billion company that is headquartered in Dublin Ireland and has 10,000 employees.1 

More than 50% of our generic drugs are supplied by one or two manufacturers. Some medications have “Thin profit margins that can lead to shortfalls, manufacturing delays, or decisions to discontinue a drug altogether.16” When several companies manufacture a medication, competition can lead to a “race to the bottom.”– A destructive drop in the prices.

In the 21st century U.S. more than 100 meds were hard to get “at any given time” Sixty three% of them were generic sterile injectable drugs.15

As meds became less profitable, manufacturers often don’t upgrade.  They keep producing the drugs in “older and less efficient production facilities.”  When contamination leads to plant closures manufacturers don’t always rebuild.3 Companies with factories that need updating “need predictability– incentives in the form of guaranteed-volume contracts to mitigate the risks of making investments.” “Without accurate information about the expected demand for low-volume, low-margin medications, companies have been reluctant to create additional manufacturing capabilities.2”  

Limited availability is also affected by business difficulties.  In December 2017, facing falling profit margins, Teva laid-off 14,000 workers and closed a few manufacturing facilities.  They were under pressure in the U.S. from “major chains, wholesalers and benefit managers who had gotten together and demanded discounts.”  To survive and be profitable they planned to discontinue some drugs and close or sell “a significant number of manufacturing plants in the United States, Europe, Israel and other markets.4”

In June 2018 after 31 senators wrote a letter to the head of the FDA “requesting his assistance with the availability problem” The agency task force suggested using “incentives” to encourage drug makers to produce scarce products.  They wanted the FTC– federal trade commission to “review drug company mergers and acquisitions.5”

In 2011 there were 257 new drug shortages.  The next three years there continued to be 250 shortfalls a year, and in 2019 the number of meds in short supply started rising. In 2015, acting on Obama’s executive order, the FDA published a number of rules to help alleviate the problem.  Before companies stop making any or enough of a needed drug, (within the limits of the law) they are supposed to notify the agency.  The government can then “determine if other manufacturers are willing and able to increase production” 

The FDA “was told to expedite inspections and reviews of submissions from manufacturers attempting to restore production, and from manufacturers who were interested in starting new production.

The agency was also told to bend a few rules: “Exercise temporary enforcement discretion for new sources of medically necessary drugs;” help affected manufacturers identify the reason there wasn’t enough of the needed medication.  They developed risk mitigation measures, like using sterile filters, to allow individual batches of a drug product initially not meeting established standards to be released.17

Currently the FDA says it has 4 “officers” and others working on the shortage problem.   Most companies were notifying the FDA as required by law, and the FDA was encouraging, talking, strategizing—and increasingly relying on foreign inspection histories.  But the agency was toothless.  They couldn’t require manufacturers to do anything.

In 2017 “Due to the ongoing critical lack of injectable drugs used in critical care” the FDA extended the expiration date of a number of Hospira injectable medications.6 

 “The effectiveness of a drug may decrease over time, but much of the original potency still remains even a decade after the expiration date. Excluding nitroglycerin, insulin, tetracycline and liquid antibiotics, most medications are long-lasting”.  So: why are drugs dated?  A law passed in 1979 requires drug manufacturers to stamp an expiration date on their products.  It marks the final month and day the company can guarantee the full potency and safety of the drug.  In August 2018 the FDA reported on a stockpile of expired drugs that was tested for the military.  As long as 15 years after their expiration date, 90% of the hundred prescription and over-the-counter medications “were perfectly good”.7  

There’s a grey market.  Nobody wants to run out of needed medications or infusions, and some facilities have paid a premium and stockpiled them.  That’s illegal you say.  Tell that to the person with a serious infection who needs the right antibiotic now.

Global demand is increasing, and some shortages are worldwide.  In Brazil, a three-year shortage of benzathine penicillin G (BPG) occurred at a time when the country was having an outbreak of syphilis, a disease linked to severe malformation in babies.  Benzathine penicillin G is the only long acting antibiotic known to cross the placenta and prevent mother-to-child transmission of syphilis.  Worldwide, “just four companies produce the active ingredient for penicillin. The medicine offers little profit, and those companies keep production levels low.8”

In the US, the number of people with syphilis has grown.  In 2019 more than 115,000 cases were reported to the CDC.  The drug that best treats the disease, Procaine Penicillin, is produced for the U.S. by Pfizer.  It was in short supply prior to March 2019.  It’s currently available.

According to the FDA approximately 20 million IV saline bags are used per month in the United States.    IV fluids are used to hydrate, as a vehicle for infusing medication, and much more.  In the U.S. they are largely supplied by: Baxter, a U.S. company with 3 manufacturing plants in Puerto Rico.   (They also have “12 manufacturing sites in the continental U.S. and eleven in Latin America and Canada.”);  Bags are also manufactured by B.Braun Medical–The American branch of a German company that has operations in 64 countries:  and Hospira (a Pfizer owned company).

The supply of sterile solutions in the U.S. had been borderline for years.  In September 2017 Hurricane Maria with sustained wind of 155 mph blew through Puerto Rico and knocked out the islands power.  When we visited San Juan the following January the warm Caribbean sun and the gentle island breezes masked the destruction.  The hotels that functioned were filled with construction workers and there were no tourists. The power in Ponce had been turned on the very day we visited a shop and spoke with the tanned, smiling proprietor. If someone in an apartment building had a generator electric wires from other apartments hung from windows and were plugged in.  Some houses were roofless.  For others blue tarps kept the rain out.

Baxter asserted that their “3 Puerto Rico sites were minimally damaged and that they had resumed “limited production activities within a week using diesel generators”; but the U.S. needed bags; and the FDA acted.  The agency can’t require a manufacturer to make more. But in March they “checked out Fresenius Kabi, Norway’s saline producing facility.  It passed inspection and the agency “temporarily allowed Fresenius Kabi to distribute normal saline in the U.S.”  In April 2017 the FDA allowed Baxter to temporarily import normal saline produced in Spain.9

The world will soon face a shortage of antibiotics that treat drug the resistant bacteria that, according to the CDC, infect at least 2.8 million Americans a year and contribute to 35,000 deaths. In the last decade at least two start ups created a drug that destroys resistant organisms.  The FDA approved their use, and they are available. But the involved companies aren’t selling enough medicine, and they are considering bankruptcy.22

  1. https://www.thebalance.com/top-generic-drug-companies-266311
  2. http://www.pewtrusts.org/en/research-and-analysis/reports/2017/01/drug-shortages
  3.  http://www.nejm.org/doi/full/10.1056/NEJMp1112633#t=article
  4. https://www.nytimes.com/2017/12/14/business/dealbook/teva-pharmaceuticals-generic.html
  5. https://www.fda.gov/media/132058/download  http://www.ajhp.org/content/early/2018/03/14/ajhp180048?sso-checked=true
  6. https://www.wisc-asc.org/news/382129/FDA-Approved-Drug-Extended-Use-Dates-List-.htm
  7. https://www.health.harvard.edu/staying-healthy/drug-expiration-dates-do-they-mean-anything
  8. https://www.aljazeera.com/indepth/features/2017/05/world-suffering-penicillin-shortage-170517075902840.html
  9. http://www.jhconline.com/iv-shortage-tests-providers-and-suppliers.html
  10. (N Engl J Med 2014: 371: 1761-1763) 
  11. https://www.kccllc.net/achaogen/document/8851500190415000000000003 
  12. https://www.in-pharmatechnologist.com/Article/2019/06/10/Achaogen-sells-remaining-assets
  13. https://www.fiercebiotech.com/special-report/30-xerava
  14. https://www.nytimes.com/2019/12/25/health/antibiotics-new-resistance . https://www.sec.gov/Archives/edgar/data/1373707/000119312513048887/d441172ds1.htm
  15. https://www.nytimes.com/2019/10/14/health/cancer-drug-shortage.html
  16. causes and non causes of drug shortages by Albert Brill.  http://getmga.com/wp-content/uploads/2017/04/HSCA-drug-shortages-Jan-2017.pdf  Drug Shortages: Root Causes and Potential Solutions A Report by the Drug Shortages Task Force 2019 a report chaired by the FDA  https://www.fda.gov/media/131130/download
  17. The generic drug industry has brought huge cost savings. That may be changing.By Carolyn Y. Johnson  Washington Post. August 1, 2017 https://www.washingtonpost.com/business/economy/the-generic-drug-industry-has-brought-huge-cost-savings-that-may-be-changing/2017/08/01/ee128d0a-68cf-11e7-8eb5-cbccc2e7bfbf_story.html
  18. Third Annual FDA Report to Congress on Drug Shortages for Calendar Year 2015  https://www.fda.gov/media/96113/download
  19. file:///C:/Users/User/Documents/Bipartisan%20letter%20to%20FDA%20on%20Drug%20Shortages%20from%20the%20Senate.pdf
  20. https://www.pewtrusts.org/en/research-and-analysis/articles/2020/01/16/antibiotic-sales-for-animal-agriculture-increase-again-after-a-two-year-decline
  21. https://cancerworld.net/spotlight-on/shortages-of-generic-cancer-medicines-are-harming-patients-so-why-cant-we-fix-it/
  22. Bruce A. Chabner, M.D.December 8, 2011N Engl J Med 2011; 365:2147-2149 https://www.nejm.org/doi/full/10.1056/NEJMp1112633 \
  23. For a startup to be financially successful they have to develop a very expensive medication (see gene therapy), create something that is truly innovative, or sell a lot of product.  Vis-à-vis antibiotics, if physicians start giving one of the new antibiotics to every sick person whose infection might be caused by resistant bacteria, the drugs will be over used.  With regard to the companies that developed the medications we need: Achaogen, incorporated in 2002, “developed and commercialized an “antibiotic treatment against multi-drug resistant gram negative infections.”  Their research was funded “in part by a $124.4 million contract” with BARDA, part of the government agency that “was established to secure our nation from biological threats…as well as emerging infectious diseases.”   Investors apparently hoped their drug, Plazomycin –Zemdri, would  bring in millions. (It’s reported revenue was $800,000 during the last 6 months of 2018)–‘Unfortunately the new antibiotic is not a true innovation.  It is an altered version of a drug that was developed in 1963 by scientists employed by Schering.  They worked with a naturally occurring product of a bacterium, a micromonospora, and they produced the antibiotic gentamycin..  Scientists were later able to chemically modify it and produce other antibiotics:  neomycin—then Amikacin– and now plazomycin.  All are aminoglycosides and can harm a person’s kidney or hearing.  Doctors mainly use them when they are really needed.11

Another new antibiotic in financial trouble, the tetracycline Xerava—Eravacycline was developed by a start up using technology pioneered at Harvard.  A legit medical advance, the drug was launched in 2018 at an announced wholesale cost of $175 per day. It effectively treats a variety of Gram-positive and Gram-negative bacteria, including multi-drug resistant strains, such as MRSA and a resistant enterobacteriae. 

The medication apparently got off the ground when Congress was convinced that its creation would have biotech signficiance.   In 2011 and 2012 Congress authorized  $67 million for the development of eravacycline “for the treatment of disease caused by bacterial biothreat pathogens.”  Currently the government money is running out; doctors are using the medication appropriately–only when indicated.  Its developer, Tetraphase, has investors and it’s struggling.12

There’s a nonprofit at Boston University that’s working on the antibiotic resistance problem.  It’s called CARB-X and it claims to be “the world’s largest pre-clinical and early development pipeline of antibiotics and other therapeutics.  Since it was established in July 2016, it has invested $160.6 million in 52 projects in seven countries.”  (Like an average of $3 million per project to develop a next generation drug.  Hmm.) It is funded by the US Department of Health and Human services, The Wellcome Trust, A UK Innovation Fund, and the Bill & Melinda Gates Foundation.13