Tufts Center for the Study of Drug Development: Study on the Structural Roots of Drug Shortages and The Shortages Effects on Kids

Pharm Exec recently asked the Tufts Center for the Study of Drug Development (TCSDD) to summarize new survey research—partly commissioned by a grant from Amgen—that documents the scope of the threat and identifies the structural roots of the shortages. In a larger sense, the study underscores how effective management of the drug supply chain is emerging as something much more than an engineering feat: instead it’s a societal obligation. 

TCSDD developed a two-part methodology that entailed building a database of current drug shortages and conducting interviews with experience hospital pharmacists to gather first-hand knowledge of how drug shortages are managed and the challenges that they pose.  Tufts CSDD staff gathered publicly available data on 240 drug shortages occurring between 2001 and February 2012, from lists maintained by the ASHP and the FDA.   

TCSDD staff coded the root cause of each drug shortage and summarized these causes by major grouping.  The vast majority (94%) of drugs were small molecule chemical entities and 6% were large molecule biologics).  Most shortages (80%) involved generic equivalents, only 20% involved branded drugs.  More than three out of four (77%) drug shortages in the sample were sterile injectables.  The number of branded large molecule therapies are projected to increase rapidly through 2016—10 of the top 20 drugs.  And the number of generic biologics (biosimilars) entering the market is also expected to rise sharply during the next 3-5 years.  Given that all large molecules are adminstred in a sterile injectable format, the incidence of drug shortages is expected to rise sharply and the challenge to manage these shortages will likely intensify.   

One out of five drug shortages (18%) involve anti-infective treatments; 17% involve drugs targeting disease of the central nervous system and pain.  Drug shortages targeting cardiovascular illnesses and cancer-related illnesses represent 12% and 11% of all shortages respectively.  

One of the causes for shortages is that the supply chain of manufacturers capable of providing sterile injectibles consists of only a few manufacturers: Teva, Hospira and Bedford Labs produced 71% of sterile injectibles between 2001 and February 2012. 

The average product shortage duration was approximately 19 months.  Four out of every 10 drug shortages is associated with manufacturing problems.  The leading cause of manufacturing delays was voluntary suspension of suppliers for requalification of equipment.  Inspection citations and raw materials shortages were infrequent reasons for drug shortages and tended to occur outside the U.S. 

The second most common reason, accounting for 27% of shortages, is high demand coming from a variety of sources including consumers, as well as competitors looking to secure comparator drugs for clinical testing.  13% of shortages are due to drug discontinuation and withdrawal from the market. 

The article also noted the significant costs associated with additional hospital pharmacy staffing.  For example, one study found that the labor cost alone to manage drug shortages is an estimated $216 million annually in the U.S.  The costs associated with pharmacists, pharmacy technicians and nurses in a 400-bed hospital (or greater) are in the range of $25,077 to $118,800 per year.   

In the UK, one survey found that 43% of pharmacists spend 2-5 hours per week sourcing out-of-stock medication.  In addition, some hospitals need to increase the medication that they hold in stock as a strategy for dealing with unrelaiability of certain drug supply chains.  This extra inventory adds to hospital pharmacy expenses and dollars must be re-allocated to cover these costs.  

Information technology systems—in particular, large databases containing inventory data and tracking capabilities—within the pharmacy play a key role in managing and resolving shortages.   

Finding alternatives to treatments also poses challenges.  Pharmacists spend time working out alternatives, and consider all guidelines, but the lack of published data available for patient outcomes “poses difficulties when assessing the impact of an alternative drug due to a shortage.” 

Drug Shortages Hurting Pediatric Cancer Patients 

Unfortunately, drug shortages have caused adverse health consequences and in some cases, have affected the life expectancy of young cancer patients.  Specifically, a recent study from St. Jude Children’s Research Hospital found that estimated two-year cancer-free survival for patients with intermediate- or high-risk Hodgkin lymphoma fell to 75% from 88% when the drug cyclophosphamide was substituted for mechlorethamine, a drug that has been in short supply. 

The study’s authors have pointed out that other treatment options were put into play and that no patients have died as a result but said, “those who relapsed received additional intensive therapy that is associated with higher odds for infertility and other health problems later,” reported FierceHealthCare.   The study, published recently in The New England Journal of Medicine, did not estimate what the long-term impact of the drug substitution will be. 

“We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution,” the researchers noted. The analysis found that, as a group, patients who received cyclophosphamide had fewer unfavorable symptoms and were more likely to have intermediate-risk, rather than high-risk Hodgkin lymphoma. The patients ranged in age from 3 to 21. Half were age 14 or younger.

“This is a devastating example of how drug shortages affect patients and why these shortages must be prevented,” said Dr. Monika Metzger, the study’s principal investigator.  “Our results demonstrate that, for many chemotherapy drugs, there are no adequate substitute drugs available.” 

The study points out what the industry knows, that shortages, particularly of generic injectable drugs like mechlorethamine, is more than a financial or regulatory hurdle to be jumped.  The drugs often bring thin margins so they may only have one supplier still making them.  If the drugmaker has a plant problem or other interruption, then a shortage can quickly materialize. Mechlorethamine, which is again available, the study points out, has been used in cancer treatment since the 1960s.  But cyclophosphamide also has been extensively prescribed for treating children and adults with Hodgkin lymphoma. Studies had shown it to be a safe and effective alternative to mechlorethamine. 

The FDA in 2011 initiated new protocols for drugmakers to give it the earliest possible warning in case of potential shortages and has worked with companies to ease the impact of shortages. It has even granted temporary permission for some companies to import drugs that are not approved in the U.S. but are used in other countries as alternatives to drugs that are now in short supply. There have been fewer new drug shortages reported this year but the problem remains a big challenge for the industry and the agency. 

The study’s authors gave the FDA credit for working to solve the shortage problem but Dr. Michael Link, the senior author of the report, said, “This puts a face on the problem of drug shortages and shows that the problem is real, not theoretical. This is about a curative therapy that we were unable to administer because the drug we needed was not available.”    

“Despite heroic efforts by the drug shortage office of the Food and Drug Administration to solve the shortages of a number of medically necessary drugs, it is clear that patients are still suffering from the unavailability of life-saving drugs. A more systematic solution to the problem is needed.” 

Drug Shortages Hamper MDR-TB Treatment 

In addition to drug shortages hurting children with cancer, a recent report from the Centers for Disease Control (CDC), reported by Medpage Today, showed that “Drug shortages have affected most U.S. health programs that deal with multidrug-resistant tuberculosis (MDR-TB).” 

“Shortages of so-called second-line drugs have lead to treatment delays, lapses, and interruptions, as well as the use of inadequate regimens,” the agency reported in the Jan. 18 issue of Morbidity and Mortality Weekly Report.  Health agencies were forced to divert staff in order to procure scarce drugs, the CDC reported. 

Drug-susceptible TB is treated with four so-called first-line drugs – isoniazid (Nydrazid), rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol) – in a 6-month standard regimen.  MDR-TB, on the other hand, is characterized by resistance to isoniazid and rifampin and must be treated for between 18 and 24 months with up to 6 drugs that are “less effective, more toxic, and more costly than first-line drugs,” the CDC report said.

Since 2005, the CDC has been told of difficulties obtaining a range of second-line drugs, including streptomycin, cycloserine (Seromycin), ethionamide (Trecator), rifabutin (Mycobutin), amikacin (Amikin), capreomycin (Capastat Sulfate), and kanamycin (Kantrex).  The current report comes as a national shortage of isoniazid is in its second month. 

The findings come from a national survey of TB control programs conducted in late 2010 by the National Tuberculosis Controllers Association, which found, the CDC reported, that shortages not only interfere with patient care but “could promote the development of drug resistance as well as the transmission of drug-resistant Mycobacterium tuberculosis.” 

“The association surveyed 61 of its 68 members and 33 (or 54%) responded, including 29 that represented state TB programs and four that represented large cities.  Of those, 26 programs – representing about 75% of the U.S. TB burden – reported having at least one MDR TB case in the previous 5 years.” 

Of the systems reporting MDR-TB, 21 — or 81% — said they had trouble getting second-line drugs.  All cited nationwide shortages, but 71% also complained of shipping delays, 62% said they lacked resources, and 48% blamed a complicated procurement process related to investigational new drug protocols. 

Nineteen of the 21 jurisdictions said shortages led to adverse outcomes, with 58% citing treatment delay, 32% reporting treatment lapse or interruption, and 32% said they had been forced to use an inadequate regimen.  “For example, the CDC report cited an April 2011 case in which shortages of capreomycin and amikacin delayed treatment for a father and his infant who had MDR-TB.” 

Despite efforts to get the drugs, treatment was delayed for 8 days, lengthening the time the father remained infectious.  At the same time, the infant, who had basilar meningitis and severe communicating hydrocephalus, “was placed in a particularly dangerous situation,” the CDC report said. 

TB meningitis in young children “is a medical emergency, and delays in treatment lead to worse outcomes, such as severe cognitive impairment, epilepsy, and death,” the report noted.  “The CDC report cautioned that, because of the 54% response rate to the survey, the results might not represent the national experience with shortages of second-line drugs.”