Global Patients Whining about the Production Suspension of the Cytarabine Manufacturer

The share of Pfizer’s cytarabine is dominating the Chinese market or even in the global market. The cytarabine referred to here is Pfizer’s product Cytosar™ which is the trade name, and its generic name is Cytarabine for Injection. It is mainly indicated for remission induction and maintenance therapy in acute non-lymphocytic leukemia of adults and children and also has therapeutic effects in other types of leukemia. According to a notice on the internet at the beginning of this year, Pfizer would conduct equipment overhaul for the production line of cytarabine, and cytarabine would be suspended production for a period of time due to the long overhaul and maintenance time. As a result, the shortage of cytarabine has been widely reported recently in China.

Similar phenomena already happened in the U.S., and it is history repeating itself

Shortages of some pharmaceutical products are a global phenomenon. Pharmaceutical product shortages of different degrees and involving different varieties happen at different times worldwide, especially generic drugs and cheap drugs that have already become off-patent. The shortage of chemotherapy drugs is normally more crucial as most of them have no equivalent substitutes. For example, the U.S. had a similar shortage of cytarabine early in 2011, and there had been no drug stock in the whole U.S., during which, doctors at a hospital in the U.S. purchased a batch of imported drugs from Switzerland, and it took at least 21 days for the drugs to go through all procedures to enter the hospital for use (AJHP, 2012, 69(16): 1416-1421.). And according to a report of FDA in 2017, there was another shortage of cytarabine in the U.S., as shown below:

Participation of cytarabine in treatment is a matter of life and death

As an old anti-cancer drug, cytarabine was first applied in 1969, and it is also a general-purpose cancer drug, for example, cytarabine used in combination with anthracycline antibiotics can treat acute myelocytic leukemia and lymphoma, etc. and it is also commonly seen in alternative regimens for treating other cancers; in particular, in some specific chemotherapy regimens, the combination of chemotherapy drugs and cytarabine can achieve a 40%-50% cure rate of leukemia, however, this figure is 0% if cytarabine is absent. For those patients, access to cytarabine is a matter of life and death.

Drugs in the "gray market" are from unknown sources with big risks

Leukemia tops in the morbidity and mortality of malignant tumors among children in China. Cytarabine is mainly used in leukemia chemotherapy and transplantation preconditioning; in particular, large doses of cytarabine are generally needed in consolidation chemotherapies following the remission of acute myelogenous leukemia and transplantation preconditioning regimens for different types of leukemia. Unlike the use of other common drugs that is measured by milligram, the use of cytarabine is measured by gram, with the difference being several orders of magnitude. The news of production suspension of cytarabine has led to the panic of tumor patients and their family members in China, who have tried to purchase from the online "grey market" for substitution in the short term.

Such drug purchase behavior is highly risky. Firstly, sources of drugs cannot be guaranteed, and there is the possibility that they will buy counterfeit drugs that are completely ineffective, such as drugs from India. India has various patent drugs and numerous generic drugs, however, it is also one of the largest producers of counterfeit drugs. Secondly, the application of cytarabine may cause various adverse reactions. For example, it can lead to certain degrees of myelosuppression; cytarabine can result in drug fever (high fever), which may be low-grade fever or high fever with temperature over 40℃ (with an increase of white blood cells, neutrophils, and c-reactive protein, etc.), requires close observation and dose adjustment after the use, and is very easily confused with bacterial infection. Finally, there is price fraud in the grey market, where those illegal drugs may be sold far higher than their original prices, resulting in a large increase in patients’ costs.

The regulatory procedures should be simplified so that the new applications of generic drugs can be completed review by FDA in 3-6 months after drug shortages are announced or imminent.

Lack of profitability is the root, and it’s difficult for generic drugs to substitute

There are many factors associated with shortages of pharmaceutical products, such as insufficient raw materials and capacity, defects of manufacturing methods, strict law enforcement, and regulatory rule modification, however, those factors are barely backed up by any actual data. In fact, if we go into the direct root of shortages seriously, it is the "profits". Most of the drugs in short supply are common drugs, the drugs themselves are not expensive with small profits and small profit margins. Restrictions on price rise of common drugs could mean that certain generic drugs will never profit as seen from the perspective of the manufacturing industry and will thus be suspended supply.

It’s worth mentioning here that such shortage of generic drugs are seldom discovered or reported in Europe and within the EU system, which is connected to the medical insurance policy and generic drug pricing system thereof. Generic drugs are priced slightly higher in Europe, and reasonable profit margins of pharmaceutical companies are guaranteed through the agreements between governments and pharmaceutical companies. Such a win-win solution ensures stable profit margins of original drug manufacturers and, to some extent, stimulates them to continue to produce cheap pharmaceutical products and home medical products. And guaranteeing reasonable profit margins of common pharmaceutical products will promote generic drug companies to be sufficiently motivated to continue to imitate and supply such drugs instead of imitating some new drugs that just become off-patent owing to the pursuit of profit margins.

Summary

To sum up, cytarabine is another vital drug to leukemia management, the lack of which may cause serious impacts to leukemia patients. And China has taken a swift response: the Department of Drug Policy and Essential Medicine of the National Health Commission of China has issued the Notice on Doing a Good Job in the Supply Guarantee of Cytarabine Injection this Jan., which proposes that the relevant Chinese enterprises will strive to maintain the market supply and Chinese-produced cytarabine can be used to substitute the similar product of Pfizer. What makes a civilized society great depends on how it treats its most vulnerable members—patients and the poor; only by treating them well can it truly become great.

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