Successful importation of cytarabine into the United States during a critical national drug shortage
The importation of cytarabine into the United States during a critical national drug shortage is described.
In March 2011, the hospital pharmacy team at an acute care hospital was struggling to supply cytarabine for four specific patients, all of whom needed critical maintenance therapy after induction. Cytarabine was not available from any source in the United States, and the team had no realistic projected release dates for back orders. Idis UK, a pharmaceuticaldistributor, was asked to identify available drug and eventually found an unrestricted source of cytarabine in Switzerland. Once available drug was identified, a price quote for the supply amount was written for our consideration. This was inspected carefully to ensure that the drug, strength, dosage form, and any other ingredients listed were indeed what were expected. The pharmacy department worked with the hospital’s department of finance and accounting to submit the necessary financial paperwork. Payment was electronically sent to the distributor before the drug was shipped. Before the order for cytarabine was placed, the associated risks and benefits were assessed. The patients provided consent to treatment with the unapproved product. Acceptance of the price quote and instructions to order the drug were e-mailed to the distributor. The necessary documentation was completed and included with the shipment. The importation process, from initial inquiries to delivery, took 21 days.
The importation of cytarabine amid a drug shortage required a complex process that involved the efforts of an overseas distributor, the cooperation of multiple health professionals, and meticulous attention to detail.
The subject of national drug shortages has left pharmacists and other health care professionals wondering if they will be able to do no harm, simply because they must prioritize rationed drugs, administer an alternative therapy that may not be optimal, or turn patients away because a drug is not available. Consequently, hospital pharmacies spend many hours locating stock at other facilities in the hope that it may be “borrowed.” Pharmacists seek updated information regarding drug shortages, trying to find alternative drugs in the same class of the drug in shortage. However, to ensure the integrity of alternative stock, pharmacies must avoid solicitation from the “gray market”—unscrupulous vendors with inexplicable supplies of drugs that are unavailable through the usual channels of distribution.
In 2005, 61 drug shortages were recorded by the Food and Drug Administration (FDA) ; this number nearly tripled in 2010, with 178 drug shortages reported. Drugs that are currently unavailable or in short supply are listed on the Current Drug Shortages page of the FDA website. Reasons for the shortage and the expected duration of the shortage may also be included. However, it is not an FDA requirement to report any shortage information; therefore, the page may not accurately reflect the true extent of a problem. Using this page with other informational sources, such as the ASHP Drug Shortages Resource Center, which allows its members to report drug shortage experiences, may lead to a more complete picture of the shortage situation. Both resources supply estimates of shipping dates, providing a glimmer of hope that back orders may be fulfilled. In reality, new supplies may be depleted quickly by the back order demand, and there are no guarantees that the drugs will be available when needed. For some of the drugs listed, class alternatives can still be obtained. Communication with health care teams and patients is necessary to reassure them that the drug they will administer or receive will be a reasonable substitute and is an acceptable alternative. Finding alternatives for optimal treatments is difficult. Some oncology diagnoses have several approved and active chemotherapy regimens, but for others there are no alternatives that will provide an optimal outcome.
In early 2011, cytarabine was in short supply. Cytarabine is an antineoplastic agent used to treat a variety of leukemias, including acute myeloid leukemia (AML), acute lymphocytic leukemia, and nonHodgkin’s lymphoma. There is no alternative drug regimen for patients with AML, and evidence suggests that patients who delay induction or interrupt maintenance therapy may have fatal outcomes. Any remission induced by therapy may be brief if therapy is not maintained[7-9]. The impact of cytarabine therapy interruption for other indications remains unknown.
Park Nicollet Methodist Hospital is a 426-bed, nonprofit, acute care hospital in St. Louis Park, Minnesota. It is recognized as an area leader in cancer care, treating approximately 2000 new patients per year with chemotherapy on an inpatient and outpatient basis.
In March 2011, the hospital pharmacy team was struggling to supply cytarabine for four specific patients, all of whom needed critical maintenance therapy after induction. Cytarabine was not available from any source in the United States, and the team had no realistic projected release dates for back orders.
Analysis and resolution
The pharmacy team began to explore whether the shortage was limited to the United States only, with the possibility that cytarabine was still available globally. Inquiries made to a contact person in England revealed that Europe was not experiencing a shortage of cytarabine at that time. One source had stock it was willing to sell, but the U.S. Food, Drug, and Cosmetic Act prohibits the importation of unapproved drugs, which includes foreign-made versions of drugs approved in the United States. This provides patients some protection against drugs that have not been subject to quality inspection or have not shown efficacy for a medical indication. However, FDA has identified circumstances in which it will “afford regulatory discretion” for the importation of a drug under the FDA Personal Importation Policy (PIP)[10,11].
To be considered for regulatory discretion, the following criteria must be met:
- The drug is “for a serious condition for which effective treatment may not be available domestically either through commercial or clinical means.”
- “There is no known commercialization or promotion to persons residing in the U.S. by those involved in the distribution of the product at issue.”
- “The product is considered not to represent an unreasonable risk.”
- “The individual seeking to import the product affirms in writing that it is for the patient’s own use . . . and provides the name and address of the doctor licensed in the U.S. responsible for his or her treatment with the product, or provides evidence that the product is for the continuation of a treatment begun in a foreign country.”
- The request generally is not for more than three months’ supply of the drug[10,11].
Interestingly, there is no mechanism for FDA to authorize importation under the PIP before the drug arrives at the port of entry in the United States; instead, the drug shipment and associated documentation are reviewed and evaluated upon receipt by the FDA district office that oversees that port of entry. If FDA sees reason not to exercise regulatory discretion, the shipment will be impounded. The FDA district office will then issue a “Notice of FDA Action,” specifying the nature of the violation leading to impounding, to the owner or consignee. The owner or consignee is entitled to an informal hearing in order to provide testimony regarding the admissibility of the product. If the owner fails to submit evidence that the product is in compliance, or fails to submit a plan to bring the product into compliance, FDA will issue another “Notice of FDA Action” refusing admission of the product. The product then has to be exported or destroyed within 90 days. After considering these conditions and risks, we decided that our patients were at significant risk if cytarabine treatment was not continued and that we would work with FDA to meet the requirements to import the drug from the global market.
Choosing a reputable supplier
We knew that the drug in shortage must be supplied by a reputable pharmaceutical distributor in order to meet criterion 3 listed above. To ensure quality standards, we wanted to find a distributor licensed by the regulatory authority for each jurisdiction it operates within, whichrequires the distributor to operate to a defined standard. We also wanted the distributor to have (1) extensive experience sourcing and supplying “unlicensed specials” (unapproved drugs) under a named-patient basis, (2) import and export licenses in place, and (3) access to a global market. It should operate with robust systems to eliminate risk and ensure a safe supply of medicines. Our health care organization wanted to work with a distributor that also mirrored our ethical values. Buying a drug from a region already experiencing a shortage—and by so doing worsening a shortage by redistribution— would negatively impact the source country, and this was ethically unacceptable to us.
We identified a pharmaceutical distributor in the United Kingdom (UK) that met our requirements. Idis UK[a] was asked to check availability of cytarabine and found that the market in the UK was closed due to contractual issues with the National Health Service. Idis UK extended the search and eventually found an unrestricted source of cytarabine in Switzerland. The drug was made by Pfizer, who had manufactured an approved form of cytarabine in the United States in the past. Drug manufacturers in Switzerland are regulated and inspected by Swissmedic to ensure the quality and efficacy of medicinal products, just as manufacturers in the United States are inspected and licensed by FDA. This information allowed us to assess the reliability of the drug source. As the pharmaceutical distributor was the owner of the import and export licenses and was operating in the UK, it was necessary for the distributor to import the drug into the UK and then export it to the United States.
Once available drug was identified, a price quote for the supply amount was written for our consideration. This was inspected carefully to ensure that the drug, strength, dosage form, and any other ingredients listed were indeed as expected. For example, our first offer was for the liposomal form of cytarabine, which was not appropriate for the patients we intended to treat.
The pharmaceutical distributor wanted a financial account opened in advance per standard practice. This part of the process was completed while the initial sourcing of drug was undertaken and did not obligate us to the order. Our pharmacy department worked with the hospital’s department of finance and accounting to submit the necessary paperwork. This included bank details and financial references for our organization. Copies of the pharmacy license and that of a designated pharmacist were also required. To avoid delays, the required documentation was faxed to Idis in the UK.
The cost of the drug was elevated above the usual contract price. This was not unexpected, because when drugs are imported under the PIP, the manufacturer is likely to be supplying a relatively small amount of drug on a one-time-order basis and cannot offer a quantity discount. Costs for drugs obtained in this manner may reflect a brand-name drug instead of a generic version. The costs also reflect the expenses of the pharmaceutical distributor in assigning experts to obtain the drug on our behalf and to ensure that all regulatory processes are satisfied in all the countries involved prior to the U.S. port of entry. Shipping and maintaining appropriate storage conditions for the drug may also add to the costs.
We considered how our health care organization would be reimbursed for these costs. We investigated whether our patients had insurance coverage that would reimburse for the full cost of the drug. Insurance companies expect usual costs, so whether they will pay outlier costs—and whether patients will pay any uncovered costs—should be determined. We also determined how much cost our institution was willing to absorb.
The cost of this shipment of cytarabine was approximately 10 times the usual contract price for the same quantity of drug. However, we deemed this cost acceptable when considering the therapeutic benefit to the patients.
Payment was electronically sent to the distributor before the drug was shipped. We understood that we would bear the financial risk in placing the order. If FDA cannot apply regulatory discretion at the port of entry, there is unlikely to be any refund unless the distributor has been negligent.
Before we placed the order for cytarabine, the associated risks and benefits were assessed. The details of the drug and the costs were communicated to all parties involved, and a discussion was held with our organization’s chief nursing officer, chief medical officer, and chair of the pharmacy and therapeutics committee. The oncologists treating the patients needed to decide if they were willing to administer an unapproved medicine. Although cytarabine is approved for use in the United States, FDA had not inspected the Swiss product, making it an unapproved drug. Responsibility for the treatment, any adverse reactions, and product quality would ultimately rest with the prescribing oncologist.
The patients provided consent to treatment with the unapproved product. The risks and benefits were explained to them, allowing an informed decision regarding ongoing treatment to be made, and patients were made aware of the financial costs involved. They were also made aware that their name and medical diagnosis would be provided to all parties involved in the importation process.
Our director of pharmacy then authorized the placement of the order.
Placing the order and preparing the shipment
Acceptance of the price quote and instructions to order the drug were e-mailed to the distributor. The distributor needed a “permission to import” document from its regulator before it could order the drug from the Swiss manufacturer. The Medicines and Healthcare products Regulatory Agency (MHRA) regulates drug distribution in the UK and typically requires 28 days for consideration of a drug to be imported into the UK. However, it will expedite the issue of a “permission to import” document if written documentation supporting clinical urgency is provided. To support our case, our oncology pharmacist worked closely with the prescribing oncologist to obtain letters of justification for each patient. These letters were then e-mailed to the distributor for transmission to MHRA, which issued the necessary documentation within 48 hours.
All of the documentation required by the PIP was included in the drug shipment packaging for inspection by the local FDA field office at the port of entry in the United States. This meant that it had to be in the hands of the distributor before our package could leave the UK. Copies of the documents were saved as portable document format (PDF) files and e-mailed to the distributor, who printed the documents and attached them to the shipment when it arrived in the UK.
The following documents were included:
- A cover letter detailing (1) our contact at the Center for Drug Evaluation and Research (CDER), (2) our use of the PIP for this import, and (3) how we had met the five PIP criteria, which was signed by the “drug shortage” pharmacist and the director of pharmacy and included contact details for both in case there were questions or concerns
- A copy of an e-mail from CDER confirming the use of the PIP, listing the requirements and stating that we had discussed the critical need for the drug with CDER personnel
- Letters signed by the prescribing oncologist stating the patient’s name, medical diagnosis, treatment regimen, quantity of drug needed, and date each patient required the drug
- A copy of the signed prescription or drug order for each patient
- A copy of the prescribing physician’s biography (name, address, specialty qualifications, and Drug Enforcement Administration number)
We likely exceeded the requirements of the PIP but believed it was necessary to include as much detail as possible to ensure the credibility of the import and facilitate the decision to afford regulatory discretion.
The distributor included additional documentation in the shipment required by FDA for importation, including a description of the drug form, details relating to the manufacturer in Switzerland, and product license numbers.
After completing a final check of the order, the distributor’s logistics specialists made arrangements to ship the drug, and tracking numbers were issued.
Port of entry
The shipping company used usually determines the port of entry. Our cargo landed at a shipping hub in Memphis, Tennessee. According to the tracking detail, and as expected, the shipment was quarantined by U.S. Customs and passed to the FDA field office for inspection, where such documentation is typically checked and verified and any further clarification is sought. Tracking details for our shipment of cytarabine revealed that the FDA field office released it without comment after 16 hours of quarantine.
Receipt of the shipment
The shipment was received at our final destination amid much jubilation and relief. The importation process, from initial inquiries to delivery, took 21 days.
Each cytarabine vial was inspected carefully to ensure that the drug name and strength on each vial were correct, there was no damage to the packaging, and there were no signs that the vial sterility had been compromised. Further, the drug solution was inspected for any signs of drug deterioration, discoloration, precipitation, or crystallization. The expiration date for each vial was also checked to ensure that it was not expired.
The drug was allocated to each patient, and the lot numbers and expiration dates were logged for future record. This information would be needed if any adverse reactions occurred. Once allocated, the drug was then quarantined to ensure that it would be used only for each named patient.
All the pharmacists involved in preparation of the drug were made aware that it was unapproved drug. Any concerns or questions that were raised were addressed.
We checked the manufacturer’s leaflet to ensure that all details of the drug were comparable with the U.S. equivalent, paying particular attention to preparation and storage details. We asked the distributor to assist with a translated version of the manufacturer’s leaflet, as we wanted to make sure that the translation information came from a reliable source.
Administration of the drug
The treatment team was reminded that the drug the patients were receiving was unapproved. As is usual with chemotherapy administration, emergency equipment was available in the event of any adverse reactions. Administration of the drug was monitored carefully, comparable with the monitoring that occurs during first-dose administration of any approved drug.
Working closely with FDA and Idis, we were able to meet the requirements of the PIP, which led to the successful importation of cytarabine for our patients. All drug administration was successful, and no adverse events on administration were reported.
Initial reimbursement requests to the insurance companies for the elevated cost of the drug were rejected. Our negotiations with the payers continue, but we expect that our organization will absorb the cost involved with this shipment.
Patient 1 is currently doing well. There was no evidence of disease three months after completing therapy, and ongoing follow-up is scheduled. This patient has returned to full-time work. Patient 2 is doing well. One year after completion of therapy, this patient has no evidence of disease and has ongoing follow-up scheduled. Patient 3 responded to induction but did not achieve full remission. In June 2011, this patient underwent stem cell transplantation at another facility, which has reported no current evidence of disease. Patient 4 was admitted to the hospital after completing the last cycle of therapy and succumbed to complications related to his immunocompromised state. There was no sign of leukemia at the time of his death.
Many drug classes seem to be affected by shortages, and more chemotherapy drugs for oncology patients have joined the growing list of medicines that are currently unavailable. There have been times recently when our inventory has been at critical lows, but we have been unable to use the PIP because of the time involved in accessing the drug abroad and shipping it into the United States. Identification of patients one month in advance is not always possible. For example, leucovorin, an oncology drug, is listed on FDA’s Current Drug Shortages website. When this drug is used for methotrexate rescue, it must be administered within 40 hours of the methotrexate dose to avoid tissue damage. There is an alternative available, levoleucovorin, but it is now in higher demand, and there are no guarantees that supply will meet this increase in demand. The manufacturer must amplify production, which is a time-consuming process. Due to the named-patient requirement and alternatives in the drug class, orders for leucovorin would be unlikely to meet the requirements of the PIP.
In an effort to ease the pressure faced by health care professionals to do no harm, the importation process must be streamlined. In an effort to ease drug shortages, FDA has given permission to individual manufacturers who have been involved in the manufacturing process of the drug in the United States to import from their own manufacturing plants overseas. For example, Teva Pharmaceuticals was given permission to import leucovorin from its manufacturing plant in Hungary. This solution to drug shortages is restrictive, because it relies on U.S. manufacturers having the same drug lines abroad. In a letter to health care professionals, Teva Pharmaceuticals stated that “no other company has been given permission by the FDA to import this drug.” The permission to import has only partially solved the problem; demand has exceeded even these supplies, and leucovorin is still on back order[5,6,15], with no supplies currently available at our usual pharmaceutical distributor. FDA is trying to meet the national requirements regarding the quantity to import. Leucovorin is available globally and may be easier to source on a smaller scale (e.g., to meet a specific order from a health care provider in immediate need). After initiating a global search, Idis was able to locate enough leucovorin to meet our immediate needs. The drug was approved and inspected for quality and efficacy in Australia, but as the PIP criteria cannot be met for this drug, we are unable to import this supply. FDA is working to prevent shortages by ensuring that U.S. drug manufacturers provide earlier notification of an impending shortage and by exercising regulatory discretion over the risks of quality and manufacturing issues causing the shortage compared with the need for the drug. However, in a situation of critical need, FDA should recognize the regulatory agencies of other countries and the standards they apply to their own products and open up the global market.
Perhaps FDA should consider allowing reputable pharmaceutical distributors in the United States to import smaller amounts of bulk drug from global manufacturers to meet any immediate need, as long as the following criteria are met:
- The pharmaceutical distributor must work in conjunction with CDER, which may provide a license to ensure that the distributor operates to CDER standards.
- Drug availability must be identified in a country with unrestricted stock.
- Drug must be sourced from reputable sites elsewhere in the world with regulatory enforcement and identifiable standards.
- The drug must be part of a critical shortage in the United States.
- The drug quantity must be enough only to fulfill an order already placed with the distributor.
- Restrictions may be made on the duration of supply, which in turn may be deemed “for immediate use.”
- The drug quantity ordered should be justified by previous demand.
Opening the global market in this way could offer patients a safer alternative than the gray market when quality issues hinder the good manufacturing processes in the United States and result in critical national drug shortages.
It is illegal to import drugs into the United States ad hoc, but it is not illegal to utilize the PIP. FDA guid- case study Cytarabine Am J Health-Syst Pharm—Vol 69, 2012 e27 ance recognizes that circumstances may exist in which the intended use of an unapproved drug is to treat a serious condition for which effective treatment may not be available domestically, either through commercial or clinical means. Although our experience involved an oncology drug, knowing the PIP requirements has helped our organization to assess each of the critical lows we have experienced with all drug classes. Pharmacists should not be afraid to work closely with FDA to meet the requirements of the PIP and attempt to obtain regulatory discretion on orders that may be critical to patient care.
The importation of cytarabine amid a drug shortage required a complex process that involved the efforts of an overseas distributor, the cooperation of multiple health professionals, and meticulous attention to detail.
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