Drug Shortages

• Backgrounder on Cancer Drug Supply Shortages
• Why do we have drug shortages?
• Prognosis
• FDA Role
• NCI (CTEP) Role
• Sources of Definitive Information
• When to Contact CTEP about Drug Shortages
• Managing the Drug Shortage Crisis
• Other Areas of Concern

Backgrounder on Cancer Drug Supply Shortages

In recent months, drug shortages have become more pronounced. Some of the drugs in short supply are critical for the treatment of cancer, but supply problems exist in other medical areas including anti-infectious drugs, autonomic and CNS drugs, as well as drugs used in EENT, electrolytes, and hormones.

On November 5, 2010, a Drug Shortages Summit was convened by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP). The goals of the summit were to:

• Discuss the scope and causes of drug shortages
• Shed light on the harm to patients that is occurring due to drug shortages
• Discuss the potential need for changes in public policy and stakeholder practices to prevent patient harm from shortages
• Develop an assertive action plan that reflects the recommendations and intent of stakeholders to work together to stop patient harm and disruptions in patient care caused by drug shortages

Summit participants included representatives from health professional organizations, pharmaceutical manufacturers, and supply-chain entities. Representatives of the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) also attended portions of the meeting as observers. The information found in this report provides valuable background information and identifies strategies for actions to alleviate drug shortages. The full text of the report can be found at:

http://www.ashp.org/drugshortages/summitreport

The NCI Cancer Therapy Evaluation Program (CTEP) staff has provided information upon request to individual centers. In view of the upsurge in requests for information related to oncology drug shortages, we have created this backgrounder to provide the cancer research community with a readily available resource. Although the agents in short supply are not investigational, they are essential for the conduct of trials.

Why do we have drug shortages?

The Waxman-Hatch Act of 1984 led to a revolution that expanded greatly the availability of low-cost, generic drugs. However, it appears, as a result, that this has discouraged manufacturers from maintaining large inventories of drugs. Thus, when manufacturing or other supply problems occur, a shortage arises quickly and rapid solutions are not available. Injectable drugs are most vulnerable due to tighter regulatory controls and limited availability of facilities to produce sterile products.

Other Factors:

• Raw and bulk material not available
• Manufacturing difficulties and regulatory issues
• Voluntary Recalls related to manufacturing issues
• Changes in product formulation or manufacturer
• Manufactures’ production decisions and economics
• Industry Consolidation
• Restricted drug product distribution and allocation
• Inventory practices
• Unexpected increases in demand and shifts in clinical practice
• Nontraditional distributors
• Natural disasters
• Hospital and pharmacy based issues
• Move to “just-in-time” (JIT) inventory management at institutional and manufacturer level

A detailed discussion of many of these issues and the impact that they have on the supply chain can be found on the website of the American Journal of Health-System Pharmacy at:

http://www.ajhp.org/content/66/15/1399.full

With fewer firms making older, generic, sterile injectable drugs, there are a limited number of production lines that can make them. The raw material suppliers the firms use are also limited in the amount they can make due to capacity issues at their facilities. This small number of manufacturers and limited production capacity for older, sterile injectables, combined with the long lead times and complexity of the manufacturing process for injectable drugs, results in these drugs being vulnerable to shortage. When one company has a problem or discontinues production, it is difficult for the remaining firms to increase production quickly and a shortage occurs.

Prognosis

The trend toward more shortages is expected to worsen. Each year, more drugs move to generic status as their patents expire. Meetings of medical experts have been held to analyze the shortages and seek action. The FDA provides a central role in providing public information about shortages, and works within its regulatory authority to mitigate the shortages. These actions are essential for the general shortage strategy. However, to date, these actions have not resulted in a plan that will solve the problem for the longer term. Most pressing is the fact that patients need these agents urgently, and, in some cases, there is no immediately available solution.

FDA Role

For manufacturing/quality problems, FDA works with the firm to address the issues. Problems may involve very low risk (e.g., wrong expiration date on package) to high risk (e.g., particulate in product or sterility issues). Regulatory discretion may be employed to address shortages to mitigate any significant risk to patients.

FDA also works with other willing firms to help them ramp up production of scarce drugs. Often these firms need new production lines approved or need new, approved, raw-material sources to help increase production. FDA can and does expedite review of these approvals to help resolve shortages of medically-necessary drugs. However, FDA can’t require firms to increase production.

When a shortage occurs and a firm has inventory that is close to expiry or already expired, if the company has data to support extension of the expiration dating for that inventory, FDA is able to review this and approve the extended dating to help increase supplies until new product is available.

When the US manufacturers are not able to resolve a shortage immediately and the shortage involves a critical drug needed for US patients, FDA searches for overseas companies that are willing and able to import the drug during the shortage. When a firm is located that is willing and able to import, FDA utilizes regulatory enforcement discretion for temporary importation to meet critical patient needs during the shortage. FDA evaluates the overseas drug to ensure that it is of adequate quality and that it does not pose significant risks for US patients. The information about the imported drug, and how patients can access supplies is posted on the FDA Drug Shortage website along with a “Dear Healthcare Professional” letter from the company that is importing the drug. FDA cannot always find a firm willing and able to import a drug during a shortage. However this is something that is explored when there is a critical shortage and the needs of US patients are not being met.

FDA works to find ways to mitigate drugs shortages; however, there are a number of factors that can cause or contribute to drugs shortages that are outside of the control of FDA.

This information is reprinted from the FDA website. Further discussion can be found at:

http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm

Questions regarding drug shortages can be addressed to the FDA Center for Drug Evaluation and Research (CDER) Drug Shortage Program at:

DRUGSHORTAGES@cder.fda.gov

NCI (CTEP) Role

CTEP does not have a supply of agents to supplement the supply at local institutions nor does it have an inside track on information that a shortage is about to start or when it will end. A very useful resource is pharmacy staff at the local level. When a shortage develops, the first people who know about it will be the pharmacy staff who attempt to order an agent that is in short supply.

Sources of Definitive Information

American Society of Health-Systems Pharmacists (ASHP) — the ASHP website is likely to provide the most current information available because the organization responds to inquiries from pharmacists practicing in the field. As soon as pharmacists identify a problem, they contact the ASHP, research on the situation is done and information is postedon its website: http://www.ashp.org/shortage

FDA — The FDA website is focused generally on longer-term, widespread shortages. The agency usually does not post information regarding a shortage that is expected to be of short duration or is highly localized.

• To receive e-mails when shortages are identified by FDA,sign up for the agency’s service MedWatch: http://www.fda.gov/medwatch
• Website for drug shortages. Provides most current information from FDA: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm

CDC — for vaccine shortages
http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm

Others — Pharmacy One Source (Free Subscription), provides MEDWATCH and other information
http://www.pharmacyonesource.com

Manufacturers — It is always important to contact the manufacturer(s) directly. They can provide the most current information and can provide guidance on any rationing strategies that are available.

Wholesalers — Contact your wholesaler on a regular basis. They can tell you when to expect shipments and provide any guidance on allocation schemes at that level.

When to Contact CTEP about Drug Shortages³

General Guidance: This guidance follows the general principles that are used when any shortage of a commercial agent(s) may affect an ongoing clinical trial. This information pertains to the continued participation of patients in clinical trials at affected sites only. The principal investigator (PI) or Cooperative Group leading an affected trial should contact the appropriate physician in CTEP as outlined below regarding necessary modifications or delays in study therapy.

Specific guidance is provided on how to address drug shortages for patients already enrolled on a clinical study as well as how to manage potential enrollment of new patients.

For Phase 1 and/or Phase 2 trials under a CTEP an investigational new drug (IND) application: The PI/Group should contact the appropriate physician in the Investigational Drug Branch (IDB) who monitors the trial if it appears sites are likely to experience a shortage of the commercial agent in order to discuss management of study patients before instituting any directives on delays or changes in therapy or submitting a protocol amendment. The CTEP Protocol and Information Office (PIO) should also be copied on this correspondence.

For Phase 3 trials under CTEP IND: The PI/Group should contact the appropriate physician in the Clinical Investigations Branch (CIB) who oversees the disease portfolio for that trial to discuss potential changes or delays in study therapy or potential study amendments. The CIB physician will also ensure that the IDB physician who monitors the trial is involved in all these discussions. The CTEP PIO should also be copied on this correspondence.

For CTEP-sponsored trials not under a CTEP IND: The PI/Group should inform the appropriate physician in CIB of any management plan instituted for enrolled subjects who do not have access to the commercial agent in short supply. The CTEP PIO should also be copied on this correspondence.

Guidance for management of patients already enrolled on study: The following general principles should be used in determining how to adjust protocol regimens for patients already enrolled on study, outside of a protocol amendment, if the commercial agent is not available at a local site because of a temporary drug shortage.

If the study PI/Group for a specific clinical trial believes or has been informed that some participating local sites will not have access to a commercial agent for on-study patients, the PI/Group should develop an appropriate management plan for the treatment of these patients so that they will all be treated in the same manner. PIs/Groups must make reasoned and good faith judgments regarding appropriate delays and/or modifications in treatment(s) for the study patients. They should also provide specific instructions to all local investigators about delays and delivery of any modified treatment(s) for on-study patients until the commercial agent is available and treatment can be resumed per protocol specifications. In addition, PIs/Groups should provide instructions to participating sites on procedures for specifying/tracking delays and modifications in treatment regimen(s) due to the shortage in order to be able to analyze study data appropriately per the study’s statistical analysis plan and handle protocol deviations at time of audit.

This general approach regarding management plans for appropriate delays and/or modifications in therapy for patients already enrolled in the research without prior IRB approval is permissible under the Department of Health and Human Services (HHS) regulations at 45 CFR 46.103(b)(4)(iii) since the modifications are being made in order to eliminate immediate apparent hazards to these patients/study subjects-in this case, providing appropriate instructions for delays and/or modifications in study treatment because an essential component of standard therapy (i.e., the commercial agent) is not available. The medical and research records of the study patients should reflect that the patient was informed of any delays and/or modifications in protocol therapy related to the shortage of the agent and the associated risks.

In addition, in accordance with HHS regulations, a local investigator must promptly inform the Institutional Review Board(IRB) of record of this unanticipated problem and of the management plan for the trial that the local investigator is participating in, as outlined by the study PI/Group conducting the trial. In accordance with local policy, the IRB may determine whether patients already enrolled should be re-consented or sign a consent form addendum. Investigators at local sites experiencing a shortage that affects patients on a particular trial should report this to the Cooperative Group leading the trial. The Cooperative Group Operations Office should then report this (if it occurs) to the NCI Adult or Pediatric Central IRB along with the management plan being used to address the shortage of the commercial agent for the affected trial(s).

Guidance for Enrollment of New Subjects: When a study PI/Cooperative Group Operations Office becomes aware of a shortage of a commercial agent affecting a CTEP-sponsored clinical treatment trial that they are conducting, the PI/Cooperative Group must advise local sites participating in the trial to check with their local pharmacists about the available supply of the commercial agent at the local site before starting to evaluate new patients for entry on a CTEP-sponsored clinical trial that involves the agent. If a sufficient supply of the commercial agent is not available to cover therapy in the respective clinical trial at a local site for the anticipated length of the shortage, the local investigators should not consent new patients for enrollment on the study. The expected duration of the shortage should be based on a reasonable assessment by the PI/Cooperative Group given what is being reported by manufacturers regarding the specific shortage. Sites should be advised that their local pharmacists might be able to obtain supplies of the commercial agent from other institutional pharmacies that have adequate supplies. A formal protocol amendment would be required before new patients could be consented and enrolled on study using an alternative/modified treatment regimen.

Managing the Drug Shortage Crisis

All health care institutions have disaster plans in place to help them respond to unexpected events. Many leaders in the health care field now feel that drug shortages constitute a situation in which a management plan is warranted. The Institute for Safe Medical Practices (ISMP) has published a guide that is helpful in developing a plan to deal with this problem. This document can be found at: http://www.ismp.org/Newsletters/acutecare/articles/20101007.asp

The ASHP website also has a number of useful tools that will help institutions develop a management plan to deal with drug shortages: http://www.ashp.org/shortage

In addition the investigators should work with the cooperative groups to identify additional resources.

Other Areas of Concern

Use of Expired Medication: Don’t use expired medication.

Medication Errors — The ISMP⁴ reports that 35% of health care practitioners who responded to a recent survey (July-September 2010) reported a near miss in the past year due to drug shortages. (A near miss is an unplanned event that did not result in injury, illness, or damage-but had the potential to do so. Only a fortunate break in the chain of events prevented an injury, fatality, or damage. Another way of explaining it is as an error that happened but did not reach the patient. The error was captured and corrected before reaching the patient-either through chance or purposefully designed system controls that have been put in place.)

One in four respondents reported actual medication errors, and one in five reported adverse patient outcomes due to drug shortages. Near misses, errors, and adverse outcomes associated with chemotherapeutic agents included:

• Cytarabine dosing error occurred when a pharmacist used a mixing protocol applicable to the usual 500 mg vials (50 mg/mL, not available) but was actually using an alternative strength 1,000 mg vial
• Pre-diluted methotrexate was unavailable; a vial of dry powder was reconstituted incorrectly and the patient received less than the prescribed dose
• VinBLAStine shortage led to replacement with vinCRIStine for a patient with a hematologic disease, but a dosing error occurred when determining the dose for the alternative drug
• IV etoposide was converted to oral dosing, but the prescriber was not aware that the oral dose needed to be double the IV dose

The entire article can be viewed at: http://www.ismp.org/Newsletters/acutecare/articles/20100923.asp

Grey Market — When there is a drug shortage, institutions may receive e-mail or other correspondence offering the agent for sale at greatly inflated prices. Care should be exercised in pursuing this option. Not only is the cost of using this option more expensive on the magnitude of 10 or even 100 times the original cost, but the drug may be expired, may have been diverted, or may be counterfeit. These communications should be reported to the FDA’s office of Criminal Investigations at:

http://www.accessdata.fda.gov/scripts/email/oc/oci/contact.cfm

References

1. American Journal of Health-System Pharmacy, August 1, 2009, Volume 66(15): 1399-1406.
2. Memo, Nov 17, 2010, from Meg Mooney, MD, Chief CIB/CTEP to PIs of Sponsored Clinical Trials that Involve Doxorubicin and Cooperative Group Chairs/Group Operations Offices, NCI-Sponsored Clinical Trials, re: Contingency Plans for Treatment Regimen Adjustments for Patients Currently Receiving Protocol-Specified Therapy on Studies Involving Doxorubicin at Sites.
3. ISMP Medication Safety Alert, Sept 23, 2010, Volume 15(18).