How FDA’s Risk Management Program Can Help Prevent or Lessen Future Drug Shortages

The severe consequences of drug shortages played out on an international and public stage during the COVID-19 public health emergency (PHE). Yet, combating drug shortages has been a focus of both regulators and the medical industry for decades.

Drug shortages impact every level of healthcare: They cause delays in patient care, lead to the use of alternative and potentially less safe and effective medicines, and divert clinicians’ attention when searching for drug alternatives. Patients have unknowingly and increasingly become vulnerable to a global drug supply chain.

This global supply chain has grown longer and more complex, with many raw materials, in-process goods and even finished goods produced overseas before being imported to the United States. Regulatory constraints intended to ensure a minimum quality standard also contribute to the drug supply challenge through bureaucratic roadblocks that slow the ability to pivot as alternatives are assessed when drug production is in crisis. Add to that a pricing structure that incentivizes low-cost drugs over innovation, and an industry that needs to flex in a time of crisis instead tends to sputter before it regroups and responds.

A recent U.S. Food and Drug Administration (FDA) guidance docu-ment outlines risk management programs (RMPs) intended to help combat future drug shortages by providing a framework with which stakeholders can assess risk and make plans to mitigate them. Though nonbinding, guidance documents share FDA’s current thinking and recommendations for best practices.

Drug Shortages Are Everyone’s Problem

The cost of drug shortages is enormous — for everyone, at every level — because they typically result in higher price points, making drug products more expensive for patients, providers and taxpayers. Drug substitutes also become more expensive thanks to increased demand. A 2019 report from the American Hospital Association, the Federation of American Hospitals and the American Society of Health-System Pharmacists found that almost 80 percent of hospitals see moderate to large increases in spending when drugs are in short supply,¹ amounting to $359 million each year in labor and $200 million attributed to substituting alternative drugs for those in short supply. Though staggering, these numbers may actually be underreported. Quantifying additional staff, rescheduled procedures, updating technology and patient burdens cannot be reasonably assessed. For instance, substituting a formulary drug with a nonformulary alternative requires multiple additional steps, including the creation of a new physician order, preparation and administration of the drug by pharmacists and nurses, as well as development of designed algorithms of its pharmacologic and pharmacokinetic properties to successfully implement mitigation strategies.²

It should be noted that patients with only one drug option such as those with rare diseases are particularly vulnerable to drug shortages.³ During the pandemic, two examples of drug shortages that have since been resolved were hydroxychloroquine and chloroquine, which are both used in the management of many autoimmune diseases. However, other shortages lingered, including drugs that treat heart disease and blood clots. In fact, a number of drugs that were in short supply are used in the treatment for many of the top-five causes of death (heart disease, cancer, unintentional injuries, chronic lower respiratory diseases and stroke). Drug shortages and adverse events from drug substitutions can negatively impact mortality rates.⁴

Drug Shortages to Date

In 2012, with the enactment of the Food and Drug Administration Safety and Innovation Act, Congress empowered FDA with tools that enabled the agency to work in collaboration with industry to prevent or mitigate drug supply disruptions and drug shortages. It also clarified current good manufacturing practice requirements relevant to oversight and controls of drug manufacturing quality. That focus honed in on quality issues as a common reason for supply chain shortages. FDA encouraged the industry to develop a long-term solution after a peak in drug shortages in 2011.⁵ Drug shortages then began a downward decline with low points reached in both 2015 and 2016 before beginning to again increase. Since 2018, the number of new drug shortages has remained steady, according to FDA; however they have grown more persistent due to lengthier active drug shortages. However, by mid-2020, during the COVID-19 PHE, the number of drug shortages amounted to 87 percent of the entire preceding year.⁴

Though quality issues certainly contribute significantly to drug shortages, natural disasters, discontinuation of components by suppliers, poor forecasting for future drug needs, cyber attacks against drug manufacturers and market withdrawals all can have an impact, too. The drug industry needs an improved plan of action.

Implementation of the CARES Act and RMPs

With the passage of the Coronavirus Aid, Relief and Economic Security Act (commonly known as the CARES Act), Congress added section 506C(j) to the Federal Food, Drug and Cosmetic Act (FD&C Act) requiring manufacturers of certain lifesaving or life-sustaining drug products to develop, maintain and implement a redundancy RMP. This RMP requires identifying and evaluating risks to the drug supply for each manufacturing establishment that supports their production. In particular, certain drug products with less redundancy in their supply chains are at higher risk of shortage.

Manufacturers must proactively notify the agency in the event of their permanent discontinuance or of significant manufacturing disruptions (and their justifications) that would negatively impact supplies of drugs and their active pharmaceutical ingredients (APIs). FDA also has the authority to include a review of RMPs as part of an inspection.

While RMPs are required by manu-facturers of certain drugs, the principles of assessment and mitigation strategies are valuable for manufacturers of all drug products, with FDA recommending RMPs be considered across the drug industry. The ability to accurately anticipate supply challenges enables pivots that could potentially ward off manufacturing complications.

There are three categories of drug products for which development of an RMP per section 506C(j) is mandatory. This affects all stakeholders as described in section 506C(a) of the FD&C Act and contract facilities producing lifesaving or life-sustaining drugs, including those used to treat or prevent debilitating diseases or conditions and those used to treat rare conditions for which there is no appropriate alternative such as biologics, including recombinant therapeutic proteins, monoclonal antibody products, vaccines, allergenic products, plasma-derived products and their recombinant analogs, as well as cellular and gene therapy products. Stakeholders producing APIs used in those drugs and medical devices used for their preparation or administration, including any constituent part of a drug-device and biologic-device combination product and constituent parts of drug-led and biologic-led products, are also included in section 506C(j).

Voluntary RMPs are recommended for additional drug categories, including products that treat rare diseases, products with only one API manufacturer source in the supply chain, products with only one finished dosage form in the supply chain and products produced in facilities (including packaging and laboratories) that received an official action indicated following an FDA inspection within the last five years and for which there are no other qualified manufacturing facilities that can produce the product. Finally, countermeasures produced in response to PHEs caused by a terrorist attack are recommended to have a voluntary RMP.

The level of the RMP will likely vary, FDA acknowledges, based on the stakeholder’s position in the drug supply chain. A primary stakeholder’s RMP will be broader in scope, developing strategies to not only identify materials and services at risk, but assess those risks and create mitigation strategies, including repairing the supply chain post-disruption. Primary stakeholders are recommended to share their RMP with secondary stakeholders such as establishments involved in blending and tableting or otherwise physically processing since they may not have visibility over the supply chain in its entirety. Finally, other stakeholders such as those producing inactive ingredients, packagers and distributors are included in RMP discussions as appropriate. This creates a holistic approach to risk mitigation up and down the supply chain and prevents duplication of efforts. Through sharing of information, secondary stakeholders have a broader opportunity to address any risks they face that might lead to shortages in the drug product’s lifecycle.

The requirement for RMP development does not apply to establishments that only perform testing, relabeling or repackaging operations. However, regardless of whether an RMP is required by FDA, manufacturers would be wise to consider how shortages or changes to the supply chain would affect their products and plan accordingly.

Quality Is Integral to an RMP

Using the International Council for Harmonisation Q9 framework as a base for RMP structure, FDA recommends quality risk assessments at all stages of the supply chain. This includes analytics to forecast demand throughout the year and development of strategies to repair unavoidable supply chain interruptions.

The first step of an RMP is to recognize everything that might go wrong, identify the subsequent effect on the supply chain and drug production and consider the resulting risk to patients. Next, RMPs should analyze the likelihood and severity of each possible disruption. These considerations should include a review of past incidences, how they were handled and their outcomes.

Steps to accomplish this include looking at inventory management and facilities such as utilities, water systems, ventilation, air conditioning and heating. Also, critical questions should be asked, including what is the lifespan of the manufacturing equipment from this point forward? What are the maintenance requirements, including replacing outdated software or replacing parts that are difficult to source? Are any of the stakeholders located in an area with geopolitical instability or regulatory uncertainty? Are supporting laboratory services nearby? How complex is the distribution chain? Is the facility in an area prone to natural disasters, particularly at key times of the year when demand is expected to be high? Is there a back-up manufacturing capability? Also, employee retention in key areas and with critical specialties should be considered, taking into account the plant’s ability to surge production rates beyond normal capacity if the need arises.

Some risks are worth accepting with no mitigation plans necessary, but others require RMPs to decrease the likelihood of risk occurring. RMPs should be reviewed annually throughout the drug’s lifecycle and as part of a post-action report if the RMP was used to assess its effectiveness. RMPs must also be reviewed when any changes to processes, facilities or suppliers are made.

Shortages may also be warded off by reviewing the drug’s stability data to determine whether it supports efficacy and safety beyond the stated use-by date.

Communication is key. FDA recommends proactively talking not only with regulators but also with appropriate stakeholders about the risk of impending shortages and established plans to adapt to them. While the comment period for FDA draft guidance closed in July 2022, the industry is already building and strengthening RMPs pending final guidance. Though imperfect, abiding by FDA’s recommendation for the creation and implementation of effective RMPs can only improve outcomes during times of future drug shortages.