All the best effort to practice science-based medicine are for naught when the optimal treatment is unavailable. And that’s increasingly the case – even for life-threatening illnesses. Shortages of prescription drugs, including cancer drugs, seem more frequent and more significant than at any time in the past. Just recently manufacturing deficiencies at a large U.S.-based contract drug manufacturer meant that over a dozen drugs stopped being produced. This lead to extensive media coverage, speculating on the causes and implications of what seems like a growing problem. So who’s to blame?

First, some perspective. Drug shortages are not a new problem. I’m a pharmacist who has worked in almost every healthcare setting – and dealing with shortages is a time-consuming and frustrating part of the the profession. However, the perception, even among health professionals, is that this situation is worsening. Statistics back this up. U.S. sources accurately track the prevalence of drug shortages and it hit a record high in the first half of 2011, with over 180 drugs reported to be in short supply. Before you blame the dysfunctional American health care system – it’s not just there. The same issues are occurring in Canada, and the United Kingdom, an some are worldwide. Managing shortages is a problem that affects all aspects of a patient’s treatment. Consider the impact of a cancer drug that disappears suddenly from the market, which looks to the be the case with the chemotherapy drug Doxil:

• Pharmacists struggle to ensure inventory levels are in place to meet treatment demands. Managing supplies can be a daily crisis.
• Cancer centres and hospitals struggle to coordinate treatment plans, unsure if necessary drugs will be available. In some cases, substitutes may be necessary. So called “grey market” vendors may take advantage of the shortage, buying up dwindling stock and then reselling it, at tremendously inflated prices [PDF].
• Insurance plans need to confirm payment of alternative treatments and elevated prices.
• Physicians are concerned about the impact on treatment regimens and the consequences of substitutions and delays on treatment plans.
• Cancer patients, already dealing with a cancer diagnosis, may be concerned about access to their treatments, and the possible health consequences of delays and changes. They’re at a greater risk of medication errors due to switches in drugs and doses.

The shortage is so bad with Doxil that new patients may not start therapy – the dwindling supplies are restricted only to patients already on treatment.  While not all shortages are this bad, sterile injectable drugs seem to have the biggest supply problems problem. And when generic versions don’t exist, there’s no exact substitute. So where are these shortages coming from?

Causes

Drugs can be in short supply for two main reasons. Demand can grow and outpace supply, or the supply can be reduced, and there’s an inability to meed demand. All signs point to current shortages being a consequence of supply problems.

There is no single cause to supply interruptions. One of the biggest factors is changes in the generic drug industry. (Generic drug manufacturer can produce a product after it losses patent protection). Consolidation in the industry means there are fewer companies that will produce any product. And the manufacturers may outsource their production to contract organizations, due to the technical requirements involved. (Take a look at this Health Canada advisory which notes that one plant manufactures drugs for several different companies) .

What causes manufacturing issues? Problems emerge throughout the supply chain. In many cases, it’s regulatory agencies like the Food and Drug Association that identify quality or safety issues, interrupting production. With manufacturing increasingly becoming a global endeavor, the FDA now sends inspectors to plants in China and India where all or part of the supply may originate. It may be difficult to obtain or process raw materials that meet FDA quality standards. When problems emerge, manufacturers may decide that supporting production for low-profit or low-volume products doesn’t make economic sense. Combined with industry consolidation, the result is a dwindling number of companies willing to produce a product – and no excess capacity when there are interruptions with one supplier. A survey conducted [PDF] by the American Society of Health-System Pharmacists identified that product quality issues were the most common reason for interruptions, followed by discontinuations, capacity issues and delays, and raw material issues.

Some have attributed shortages to being a consequence of generic drug reimbursement policies. That’s what Ezekiel J. Emanuel argued in a recent New York Times op-ed. He argues that (U.S.) Medicare pricing policies have made selling generic drugs unprofitable, driving companies from the market.  But given shortages are are nothing new, sometimes involuntary, and exist worldwide, there’s no persuasive evidence that directly links reimbursement rates to supply issues. Tendering and bulk purchasing of pharmaceuticals, another common approach to purchasing, have the potential to impact supply, if a manufacturer given market exclusivity is suddenly unable to meet demands. But again, there’s no direct evidence that’s been the case, either in Canada or the USA.

A drug shortages summit in 2010 [PDF] pointed to FDA regulations and barriers as significant factors that contribute to shortage. Problems included the inability to require shortage notifications from manufacturers, as well as a FDA initiative to require manufacturers to properly license previously unapproved drug products.

Analysis

While there is no shortage of policy papers, summits and calls for greater (or reduced) regulation, there’s been very little concrete action taken to actually solve the problem. And that’s because no group, agency or even country has control and influence over the entire supply chain. And more importantly, no group or regulator has the responsibility for ensuring that shortages don’t occur.

The supply chain that links the chemical synthesis to the administration to a patient is intricate, to put it mildly. This process involves companies that manufacture the active pharmaceutical ingredient (the active ingredient), to the company that packages it for administration, to the pharmaceutical company that sells and distributes the product. Regulators (one for each country) verify manufacturing standards before allowing sale. Once licensed for sale, wholesalers distribute the drug, group purchasers consolidate purchasing among hospitals or HMOs, insurers and public payers decide which drugs will be benefits, and then hospitals purchase and administer the drug.  Depending on your health system, the players may be different. But one feature is universal between health systems:There is no single organization responsible for ensuring this complicated process ensures that once started, supply isn’t interrupted.

Looking for solutions

There’s no sign that drug shortages will disappear in the future. Signs point to continued or worsening challenges, if no action is taken. Can this problem be solved?

In the USA, legislation has been proposed that would require manufacturers to notify the market six months before any supply interruption, and make other changes to improve transparency about supply interruptions. There have also been proposals that the US Centers for Disease Control should stockpile chemotherapy products, like it already does for other drugs.

But these approaches don’t affect underlying challenge: No-one “owns” the supply issue.  And there is no single cause of shortages. That’s the challenge: Building accountability for drug supply throughout this complex pathway. There are other complicated supply chains in the world – perhaps there’s something that can leveraged from other industries and transplanted into healthcare. Because we all need to stay focused on who is at the receiving end of the supply chain: The patient, wondering if they’re going to get their medicine.

<!--<!--