I’ve been reading the Institute of Medicine (IOM) report called “Countering the Problem of Falsified and Substandard Drugs” that was published last week.  At 360 pages, it is quite literally a book, and you can buy it that way.  But they also allow you to download the “Pre-publication Copy:  Uncorrected Proofs” version in a 300 page PDF for free.  I’m not sure why they would post uncorrected proofs rather than the final document on their site but I assume the text is in its final edited form and only the formatting might be different between the book and the PDF.  I hope so anyway.

I have not yet read the whole thing so this isn’t intended to be a proper review (see the Regulatory Focus article about it).  The document offers committee recommendations that target the problem of falsified and substandard pharmaceuticals on a global basis and I generally focus my writing on the finished goods pharma supply chain in developed countries, primarily the US, so I skipped around and only skimmed chapters that focus on the problems in developing countries.

I paid particular attention to Chapter 5, “Weaknesses In The Drug Distribution Chain” because it includes a discussion of the problems and potential solutions closest to my area of expertise.  That chapter covers weaknesses in the supply chains of developed and developing countries.  You have to read very carefully, though, because sometimes they switch between developed and developing countries so fast that you need to carefully parse the sentences to keep it straight.  Casual readers may get confused by this mix and assume that the magnitude of the problem in developed countries is nearly as bad as it is in developing countries.  I think the authors would agree that this is not the case, so I wish they had been a little more careful.

In fact, there are very few similarities between the pharmaceutical supply chains of the United States and developing countries, but the authors make them sound very similar, describing one without clearly identifying it, and then describing some other characteristic of the other without clearly identifying that they have switched.

THE WHOLESALE SYSTEM

For example, in the section titled “The Wholesale System”, the first paragraph explains the difference between primary, secondary and regional wholesalers, mentioning the United States.  Here is the second paragraph:

“As Figure 5-1 suggests, the distinction between the primary and secondary wholesalers is not always clear. Primary wholesalers may, for example, buy products from secondary wholesalers as well as manufacturers (Ziance, 2008). The back and forth sales are common among drug wholesalers, who buy and sell medicines to accommodate market demand. That is, when they see a medicine is scarce in one region, they can buy the same medicine from other wholesalers that may be flush with it. The markets are constantly fluctuating; products change hands many times.”

This paragraph is describing a practice that I understand is quite common all over the world, but by comparison is practiced only on a very tiny scale here in the United States since about 2006.  The authors are either describing what happens outside the US or they are describing a weakness that used to exist here until the three large primary wholesalers agreed to shut down their secondary market trading companies and agreed to only buy direct from the drug manufacturers.  That reduced the problem by about 90% in the space of a single year.  See my essay, “Do We Even Need To Mandate Drug Pedigrees Anymore?“.

In the fourth paragraph in that section the authors say:

“Wholesalers may sell and resell medicines repeatedly among themselves before filling a pharmacy order. Wholesalers often repackage products with every sale, or at least repackage individual containers for final sale (Catizone, 2006; Laven, 2006). Through a process called salting, legitimate and fake drugs are mixed at wholesale, and in the wholesale repackaging, the fake products gain authentic labels (Donaldson, 2010a; Liang, 2006). Salting can be done unknowingly, such as when primary wholesalers buy from other intermediaries, accidentally launder fake products, package them in authentic labels, and send them to pharmacies (Spies and VanDusen, 2003). In repackaging the manufacturer’s expensive fraud-protection packaging can be removed, and batch numbers reprinted (Satchwell, 2004). Not only does this interfere with tracking requirements, but it leaves the wholesaler repackagers with clean, unused packaging that is not always destroyed (Satchwell, 2004).”

Are they still taking about the United States?  I thought so.  The last country they mentioned was the US, but this is a pretty bad representation of what goes on in the US supply chain today so I assume the authors are describing what goes on elsewhere.  In fact, such a tiny percentage of drugs in the US are repackaged by legitimate wholesalers that it wouldn’t even register in comparison to drugs in the EU, for example, where wholesaler repackaging is a widely used and accepted business practice.  The tiny fraction that are repackaged in the US are done under the same FDA oversight that the original manufacturer is under and there is nothing nefarious about it.  What this paragraph is apparently describing are the historical actions of a number of criminals who, unfortunately, were issued drug wholesaler licenses by a few States back in the early 2000’s, not normal practices by the industry.

Attributing the actions of criminals as if they were standard operating procedure within the industry, and then using them as the basis for recommending national and global policy is inexcusable.  In fact, falsified medicines are very rare in the US legitimate supply chain today (see my essays, “Illegitimate Drugs In The U.S. Supply Chain: Needle In A Haystack“, and “The Built-in Protections Of The U.S. Pharma Supply Chain“).

SLOPPY RESEARCH

In the fifth paragraph, a fact is embellished so badly that it raises questions about the quality of the author’s research:

“Manufacturers usually have no distribution agreements with secondary wholesalers (Ziance, 2008). The firms may trade in many kinds of products other than pharmaceuticals. Their staff are not required to show skills in pharmaceutical warehousing and management, often with disastrous consequences (Ziance, 2008). In 2001, for example, a falsified version of Epogen, one of the most expensive drugs in the Medicare formulary, killed a 16-year-old boy in New York (Gressit, 2007; Ziance, 2008). Eleven secondary wholesalers had traded the Epogen that killed him (Engelberg et al., 2009; Gressit, 2007; Whoriskey, 2012). Though it is impossible to recreate the drug’s exact path, it was briefly stored in a drinks cooler above a Florida strip club (Brown, 2005).”

Most of the facts included in this story of the boy who was killed by falsified Epogen fit the well known case of Timothy Fagan as documented in Katherine Eban‘s great book, “Dangerous Doses” (see my essay, “Dangerous Doses“).  Those facts include the timing, the location, the drug, the trades by secondary wholesalers (criminals, I might add) and even the strip club.  The Fagan case was a very scary and a particularly egregious example of the real problems that existed in the US supply chain in the early 2000’s.  It quite rightly was one of the cases that led Elliot Spitzer, Attorney General of New York, to bring actions against legitimate drug wholesalers for participating in the grey market back then, which unintentionally opened the door to exploitation by true criminals.

It’s just that, Fagan didn’t die.  If there were another case with these facts where the boy died, I think I would have heard about it and I think Eban would have written about it, so I can only conclude that this is an inflation of the facts to make the story even more compelling.  Either way, so many things have changed about the operation of the supply chain that this sequence of events would not even be possible today…since 2006!  That makes the whole story completely irrelevant to the discussion today.  (See my essay, “The Built-in Protections Of The U.S. Pharma Supply Chain“.)

WHAT DO THE AUTHORS SAY ABOUT CRIMINAL MEDICAL PROFESSIONALS?

These stories and stale “facts” about wholesalers do not reflect the current problems in the US and if a policy is developed based solely on them, that policy will be mis-directed.  The authors had an opportunity to explain the real problems that we see in the US supply chain today but they squandered it.  That is very unfortunate.  I only hope their discussion of the problems and potential solutions outside the US are better.

Lately we have seen criminal activity shift into the medical professional ranks where criminal physicians are willing to buy low cost drugs that aren’t even labeled for sale or use in the US and dispense them to their unsuspecting patients.  What does the paper have to say about that problem?

First, here is what the authors say about criminals in the wholesaler ranks:

“In a recommendation to the state legislature, a Florida grand jury described some of the states’ drug wholesalers as, ‘uneducated, inexperienced, … rank amateurs, many with criminal records’ (Appleby, 2003).  As the grand jury description implies, many of these companies are looking to increase their profits at any costs.“

Of course the authors called them “wholesalers”, but what the grand jury was describing were criminals who were acting as wholesalers.  There were quite a few of those in Florida back in 2003.

In contrast, here is what the authors say about today’s criminals acting as physicians as in the recent Avastin cases:

“The high cost of such drugs, at times exacerbated by shortages, may tempt physicians to seek out alternative suppliers to lower their own and their patients’ costs and assure a steady supply. At a price several hundred dollars lower per vial than the standard, the falsified Avastin was a good deal for such practices (Weaver and Whalen, 2012). The same forces that lead patients to buy unreliable drugs can lead doctors to do the same, creating yet another vulnerable link in the medicines supply chain.”

That’s a pretty soft rationalization for a crime.  The Avastin that these physicians allegedly bought were not simply lower cost, they were not even labeled as Avastin but as Altuzan which isn’t approved by the FDA for use here and the packages did not have an FDA NDC or other necessary elements.  That would have made it clear to these professionals that what they were allegedly doing was illegal and would place their patients at risk.  (See my essays, “How Counterfeit Avastin Penetrated the U.S. Supply Chain“, “InBrief: Pharma Supply Chain Criminals Get Justice, Part 2“, and “InBrief: Illegally Imported Drugs Found To Be Counterfeit…Again“.)

Further, this isn’t an example of a medical professional attempting to “…lower their own and their patients’ costs and assure a steady supply” in the face of a shortage.  They used the full price in their reimbursement claims and Avastin was not in short supply!  So weren’t these criminal physicians simply “…looking to increase their profits at any cost” just like the criminals who acted as drug wholesalers?  Of course they were–that’s what criminals do.  Don’t try to soften or justify their alleged crimes directed against their patients to maximize their profits.

WELL INTENTIONED, MISSED OPPORTUNITY

One of the committee recommendations that arises from the global supply chain discussion is this:

“Recommendation 5-2: Congress should authorize and fund the U.S. Food and Drug Administration (FDA) to establish a mandatory track and trace system. In the interim, the FDA should convene a working group of stakeholders including the International Federation of Pharmaceutical Manufacturers and Associations and the Generic Pharmaceutical Association to promote voluntary track and trace for all supply chain actors in accordance with existing guidance.”

As part of making this recommendation the authors say:

“Tracking pharmaceuticals through the global distribution chain with unique serial numbers is a good defense against criminal infiltration. A method of tracking individual packages of medicines from the factory to the consumer could greatly reduce the chances of a dangerous product being sold at a reputable pharmacy.”

First of all, we already have “voluntary track and trace” and you can see how widely that’s been adopted.  More importantly, the establishment of a mandatory track and trace system may or may not be the right thing for Congress and the FDA to do, but this chapter fails to explain exactly how it would “greatly reduce the chances of a dangerous product being sold at a reputable pharmacy” in the US–even after the authors’ use of inflated facts from the early 2000’s and those from other countries.  On top of that, the authors demonstrate a poor understanding of the current state of serialization and track & trace technologies.  You can’t just write about the problems from 10 years ago, then write about some technology and then claim that it will solve today’s problems without explaining how.

The intentions of the IOM Committee are obviously good.  Their recommendations for action outside the United States might be right on, I can’t vouch for those either way.  But what we need right now is for a reputable group who really understands the history and current state of the industry, the crimes and the technology, to perform an analysis that would point the way toward fixing the actual problems we have in the US today and show how that would be accomplished.  Perhaps they could make realistic recommendations that follow directly from their findings.  I’m very sorry but, for the US, the IOM paper isn’t it.

Dirk.