By Thomas T. Kubic, Executive Director, Pharmaceutical Security Institute, Vienna, Virginia; and Former Deputy Assistant Director, Criminal Investigative Division, U.S. Federal Bureau of Investigation
very day, law enforcement officers throughout the United States are engaged in court-authorized searches of persons, vehicles, homes, and businesses. On occasion, during these searches, officers are surprised at what they uncover. For in some of the most unlikely places, their searches have disclosed some of the most advanced medicines available: biologics, pharmaceutical products critical to the health of seriously ill citizens.
Security professionals from pharmaceutical manufacturers are concerned that little is known about the public health threat posed by counterfeit, stolen, or illegally diverted medicines. Due to many significant enforcement priorities, the authorities have been unable to commit sufficient resources to conduct crime surveys and to otherwise monitor these types of crime. Five years ago, research-based pharmaceutical manufacturers established a nonprofit organization, the Pharmaceutical Security Institute (PSI), to begin collecting data about the nature and extent of pharmaceutical crime.1 This information is shared with law enforcement and drug regulatory authorities throughout the world with the goal of protecting public health.
The potential for high profits from pharmaceutical crime and the low probability of detection have drawn more and more criminals into this lucrative, illicit trade. The Organization for Economic Cooperation and Development (OECD) studied one criminal group and concluded that with a relatively small outlay of $2.42 million, these individuals would have made almost $46.53 million in profit.2 This group was engaged in counterfeiting biologics—a category of medicines particularly valuable but also extremely sensitive to even modest environmental changes.
It Can Happen Anywhere
In the summer of 2001, the residents of Kansas City, Missouri, were surprised to learn that a trusted member of their community, Robert Ray Courtney, a pharmacist who owned and operated the local Research Medical Tower Pharmacy had just been arrested by the U.S. Federal Bureau of Investigation (FBI). Robert Courtney had, over a period of nine years, diluted the medicines specified in as many as 98,000 prescriptions. In all, about 4,200 patients were affected by his actions; many cancer patients received a tiny fraction of their prescribed dosage.3
Courtney was not the only individual diluting, mislabeling, or misbranding medicines. Twelve hundred miles to the east, another group based in Miami, Florida, but operating throughout much of the United States was engaged in similar criminal conduct. But this time, the subjects were not as diligent as Courtney. Rather than keeping counterfeit medicines in a pharmacy, the perpetrators’ drugs were stored in a place many would find unthinkable. During this major investigation in Florida, state investigators discovered that the regular storage facility for cancer medicines was an oversized cooler in a back room of a topless dance club.4
Fortunately, these Florida investigators were well aware of the dangers posed by reckless handling of medicines, but do patrol officers or detectives investigating robberies understand what the terms biologics, biological drugs, and biotech drugs mean or how these very sensitive medicines differ from chemical-based medicines? Clearly, law enforcement officers need to know more about this evolving crime problem, since one day they may find themselves asking, “Are those biologics in that beer cooler?”
An early definition of biological products appeared in the U.S. Code. After several children had died due to contaminated diphtheria antitoxin, the U.S. government enacted the Virus-Toxin Law in July 1902, defining a biological product as “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man.”5 With minor changes, this definition remained the same in 1946, when it was incorporated into section 351 of the Public Health Service (PHS) Act.6
Even still, the general public remained unfamiliar with the term or what it meant. Fifteen years ago, Kevin L. Ropp asked, “Just what is a biologic, anyway?” in an article written for the magazine FDA Consumer. 7 Using a simple definition from the U.S. Food and Drug Administration (FDA), Ropp noted that biological products are made from living organisms. Specifically, according to Michael Beatrice, then associate director for policy coordination and public affairs in the FDA Center for Biologics Evaluation and Research (CBER), “[They] are derived from living material—human, plant, animal, or microorganism—and they’re used for the treatment, prevention, or cure of disease in humans.”8
The U.S. definition of biologics does not differ substantially from that used by the World Health Organization (WHO) for over 50 years. The WHO uses the term biological medicines instead, but the subject is the same. The WHO’s list of biological medicines includes vaccines, blood products, cell regulators, and related in vitro diagnostic tests, recognizing these medicines as lifesaving elements in the daily practice of medicine by physicians worldwide.9
Beginning with its definition, the WHO warns specifically that the quality assurance of such essential biopharmaceutical products raises particular safety considerations due to the biological nature of the starting materials used, the manufacturing process involved, and the tests and methods needed to ensure the consistency of production. The increasing complexity and sophistication of biological products and the rapid growth in this field presents considerable challenges for drug regulatory authorities and for manufacturers. Needless to say, law enforcement authorities share these concerns with the regulatory authorities and have some additional concerns of their own.
One of the most clear, concise, and useful definitions of biologics comes from the American Heritage Stedman’s Medical Dictionary. The terms biologic or biological are used interchangeably. A biologic is a “preparation, such as a drug, a vaccine, or an antitoxin, that is synthesized from living organisms or their products and used medically as a diagnostic, preventive, or therapeutic agent.”10
So whether the medicine is referred to as a biological medicine, a biological, biologics, a biopharmaceutical product, or a biotechnology product; or whether the WHO or a U.S. definition is used, law enforcement authorities need to remember three pieces of information regarding this group of medicines:
- Biologics have fallen into the hands of criminals in the past due to their high commercial value.
- Criminals can increase the value of these medicines by changing the label or refilling used vials.
- As biologics are made from living organisms, if they are discovered outside the normal supply chain, their therapeutic value can be greatly impaired.
Investigators should determine the facts and circumstances surrounding an individual found in possession of these medicines, noting that extra care must be taken wherever these drugs are found.
Brief History of a Lifesaving Biologic
To supplement these definitions and to foster an even greater understanding of the value of biologics, a brief history of a particular biologic—the first vaccine, developed to protect humans against one of the most deadly diseases in the world—is instructive.
By the late 18th century, smallpox was an extremely prevalent and deadly disease. In France, it was estimated that as much as 60 percent of the population developed the disease, and 20 percent died from it. In the Americas, the mortality rate reached 90 percent. 11 Smallpox killed millions. For example, in 1509, when the Spanish attempted to colonize the Caribbean island of Hispaniola to harvest sugar cane, in a mere nine years, every single one of an estimated 2.5 million people died from smallpox.12
In 1796, Edward Jenner, an English doctor, carried out a decisive experiment. A naturalist and keen observer, he noticed that patients developing cowpox were protected against smallpox.13 Testing his observations, Dr. Jenner inoculated a healthy subject with pus taken from a person with cowpox. By then injecting the healthy subject with smallpox, he demonstrated that the subject did not develop smallpox. Dr. Jenner named his discovery “vaccine,” derived from the Latin term vacca meaning “cow,” and the process “vaccination.”14 The significance of Dr. Jenner’s work was quickly recognized, and in less than 10 years, people around the world were being vaccinated against smallpox.
Over the ensuing years, additional vaccines were added to the physician’s toolkit, and today the WHO lists over 20 different diseases, ranging from tuberculosis to yellow fever, that can be either prevented or treated with vaccines.
The chart in figure 1, adapted from the CBER Web site, illustrates some of the more significant developments in the progression of biologics.
Trends in Biologics
Today, newer biologics are created by splicing genetic material into living cell cultures. The resultant new proteins have led to breakthrough therapies, from bevacizumab (trade name Avastin), which chokes off the blood supply to cancerous tumors, to imiglucerase (trade name Cerezyme), which treats a rare genetic disorder known as Gaucher’s disease. According to IMS Health, a consulting and data services company that supplies the pharmaceutical industry with sales data and consulting services, the total cost of biologics reached $52.7 billion in 2005 and represented 13 percent of U.S. drug spending. IMS Health estimates that this figure will rise to $90 billion by 2009.15
Research and development are top priorities for drug manufacturers. IMS Health reports, “At the end of 2006, some 2,075 molecules were in development, up 7 percent from 2005 levels, and up 35 percent from the end of 2003. In addition, a promising range of drugs are now in Phase III clinical trials or pre-approval stage, including 95 oncology products, 40 for viral infections and HIV, and 27 for arthritis/pain. Of the total pipeline, 27 percent of these products are biologic in nature.”16
In short, it appears that biologics now under development will likely continue to provide patients with new, lifesaving treatment options well beyond the scope of traditional chemical medicines. Law enforcement authorities need to know that major increases in new spending, such as that authorized by the Medicare prescription drug benefit, and new lifesaving medicines likely to be in great demand will attract criminals anxious to exploit any potential weakness in the system.
Nature of Counterfeit Biologics
PSI manages the Counterfeiting Incident System (CIS), a secure database used to record incidents of counterfeiting, theft, and illegal diversion of pharmaceutical products worldwide. (For more information on recent trends in CIS data, see the article “Pharmaceutical Counterfeiting: Understanding the Extent of a New Transnational Crime,” on pages 38–43.) CIS incidents come from a variety of sources, including open media reports, PSI member company submissions, and public–private sector partnerships. An incident may be reported by anyone, including drug inspectors, customs officials, police officers, or the general public. Illegally diverted or counterfeit pharmaceuticals can be discovered through government or industry market surveillance or through a law enforcement seizure, such as a customs seizure or police raid.
In 2006, PSI documented a record number (1,371) of new incidents. Counterfeiting was the most common crime, involved in 1,184 incidents or 86 percent of the total. There were 133 incidents, or 10 percent of the total, involving the illegal diversion of pharmaceuticals. Also identified were 54 cases of major pharmaceutical theft, which represents about 4 percent of the 2006 total. Combining the 1,184 incidents in 2006 with the revised 2005 data (899 counterfeiting incidents), the two-year total for counterfeiting stood at 2,083 incidents on December 31, 2006. The number of documented counterfeit biologics incidents worldwide during the same period was 26 incidents, or 1.23 percent of the overall total.
Why 1.23 Percent Matters
All counterfeit medicines represent a threat to the health and safety of the individuals taking them. The adverse impact can range from no therapeutic results—that is, the patient fails to improve or to receive any benefit from the medicine—to serious injury or death.
Even though counterfeit biologics make up less then 2 percent of the total number of known incidents of counterfeiting, this group of counterfeit medicines poses a special problem greater than its statistical representation. Chemical medications are somewhat easier to manufacture with at least a partial degree of success. However, the probability of a counterfeiter successfully creating a biologic with any therapeutic value is remote and virtually zero. Manufacturing biologics is a complex, exacting procedure. These medicines are continuously tested and validated to prevent even the smallest of variations. For example, in the typical manufacture of chemical medicines, 40 to 50 critical tests are conducted. For each biologic, 250 or more tests are conducted.17
PSI incident data suggest that rather than attempting to manufacture biologics, illegal pharmaceutical traffickers engage in the following practices in the most common schemes:
- Recycling of expired products by altering the expiration date
- Refilling discarded vials recovered from hospitals and/or clinics
- “Up-labeling” low-dose medicines to give users the impression that they are taking high-dose versions
- Purchasing stolen and illegally diverted biologics
Despite the difficulty in manufacture, counterfeit biologics are extremely difficult to detect. Most often, these medicines are administered as injections. They have the appearance of either a clear or white liquid or powder. Patients frequently do not even see the medicine. They cannot distinguish the correct form of the medicine by taste—a crude form of testing that has led to the detection of counterfeit medicines in the past. Furthermore, many biologics are administered to healthy individuals as preventive measures, such as influenza vaccines; the effects of these drugs are not immediately apparent. Counterfeiters can easily substitute sterile water knowing that their actions will not be detected for months, since any given patient might or might not develop the flu.
Biologics, in particular vaccinations, are often given to a large number of persons at one time, increasing the potential for a catastrophic event. For example, up to 200 individuals could be inoculated at a school or a nursing home in a single function. The potential impact of a counterfeit biologic is magnified in these cases, as a large number of multiple adverse reactions could result from one incident.
Finally, each incident with biologics is important because these medicines are extremely vulnerable to environmental degradation, more so than other drugs. The proper handling of biologics is critical to their efficacy and the retention of their therapeutic properties. In many incidents of illegal diversion, biologics are shipped around the world with little care or understanding of the impact that the multiple temperature changes at different destinations could have on the medicine.
In illustration of this point, to make a test purchase a few years ago, PSI placed an online order for a biologic. The company that owned the Web site, a supposed manufacturer in Asia, shipped the drug without a prescription. The drug was sent from Lahore, Pakistan, on July 23 and arrived in Washington, D.C., on July 30. Safe transportation of this drug requires use of a cold pack but, needless to say, the test sample arrived without one.
What Else Do the Incident Data Tell Us?
CIS data reveal that the kinds of products most frequently involved in these schemes are vaccines, cancer drugs, arthritis medications, and growth hormone. The main reason vaccines are a prime target is set forth earlier; that is, they are distributed on a large scale, and most patients do not expect any overt beneficial health effect to be evident immediately after the delivery of the drug.
In April 2006, the Brazilian pharmaceutical regulatory body, ANVISA, ordered the recall of counterfeit influenza vaccines carrying the brand name Fluarix. The British pharmaceutical manufacturer that produced the genuine biologic stopped marketing the vaccine under the name in Brazil two years before the incident. The illegal form of the drug was discovered just as a campaign to inject 18 million Brazilians had begun.18
In another case that successfully exposed the extensive nature of this criminal activity, a Mexican prosecutor, along with agents from the federal police, seized 12,319 boxes of medicines and packing materials. These counterfeit medicines were expensive injectable antibiotics and other biologics.19
Overall, in 2005–2006, counterfeit biologics were found in 10 countries, including Brazil, China, Colombia, India, the Isle of Man (dependency of the British Crown), Mexico, Nigeria, Russia, Ukraine, and the United States. In contrast, there were incidents of counterfeiting, illegal diversion, and theft in 101 and 100 countries in 2005 and 2006, respectively.
Biologics are important medicines that save lives and prevent sickness. Many novel biologics are under development. These medicines have fallen into the hands of criminals in the past and are susceptible to simple alterations that increase their value, such as changing a label or refilling a vial. As they are made from living organisms, if they are discovered outside the normal supply chain, their therapeutic value may be greatly impaired.
Law enforcement authorities can contribute to improved patient safety and assist in maintaining the integrity of the drug supply by remaining alert for the presence of biologics during the course of their normal patrol and investigative activities.
For more information, the author can be reached via e-mail at firstname.lastname@example.org.
The author acknowledges the research assistance provided by Sebastian J. Mollo, M.D., medical affairs consultant at PSI. ■
1The Pharmaceutical Security Institute, Inc. (www.psi-inc.org), incorporated as a nonprofit association in 2001, is based in Vienna, Virginia. Its members include 26 research-based pharmaceutical manufacturers.
2The Economic Impact of Counterfeiting and Piracy: Part III: Industry Sectors, OECD draft paper, 2007, 94, http://www.oecd.org/dataoecd/36/34/39543417.pdf (accessed June 11, 2008).
3Robert Draper, “The Toxic Pharmacist,” New York Times, June 8, 2003, http://query.nytimes.com/gst/fullpage.html?res=9502E2DA1230F93BA35755C0A9659C8B63&sec=health&spon=&pagewanted=3 (accessed June 12, 2008).
4Katherine Eban, Dangerous Doses: How Counterfeiters Are Contaminating America’s Drug Supply (Orlando, Florida: Harcourt, 2005), 198. Club manager Benjamin R. Ojeda, a convicted cocaine distributor, said the owners of the Playpen South engaged in this activity.
5Kevin L. Ropp, “Just What Is a Biologic, Anyway?” FDA Consumer, April 1993, http://www.fda.gov/bbs/topics/CONSUMER/CON00202.html (accessed June 14, 2008).
6See “Frequently Asked Questions about Therapeutic Biological Products,” U.S. Food and Drug Administration, Center for Drug Evaluation and Research, July 26, 2006, http://www.fda.gov/cder/biologics/qa.htm (accessed June 14, 2008), regarding the biologics definition in the new law.
7Ropp, “Just What Is a Biologic, Anyway?”
9“Biologicals,” World Health Organization, http://www.who.int/biologicals/en (accessed June 14, 2008).
10The American Heritage Stedman’s Medical Dictionary, 2nd ed. (Boston: Houghton Mifflin, 2004).
11“Smallpox’s History in the World,” http://www.seercom.com/bluto/science/2/immunoweb/bad/invaders/viruses/smallpox/history.html (accessed June 14, 2008).
13Cowpox is an infectious disease of cows involving rash and transmissible to man.
14Stefan Riedel, “Edward Jenner and the History of Smallpox and Vaccination,” Baylor University Medical Center Proceedings 18, no. 1 (January 2005): 21–25, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1200696 (accessed June 12, 2008).
15“Dr. Waxman’s Drug Lab,” editorial, Wall Street Journal, April 10, 2007.
16“IMS Health Reports Global Pharmaceutical Market Grew 7.0 Percent in 2006, to $643 Billion,” IMS press release, March 20, 2007, http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_3665_80560241,00.html (accessed June 14, 2008).
17“Healthcare Biotech Fact Sheet: Biological and Biosimilar Medicines,” European Association for Bioindustry, http://www.europabio.org/documents/FS-Biosimilar.pdf (accessed June 14, 2008), 2.
18For photos comparing the counterfeit with the genuine package, see “Dossiê Fotográfico Caso Fluarix” [in Portuguese], Agência Nacional de Vigilância Sanitária (ANVISA), March 2006, http://www.anvisa.gov.br/divulga/noticias/2006/0600406_fotos_fluarix.pdf (accessed June 14, 2008).
19Procuraduría General de la República (PGR), “PGR Aseguro Mas de 12 Mil Cajas de Distintos Medicamentos de Contrabando” [in Spanish], October 19, 2006, http://www.pgr.gob.mx/cmsocial/bol06/oct/b133306.htm (accessed June 14, 2008).
From The Police Chief, vol. LXXV, no. 8, August 2008. Copyright held by the International Association of Chiefs of Police, 515 North Washington Street, Alexandria, VA 22314 USA.