Ensuring the Safety and Integrity of the World's Drug, Vaccine and Medicines Supply PART TWO
After nearly two years of closed-door meetings, research and negotiations at the Council on Foreign Relations we came up with a six-point policy recommendation for the G8/20, Ensuring the Safety and Integrity of the World’s Drug, Vaccine, and Medicines Supply. In yesterday’s blog post I provided an annotated backgrounder explaining the nature of the problem. Today’s blog is a similarly annotated look at our key findings.
Overall we find that very little data regarding the scale and impact of the unsafe drugs, medicines, and vaccines problem is reliable.[i] Though the scale of the problem has clearly reached crisis proportions, no agency on a multilateral or national level is consistently tracking incidents or their impacts on human health. Indeed, many countries lack both the capacity to track substandard or dangerous products, and to enforce front-end product registration. Thus, even rudimentary baseline data on the inflow of drugs, medicines, and vaccines is dubious or nonexistent.[ii] Caution is advised when using any commonly-cited data regarding medicines safety or crime.
Confusion is heightened by political controversy surrounding the very words used to describe the problem. One word in particular–“counterfeit”–has become the Maginot Line dividing stakeholders: commonly used by pharmaceutical innovators and criminal enforcement agencies, the word is viewed by other stakeholders as a foil for intellectual property and trade protection.[iii] A vast and far flung network of criminals counterfeits drugs such as Viagra and Cialis with such precision that discerning real versus fake packaging and pills visually may be impossible.[iv] Only with microscopic and chemical scrutiny can the intended fraud be verified.
As production of essential vaccines and medicines has globalized, few products sold in 2012 are entirely derived from local resources, purified, formulated, packaged and regulated inside a single nation, weakening the capacity of any given country to regulate the safety of medicines sold to its people.[v]
The 2012 litany of life-threatening or –claiming events resulting from this problem includes distribution in China of 77 million medicine capsules tainted with toxic chromium; discovery that some 30 percent of malaria drugs available in Uganda, imported from India and China, contain no, or insufficient, active ingredient; identification of fake bevacizumab cancer treatment in the U.S. containing no active ingredient; interdiction in Spain and the United Kingdom of shipments of 300,000 doses of fake Viagra; announcement by the Global Alliance of Vaccine Initiatives (GAVI) that the quality of Indian-made vaccines is proving “challenging”; government alerts issued in Tanzania and Kenya, warning their citizens about a flood of false, ineffective malaria medicines; alarm issued by the Infectious Diseases Society of America that shortages of a broad range of antibiotics has become so severe that desperate patients are turning to illegal, unsafe sources for life-sparing medicines; and Pakistani authorities’ finding that 109 heart disease patients died in that country as a result of fake cardiovascular medicine.[vi] All of these incidents came to light between January 1 and April 25, 2012.
Recently, cancer patients in the United States were given a product labeled as the chemotherapy agent Avastin that turned out to be a fraudulent compound containing no active ingredient, made and processed and handed off between brokers through at least seven countries before reaching the American patients.[vii] After the United States FDA identified the fake cancer treatment, the criminals responsible simply shifted sales to less-regulated markets: in April 2012 the fake Avastin turned up in the pharmaceutical supply chain of Indonesia.[viii] Nigerian authorities have seized bogus antibiotics, labeled as drugs manufactured by a reliable Indian company, but actually made by outlaw firms in China.[ix] The credibility of “brand India” is undermined both by such practices and its own substandard productions, imperiling faith in its critical role in bringing some $8.5 billion worth of affordable medicines to developing countries annually.[x]
The integrity of the global manufacture, supply, and distribution chain for pharmaceuticals, over-the-counter drugs, vaccines, and medicines used to combat physical and mental diseases, manage pain, and control epidemics is compromised.[xi] The raw ingredients used worldwide for drug formulation are now primarily made or purified by some 10,000 companies located in India and China, where regulatory lapses have proven serious, even fatal, in numerous cases.[xii] A vast network of brokers creates an opaque barrier between active pharmaceutical ingredient and excipient (inert ingredients) manufacturers, and the next links in the production chain, including regulators.[xiii] Some provide their services on-line, with Made-in-China.com offering to link buyers to 703 API and excipient makers in that country, and Indiamart.com providing similar connections to 2,496 companies in India.[xiv] “There’s a massive racket in substandard drugs,” India’s Deccan Herald declared in 2011, noting health sector estimates that 10 percent of domestic medicines sales are fake, or substandard.[xv] In September 2011, India’s Central Drug Standard Control Organization told Parliament that it needed minimally 3,200 inspectors, but was funded for only 900.[xvi] In his presentation to the U.S. Institute of Medicine on March 13, 2012 Sameer Barde of the Federation of Indian Chambers of Commerce and Industry characterized the nation’s drug industry as unregulated and without fear of penalties for deliberate or mistaken errors: “If you’re not scared of being caught you will make false drugs. It’s the business to be in.”
The full extent of criminal and substandard activity in the drug industry, and numbers of people that have suffered health damages or deaths as a result, is not known for two reasons: few countries have adequate regulatory systems in place to track such matters; and the primary repository of such data from the innovator industry is confidential (though the Pharmaceutical Security Institute does disclose the data on request to government regulators).[xvii]
The World Health Organization reckons some 60 percent of fake, spurious, and substandard drugs wind up in developing countries, where the death tolls have increased steadily every year and now reach staggering proportions.[xviii] Inside China, alone, some 300,000 people die annually from such false products.[xix] An October 2011 opinion survey of 1000 people in 17 African countries found an astonishing 20 percent said that either they, or an immediate family member had within the previous 12 months been the victim of false or fraudulent drugs.
Combined counterfeiting (a branding violation which may not always have public health implications), substandard formulation, contamination, fakery and active ingredient substitution is, according to WHO, a $431 billion market; 83.4 percent of that constitutes fraud, fakery or substandard formulations with direct public health impact, for a 2009 estimated value of $359 million – a 300 percent increase over such sales in 2000.[xx]
The danger posed by bad medicines ranges from widespread substandard formulations for upwards of half of products distributed in Africa, to highly sophisticated counterfeiting of popular pharmaceuticals executed on a massive scale by multinational crime syndicates.[xxi] Increasingly emerging market generic drug manufacturers are experiencing difficulty in obtaining reliable APIs and excipients, compromising the ability of nations such as Brazil, Mexico, and South Africa to manufacture products for domestic consumption and affordable use in poorer countries.
Desperation is driving dangerous purchasing. In developing countries stock-outs and chronic shortages of basic medicines are common. Middle income countries find drug shortages and blackmarkets often result from consumer demand that is heightened by the countries being “too wealthy” to qualify for GAVI, Global Fund, World Bank, or bilateral donor contributions.[xxii] Patients seek medicines from virtually unregulated marketplaces. In middle income and wealthy countries internet purchasing of recreational and lifestyle drugs from dealers that do not require physician prescriptions is increasingly common.[xxiii] And in some wealthy countries where legitimate manufacturers have ceased making low-profit medicines, such as many types of chemotherapies, shortages now impel a far-flung gray market through which hospitals and physicians purchase otherwise unavailable products at price mark-ups as much as 4,500 percent above legitimate costs from third-party distributors.[xxiv] As the phrase “gray market” implies, the bartering and selling of products amid severe shortages – even price gouging – is not illegal, but it does dance on the perimeters of legality and ethical medical practices, and serves as an indicator of desperation-driven purchasing. In 2011, the Institute for Safe Medication Practices surveyed 549 U.S. hospitals, finding that 52 percent had purchased gray market medicines over the previous 12 months.[xxv]
Fraudulent distributors and manufacturers are exploiting these weaknesses and vacuums in the legitimate drug market. The 2012 fake Avastin sales, for example, involved a cancer “treatment” that contained no API, was routed through at least seven countries and sold directly to American physicians and hospitals through the gray market. [xxvi] “Buyer, beware” is not an appropriate warning for essential medicines, as individual patients and physicians cannot typically discern the authenticity and safety of the treatments that they use. Criminally distributed products are packaged and labeled to closely mimic legitimate ones.
Additionally, mal-produced drugs and substandard medicines made by legitimate manufacturers that operate with minimal capital in suboptimal facilities can be the most difficult to identify as they offer a modicum of relief from illness, yet lack fully curative dosage. Patients and physicians may fail to appreciate the danger inherent in such weak drugs until drug-resistant malarial parasites, tuberculosis bacteria, HIV viruses, or other infections have emerged, often rendering their illnesses incurable. A 2011 Global Alliance for TB Drug Development study found that in the ten countries where most of the world’s active TB cases emerge chaotic private antibiotic sales are responsible for half of all treatment, and at least a third of the regimens are inappropriate, even dangerous.[xxvii] A 2009 study reckoned that 700,000 people are killed annually due to use of substandard treatments for TB and malaria.[xxviii] “All of this tells us,” World Health Organization TB control director Mario Raviglione concluded, “that without better regulation of the drugs, we are running the risk of anarchy.”[xxix]
NEXT BLOG: SOLUTIONS
[i] Clift C. A Review of Statistical Information on Counterfeiting and Piracy. Advisory Committee on Enforcement, Seventh Session, World Intellectual Property Organization WIPO/ACE/7/5. Geneva 2011; Government Accountability Office. Intellectual Property: Observations on Efforts to Quantify the Economic Effects of Counterfeit and Pirated Goods. Washington, DC: Government Accountability Office, 2010.http://www.gao.gov/new.items/d10423.pdf.
[ii] Newton P, Fernandez F, Green M, Primo-Carpenter J, and White N. Counterfeit and Substandard Anti-infectives in Developing Countries. Antimicrobial Resistance in Developing Countries. Springer, 2010: 413- 443.
[iii] Clift C. Meeting Summary: Combating counterfeit, falsified, and substandard medicines. London, UK: Chatham House, 2010; International Centre for Trade and Sustainable Development. WHO Talks on ‘Counterfeit’ Medicines, Reform Move Forward. 2012. https://ictsd.org/i/news/bridgesweekly/124166/; The Partnership for Safe Medicines. Interchange 2011. Washington, DC: The Partnership for Safe Medicines, 2011; OXFAM. Eye on the Ball; Newton P, Amin A, Bird C et al. The Primacy of Public Health Considerations in Defining Poor Quality Medicines. PLoS Medicine 2011; Clift C, Combating Counterfeit, Falsified, and Substandard Medicines.
[iv] Jackson G, Patel S, and Khan S. Assessing the problem of counterfeit medications in the United Kingdom.Int J Clin Pract 2012; 66: 241-250. http://www.ncbi.nlm.nih.gov/pubmed/22070229 ; The counterfeit conundrum. Int J Clin Pract 2012; 66: 229-233.
[v] Garrett L and Huang Y. Food and Drugs: Can Safety Be Ensured in a Time of Increased Globalization? New York: Council on Foreign Relations, 2011; Woo J, Wolfgang S, and Batista H. The Effect of Globalization on Drug Manufacturing, Production, and Sourcing and Challenges for American Drug Safety. Nature 2008; 83; Fake Avastin Shows Very Little Protects Drug Supply. Reuters, 2012; Foreign drugmakers escape FDA scrutiny. MSNBC, 2007. http://www.msnbc.msn.com/id/21566364/ns/health-health_care/t/foreign-drugmakers-escape-fda-scrutiny/; Newton P, Fernández F, Plançon A, et al. A Collaborative Epidemiological Investigation into the Criminal Fake Artesunate Trade in South East Asia. PLoS Medicine 2008; 5.http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050032 .
[vi] Blanchard B. China detains dozens in poison drug capsule scandal. Chicago Tribune 2012; Onyango E. Uganda: Malaria Medicines Most Counterfeited. AllAfrica 2012; Counterfeit version of bevacizumab product contains no active ingredient. ModernMedicine 2012; Fake Viagra arrests in UK and Spain. BBC News 2012; Vaccine quality vexing global procurers. The Hindu Business Line 2012; Songa S. Tanzania: TFDA - Beware of Fake Malaria Drugs. AllAfrica 2012; Anti-Infective Drug Shortages Pose Threat to Public Health and Patient Care. Science Daily, 2012; Pakistan fake drugs kill 109. Greater Kashmir, 2012; Pakistani nabbed for fake drugs. Tempo 2012.
[vii] Weaver C, Whalen J, and Faucon B. Drug Distributor Is Tied to Imports of Fake Avastin. Wall Street Journal 2012.
[viii] Sagita D. Concerns Fake Cancer Medicine on Indonesian Market. The Jakarta Globe 2012.
[ix] Abijade C. Nigeria: Fake Drugs – Raising Standards Against All Odds. AllAfrica 2011; Alexander J. Fake Chinese drugs ‘made in India’ labels continue to hit African markets, says Nigerian FDA chief. PharmaBiz 2011; Bate R and Woods T. ‘Made in India,’ Faked in China. The American 2010; Nagarajan R. Chinese passing off fake drugs as ‘Made in India’. The Times of India 2009; Bhaumik A. India, Africa to check fake drug menace.Deccan Herald 2010. http://www.deccanherald.com/content/58228/india-africa-check-fake-drug.html .
[x] Taylor P. India to Set Life Sentences for Nigerian Drug Counterfeiters. SecuringPharma 2011; Shankar R. Indian Drug Regulators Complete First Ever Auditing and Inspection of MFG Plants in China. PharmaBiz 2011.
[xi] McKee S. Man jailed for worst ever breach of medicines supply chain. Pharma Times 2011.
[xii] Bate R. Are Drugs Made in Emerging Markets of Good Quality? Economic Affairs 2010; Major counterfeiting ring busted in China. SecuringPharma 2011.
[xiii] Pitts P, ed. Coincidence or Crisis? Prescription medicine counterfeiting. London, UK: The Stockholm Network, 2006.
[xiv] Pharmaceuticals Importers, Exporters, Manufacturers Directory. Pharmaceuticals Importers, Exporters, Manufacturers Directory. http://www.pharmabuyers.com/ (Accessed January 12, 2011); Pharmaceutical Raw Material, China Pharmaceutical Raw Material, Pharmaceutical Raw Material Manufacturers, China Pharmaceutical Raw Material Suppliers. http://www.made-in-china.com/products-search/hot-china-products/Pharmaceutical_Raw_Material.html (Accessed January 12, 2011); Pharmaceutical Drugs Manufacturers, Wholesale Pharmaceutical Drugs, Pharmaceutical Drugs Suppliers.http://catalogs.indiamart.com/manufacturers/pharmaceutical-drugs-formulations.html (Accessed January 12, 2011).
[xv] Death Merchants. Deccan Herald 2011. http://www.deccanherald.com/content/146382/death-merchants.html .
[xvi] Sinha K. Acute Drug Inspectors Crunch Hurdle to Sniff Out Spurious Drugs. Times of India 2011.http://articles.timesofindia.indiatimes.com/2011-09-06/india/30118239_1_spurious-drugs-cdsco-fake-drugs .
[xvii] Fighting fake drugs: The role of WHO and pharma. Lancet 2011; 377.
[xviii] General Information on Counterfeit Medicines. World Health Organization.www.who.int/medicinces/services/counterfeit/overview/en/.
[xix] Feeney J, Goldsmith A, et. al. A Prescription to Kill. International Focus 2007.http://www.kellogg.northwestern.edu/Departments/International/InternationalFocus/Article/2007_A_Prescription_to_Kill.aspx; Shah S. Spurious drugs cause over half-a-million deaths each year. The News International 2012.
[xx] General information on counterfeit medicines. World Health Organization.
[xxi] African Union. Counterfeit Drugs: Africa’s Silent Public Health Crisis. Modern Ghana News 2011;
Bhandari M. A Quarter of Vital Donated Medicines Missing or Stolen. IPS 2011; Kaiser Family Foundation. More Than Half Of Malaria Drugs In West Africa 'Sub-Standard Quality,' Says UNODC. Kaiser Daily Global Health Policy Report 2009; Weir W. Counterfeit Drugs: The Science of Telling The Real From The Fake. Los Angeles Times 2011; Odeh O. Nigeria: Orhii Seeks International Backing Against Fake Drugs. Daily Independent 2011; South African Police Service. Two Suspects Arrested in German-South African Operation. South African Government Information 2011. http://www.info.gov.za/speech/DynamicAction?pageid=461&sid=23130&tid=48718; Siva N. Tackling the booming trade in counterfeit drugs. Lancet 2010;376; Omandi G and Muiruri M. WHO names Kenya as safe haven for fake drug cartels. Business Daily 2012.http://www.businessdailyafrica.com/Corporate%20News/-/539550/1050938/-/11ngusaz/-/index.html.
[xxii] Waters H. Cheap drugs pulled despite wealth gap in middle-income countries. Nature Medicine 2011;17:1023. http://www.nature.com/nm/journal/v17/n9/full/nm0911-1023.html ; Morel C, McGuire A and Mossialos E. The Level of Income Appears To Have No Consistent Bearing On Pharmaceutical Prices Across Countries. Health Affairs 2011; 30: 1545-1551. http://content.healthaffairs.org/content/30/8/1545.
[xxiii] Bate R and Hess K. Assessing Website Pharmacy Drug Quality: Safer Than You Think? PLoS One 2010;5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921371/ .
[xxiv] Gatesman M and Smith T. The Shortage of Essential Chemotherapy Drugs in the United States. NEJM2011; 365:1653-1655. http://www.nejm.org/doi/full/10.1056/NEJMp1109772; Liang B. Fade to Black: Importation and Counterfeit Drugs. Am J Law Med 2006; 32: 279-323.http://anesthesia.ucsd.edu/research/faculty-research/Documents/AJLMFadetoBlack.pdf .
[xxvi] Weaver C, Whalen J, and Faucon B. Drug Distributor is Tied to Imports of Fake Avastin. Wall Street Journal 2012. http://professional.wsj.com/article/SB10001424052970203370604577261343974214110.html?mg=reno64-sec-wsj; Palmer E. Fake of Roche’s Avastin Shipped from Canadian Supplier. FiercePharma Manufacturing 2012. http://www.fiercepharmamanufacturing.com/story/fake-roches-avastin-shipped-canadian-supplier/2012-03-07.
[xxvii] Wells W, Ge C, et. al. Size and Usage Patterns of Private TB Drug Markets in the High Burden Countries. PLoS One 2011; 6.
[xxviii] Harris J, Stevens P, and Morris J. Keeping it Real: Combating the Spread of Fake Drugs in Poor Countries. International Policy Network: Health Issues.www.policynetwork.net/sites/default/files/keeping_it_real_2009.pdf
(accessed January 12, 2011).
[xxix] Check-Hayden E. Market overlap points to irresponsible use of tuberculosis drugs. Nature Medicine 2011;17.
[L1]From Pew Health Group