1. Joyce Primo-Carpenter, M.D.
The VIth National Congress of Pharmacology, Therapeutics and Clinical Toxicology Substandard and Counterfeit Drugs: A Global Health Risk
Joyce Primo-Carpenter, M.D.
Associate Director, Global Assistance Initiatives
Drug Quality and Information Program (DQI)
United States Pharmacopeia
June 2005

2. Presentation outline Overview Factors/causes Importance Case Examples
Consequences
Possible Solutions
Role of healthcare professionals
Conclusions

3. Good Quality Medicines
Good quality medicines meet official standards for identity, strength, purity, quality, packaging, and labeling.

4. Poor quality drug products
Fake/counterfeit – deliberately and fraudulently mislabeled with respect to identity and/or source. (No active ingredient or a different active ingredient than on the label)
WHO definition
Substandard – legal innovator or generic product, but does not meet official standards for identity, quality, purity, strength, packaging and labeling.
Cx ingred, wrong ingr etc.

5. Factors/causes of poor quality drugs
Lack of legislation and/or weak penal sanctions
Absent/weak drug regulatory authority
Corruption/conflict of interest
Trade involving many intermediaries
Demand exceeding supply
High prices
Inefficient cooperation between stakeholders
Lack of control over export
Sophistication in clandestine operation
Lack of Good Manufacturing Practices compliance
Inappropriate drug storage

6. Why be concerned about drug quality?
Because counterfeit and substandard drugs are widely available which are a constant threat to global health

7. ALARMING FIGURES
estimated 10% of global pharmaceutical commerce (US$21 billion) are counterfeit
WHO/EDM/QSM/99.1
> 50% of the drug supply in some countries are counterfeit

8. Geographic distribution
WHO report ( ) on documented cases of drug counterfeiting by region:
48.7% ─ Western Pacific developing countries
19.7% ─ Africa developing countries
13.6% ─ Europe industrialized countries

9. What drugs are being counterfeited?

10. U.S.A. counterfeit drug
PROCRIT® (epoetin alfa)* 40,000 U/mL vials (2002)
Use to treat anemia associated with chemotherapy, chronic renal failure (pre-dialysis), & zidovudine treatment
Low-dose vial relabeled as high dose
Same vials used
Patients could be under-dosed

11. Malaria 300 to 500 million cases annually
1.5 to 3 million deaths (mostly children)
Increasing drug resistance in Southeast Asia, Africa, and South America
Repeated exposure of Plasmodium falciparum--the most lethal form of malaria--to sub-lethal doses of antimalarial drugs, e.g., through substandard medicines, allows the parasite to adapt before being killed.
Chloroquine-resistant P. falciparum malaria is now widespread in Africa.
Sulfadoxine + pyrimethamine (SP) is replacing chloroquine as first line treatment, but serious quality problems with dissolution.
In Southeast Asia resistance has developed not only to chloroquine and SP, but also to mefloquine and quinine.
Currently, the only individual drugs effective against MDR-malaria parasites are artemisinin derivatives such as artesunate.
Combination drug products are in development, but are more costly. Only one FDC approved by WHO – Coartem by novartis, lumefantrine and artesiminin
A.Clements, USAID/ANE/TS, Addressing Multidrug-Resistant Malaria in Southeast Asia, April 2003

12. Artesunate in Southeast Asia
One study showed 38% of "artesunate" samples collected from drug shops in Burma, Cambodia, Laos, Thailand, and Vietnam contained insufficient or no active ingredient.
Newton P, et al. Lancet 2001; 357:
Artesnuate is a relatively new drug extracted from the artemisia
plant, grown in China and Vietnam.
In some southeast Asian countries it is the only
medicine still effective against malaria.

13. Counterfeit artesunate
Fake found in 2002/03 in Laos and Cambodia
Genuine artesunate hologram of Guilin Pharmaceutical Co.

14. Poor quality SP in Africa
Country
Content failure
Dissolution failure
Gabon
18%
97%
Ghana
45%
78%
Kenya
10%
55%
Mozambique 7%
70%
Zimbabwe 5%
79%
SP is significant because it is the first or second line drug
for Malaria in many countries and the drug of choice IPT –
intermittant presumptive treatment during pregnancy.
WHO Annual Report 2001

15. Tuberculosis
1/3 of the world’s population is currently infected with TB
1.7 million deaths in 2003
Incomplete treatment is largely responsible for development of resistance
For MDRTB, the probability of cure is <50%
Iseman MD et al.Drug-resistant tuberculosis.Clin Chest Med 1989; 10:
Treatment may become impossible, or nearly so.
New cases of MDR TB in the U.S. <2%
MDR TB and resistant strains of HIV can be transmittedNew cases ARV-resistant HIV infection is 5-10% in U.S. and growing.
Fixed-dose combination products are the hope for reducing resistance, but quality must be assured by bioavailability (BA) testing.
BA is how quickly and how much of the API gets into the human circulatory system from a dosage form.
BA- as determined by its concentration relative to time in
the systematic circulation or by its excretion in urine.
There is a move toward FDC for ARV’s, but this has to be
done very carefully due to drug quality issues.
You cannot assume that two actives when combined will
necessarily function exactly as they do when in two separate
products – drug-drug interactions.
TB drugs have been around a lot longer than ARVs,
more know about their actions and interactions. .

16. Isoniazid (INH) & Rifampicin (RMP)
In one study, overall, 10% of all INH & RMP samples collected from selected TB programs/pharmacies in Colombia, Estonia, India, Latvia, Russia and Vietnam were tested using TLC were found to be substandard.
Laserson KF et al. Int J Tuberc Lung Dis 2001; 5(5)::

17. HIV/AIDS
Transmission of HIV-1-resistant variants can occur at time of the infection.
One in five HIV-infected patients have a major drug resistant mutation.
Fewer options for initial treatment allows the disease to progress more rapidly and suboptimal response among recently infected may increase transmission.
In 2003
4.8 million new cases of HIV
37.8 million living with HIV
2.9 million died of HIV
>20 million first cases of AIDS identified since 1981
Drug-resistant HIV-1 variant can be caused by sub-optimum treatment or incomplete adherence to therapy
Hirsch et al. antiretroviral drug resistance testing in adults with HIV infection. JAMA 1998; 279:
HIV-1 can mutate spontaneously and proportion of new HIV infections with drug-resistant virus is increasing.
Emergence of drug-resistant HIV-1 variants is caused mainly by sub-optimum treatment or incomplete adherence to therapy.
Slower response to treatment and more limited viral suppression permit increased viral replication in the presence of ARV drugs, facilitating greater drug resistance.

18. Ginovir 3D (zidovudine, lamivudine, & indinavir)
Analysis of this ARV triple drug combination showed the samples did not contain lamivudine or indinavir but instead, contained zidovudine, stavudine and an unidentified substance.
Counterfeit triple antiretroviral combination product (Ginovir 3D) detected in Cote d’Ivoire. WHO QSM/MC/IEA.110, Nov 28, 2003.
Counterfeits cost the industry about $22 billion per year, or about 10% worldwide sales. FDA does not consider it widely prevalent in the US, but it has been increasing in recent years. FDA now has 20 open cases under investigation.

19. Consequences (1)
People living in countries with limited regulatory capacity and resources are most affected
Waste scarce financial resources
Erodes public confidence in medical care
Counterfeits cost the industry about $22 billion per year, or about 10% worldwide sales. FDA does not consider it widely prevalent in the US, but it has been increasing in recent years. FDA now has 20 open cases under investigation.

20. Consequences (2) Health risk: - No quality control
- Non-treatment/ineffective treatment/undertreatment
- Public health risk (ineffective antibiotics/vaccines)
- Drug resistance & loss of life-saving therapies
- Toxicity
- Increased morbidity
- Mortality

21. Poor quality drugs are dangerous
Substandard and counterfeit drugs can kill
Substandard: e.g., diethylene glycol
US 1938: 120 died
Nigeria 1990: 109 children died
Bangladesh 1992: 223 children died
Argentina 1992: 23 patients died
Haiti 1995/1996: 89 children died
Counterfeit: e.g., meningitis vaccine with no antigen
Nigeria 1995: around 2500 deaths
Source: WHO

22. Antimicrobial resistance
Substandard antibiotics can increase global problem of antimicrobial resistance
Poor response to substandard narrow-spectrum antibiotics may lead to unnecessary prescription of newer and more expensive broad-spectrum antibiotics.
Wider exposure to these drugs creates opportunity for more kinds of bacteria to develop resistance.

23. Paraguay AMR surveillance network
Trimethoprim-sulfamethoxazole

24. Possible Solutions No simple solutions Drug quality assurance
-drug regulatory agency
-use of recognized standards
-good manufacturing practices (GMP)
Awareness
-information dissemination/education
Legal actions
-counterfeiting as criminal offense
Collaboration of stakeholders

25. The Role of Healthcare Professionals
Participate in the fight against counterfeit drugs
Alert for any failure of treatment (could be a sign of counterfeit)
Beware of unusually low prices
Use only authorized sources of drug supply
Report
Communicate with national drug regulatory agencies, exchange information
Raise awareness, educate
World Health Professional Alliance at the 2nd Global Forum on Pharmaceutical Anticounterfeiting , Paris, France; March 2005.

26. Conclusions
Poor quality drugs are widely available and continue to be a global problem
Incidences are increasing
Health is at risk
Urgent measures are needed
Increased collaboration among stakeholders to include healthcare professionals is necessary

27. United States Pharmacopeia
Private, not-for-profit organization since 1820
Establishes official pharmaceutical manufacturing standards enforceable by the U.S. FDA and many other countries
Publishes USP/NF annually
Distributes chemical reference substances used in testing for product identity, strength, quality, purity
400 member organizations/650 volunteer experts
Global Assistance Initiatives USP DQI focuses on ensuring the quality of pharmaceuticals and their informed and appropriate use worldwide, continuing education for healthcare professionals, & developing evidence-based drug/therapeutic information.
Patient Safety, Dietary Supplements Verification