The Fake Drug Problem

 

By Gesa Junge, PhD

Tablets, injections, and drops are convenient ways to administer life-saving medicine – but there is no way to tell what’s in them just by looking, and that makes drugs relatively easy to counterfeit. Counterfeit drugs are medicines that contain the wrong amount or type of active ingredient (the vast majority of cases), are sold in fraudulent packaging, or are contaminated with harmful substances. A very important distinction here: counterfeit drugs do not equal generic drugs. Generic drugs contain the same type and dose of active ingredient as a branded product and have undergone clinical trials, and they, too, can be counterfeited. In fact, counterfeiting can affect any drug, and although the main targets, particularly in Europe and North America, have historically been “lifestyle drugs” such as Viagra and weight loss products, fake versions of cancer drugs, antidepressants, anti-Malaria drugs and even medical devices are increasingly reported.

The consequences of counterfeit medicines can be fatal, for example, due to toxic contaminants in medicines, or inactive drugs used to treat life-threatening conditions. According to a BBC article, over 100,000 people die each year due to ineffective malaria medicines, and overall, Interpol puts the number of deaths due to counterfeit pharmaceuticals at up to a million per year. There are also other public health implications: Antibiotics in too low doses may not help a patient fight an infection, but they can be sufficient to induce resistance in bacteria, and counterfeit painkillers containing fentanyl, a powerful opioid, are a major contributor to the opioid crisis, according to the DEA.

It seems nearly impossible to accurately quantify the global market for counterfeit pharmaceuticals, but it may be as much as $200bn, or possibly over $400bn. The profit margin of fake drugs is huge because the expensive part of a drug is the active ingredient, which can relatively easily be replaced with cheap, innate material. These inactive pills can then be sold at a fraction of the price of the real drug while still making a profit. According to a 2011 report by the Stimson Center, the large profit margin combined with comparatively low penalties for manufacturing and selling counterfeit pharmaceuticals make counterfeiting drugs a popular revenue stream for organized crime, including global terrorist organizations.

Even though the incidence of drug counterfeiting is very hard to estimate, it is certainly a global problem. It is most prevalent in developing countries, where 10-30% of all medication sold may be fake, and less so in industrialized countries (below 1%), according to the CDC. In the summer of 2015, Interpol launched a coordinated campaign in 115 countries during which millions of counterfeit medicines with an estimated value of $81 million were seized, including everything from eye drops and tanning lotion to antidepressants and fertility drugs. The operation also shut down over 2400 websites and 550 adverts for illegal online pharmacies in an effort to combat online sales of illegal drugs.

There are several methods to help protect the integrity of pharmaceuticals, including tamper-evident packaging (e.g. blister packs) which can show customers if the packaging has been opened. However, the bigger problem lies in counterfeit pharmaceuticals making their way into the supply chain of drug companies. Tracking technology in the form of barcodes or RFID chips can establish a data trail that allows companies to follow each lot from manufacturer to pharmacy shelf, and as of 2013, tracking of pharmaceuticals throughout the supply chain is required as per the Drug Quality and Security Act. But this still does not necessarily let a customer know if the tablets they bought are fake or not.

Ingredients in a tablet or solution can fairly easily be identified by chromatography or spectroscopy. However, these methods require highly specialized, expensive equipment that most drug companies and research institutions have access to, but are not widely available in many parts of the world. To address this problem, researchers at the University Of Notre Dame have developed a very cool, low-tech method to quickly test drugs for their ingredients: A tablet is scratched across the paper, and the paper is then dipped in water. Various chemicals coated on the paper react with ingredients in the drug to form colors, resulting in a “color bar code” that can then be compared to known samples of filler materials commonly used in counterfeit drugs, as well as active pharmaceutical ingredients.

Recently, there have also been policy efforts to address the problem. The European Commission released their Falsified Medicines Directive in 2011 which established counterfeit medicines as a public health threat and called for stricter penalties for producing and selling counterfeit medicines. The directive also established a common logo to be displayed on websites, allowing customers to verify they are buying through a legitimate site. In the US, VIPPS accredits legitimate online pharmacies, and in May of this year, a bill calling for stricter penalties on the distribution and import of counterfeit medicine was introduced in Congress. In addition, there have also been various public awareness campaigns, for example, last year’s MHRA #FakeMeds campaign in the UK,  which was specifically focussed on diet pills sold online, and the FDA’s “BeSafeRx” programme, which offers resources to safely buying drugs online.

In spite of all the efforts to raise awareness and address the problem of fake drugs, a major complication remains: Generic drugs, as well as branded drugs, are often produced overseas and many are sold online, which saves cost and can bring the price of medication down, making it affordable to many people. The key will be to strike the balance between restricting access of counterfeiters to the supply chain while not restricting access to affordable, quality medication for patients who need them.

From Bed[side] to Bench: Involving Patients and the Public in Biomedical Research

By Celine Cammarata

 

Many of us doing biomedical science never really see patients, the very people our work will hopefully one day help. But what if we did – what if those individuals who will eventually be using our research on a daily basis were in fact involved in the work from the start? How would research change?

 

This is the concept underlying the movement toward Patient and Public Involvement or PPI, a title that (logically enough) refers to efforts by researchers and institutions to engage patients and members of the public in the process of biomedical research and, in doing so, fundamentally change the way scientific information is created and disseminated. Traditionally, the flow if information between science and society was seen as relatively unidirectional, with researchers passing scientific knowledge down to an uninformed, receptive public. More recently, however, there has been a growing recognition that information flow from the end-users of research back to investigators is also critical.

 

One way to accomplish this is to directly incorporate those users – broadly defined as patients, caregivers, members of the public rather than clinicians or practitioners – into the research process. A prominent definition of PPI is “research being carried out ‘with’ or ‘by’ members of the public rather than ‘to’, ‘about’ or ‘for’ them” (INVOLVE). Individual instances of PPI can be quite variable, though most engage users in some form of advisory role, often through interviews, surveys, focus groups, and hosting users alongside researchers on regularly-meeting advisory groups (Domecq et al., 2014). PPI is represented at all stages of research, from inception of project ideas through the data collection process to implementation of findings and evaluation and is most prevalent in research that is either directly related to health or social issues and services.

 

A primary driving force behind PPI is the belief that input from users will push research toward questions that are more relevant to those users. Individuals with first-hand experience of an illness or other condition are thought to hold a particular kind of expertise and therefore able to craft more immediately relevant research questions than an academic investigator in the field might.

 

One important stage at which patients and the public are having an impact is by working with funding agencies to establish research priorities. For instance, the UK’s NHS Health Technology Assessment program involves users alongside clinicians and researchers in the development and prioritization of research priority questions. Members of the public were engaged in several different stages of the process, from initial suggestion of research ideas through to selecting topics that would be developed into solicitations for research. Analysis revealed that overall these lay members exerted an influence on the research agenda approximately equal to that of academic and clinical professionals (Oliver, Armes, & Gyte, 2009).

 

PPI can also increase the relevance of individual studies, with specific examples including: users of mental health services shifting outcome measurement in a study of therapies to improve cognition away from psychological tests in favor measuring performance on daily activities; the investigation of environmental factors such as radiation, which researchers originally considered negligible, in a study of breast cancer; and the development of new assessment tools to measure the mental and psychological condition of stroke victims in a study that initially planned to focus only on physical health outcomes (Staley, 2009).

 

Users may express particular suspicions or hunches about their condition that they believe should receive further investigation, may increase pressure on investigators to clearly state how their work will contribute to the public, and may challenge whether a project is even conceptualized in a way relevant to those who experiencing the situation in question, helping to determine whether a research problem is truly a “problem” at all. An excellent example of the impacts of PPI in research commissioning is the Head Up project, an entirely user-driven project in which patients with motor neuron disease working with one of the CCF programs pushed for research on an improved supportive neck collar.

 

PPI may also help increase the up-take of research findings because user’s are generally able to relate to and communicate with other users and practitioners in a uniquely meaningful way. Patients and members of the public may help to write up study findings, present at conferences or, importantly, bring findings directly to the user community.

 

Of course, nothing comes without a cost. A number of challenges in conducting PPI have consistently been identified, including: insufficient time and funding; tension over roles on the project and difficult relations between academic researchers and users; lack of training for both users and researchers; and a tokenistic attitude toward PPI on the part of investigators. Still relatively little is known about the precise effects of PPI or best practices. However, these are active areas of scholarship. Also of note is the relative lack of PPI in basic science research; PPI is predominantly relegated to applied health and social research. An important step in furthering PPI would be to establish who the “users” of basic research are, whether PPI in basic research is likely to be beneficial, and how the practice could be implemented.

 

Overall, it is clear that the end-users of research can be incorporated into setting the research agenda, designing studies and communicating results, and suggests that such user engagement can increase the relevance of research and the dissemination and adoption of findings.

Extra Protection: New HPV Vaccine Extends Protection to Nine Strains of The Virus

 

By Asu Erden

The human papillomavirus (HPV) is responsible for 5% of all cancers. Until, 2006 there were no commercially available vaccines against the virus. That year, the Food and Drug Administration (FDA) approved the first preventive HPV vaccine, Gardasil (qHPV). This vaccine conveys protection against strains 6, 11, 16, and 18 of the virus and demonstrates remarkable efficacy. The Centers for Disease Control (CDC) estimates that this quadrivalent vaccine prevents 100% of genital pre-cancers and warts in previously unexposed women and 90% of genital warts and 75% of anal cancers in men. While this qHPV protects against 70% of HPV strains, there remains a number of high-risk strains such as HPV 31, 35, 39, 45, 51, 52, 58 for which we do not yet have prophylactic vaccines.

 

In February of this year, a study by an international team spanning five continents changed this state of affairs. The team led by Dr. Elmar A. Joura, Associate Professor of Gynecology and Obstetrics at the Medical University, published its study in the New England Journal of Medicine. It details a phase 2b-3 clinical study of a novel nine-valent HPV (9vHPV) vaccine that targets the four HPV strains included in Gardasil as well as strains 31, 33, 45, 52, and 58. The 9vHPV vaccine was tested side-by-side with the qHPV vaccine in an international cohort of 14, 215 women. Each participant received three doses of either vaccine, the first on day one, the second dose two months later, and the final dose six months after the first dose. Neither groups differed in their basal health or sexual behavior. This is the immunization regimen currently implemented for the Gardasil vaccine.

 

Blood samples as well as local tissue swabs were collected for analysis of antibody responses and HPV infection, respectively. They revealed the same low percentage of high-grade cervical, vulvar, or vaginal. Antibody responses against the four HPV strains included in the Gardasil vaccine were similar in both treatment groups. Of note is that participants in the 9vHPV vaccine group experienced more mild to moderate adverse events at the site of injection. Dr. Elmar A. Joura explained that these effects are due to the fact that the “[new] vaccine contains more antigen, hence more local reactions are expected. The amount of aluminium [editor’s note: the adjuvant used in the vaccine] was adapted to fit with the amount of antigen. It is the same amount of aluminium as used in the Hepatitis B vaccine.”

 

These results confirm that the novel 9vHPV vaccine raises antibody responses against HPV strains 6, 11, 16, 18 that are as efficacious as the original Gardasil vaccine. In addition, the novel vaccine also raises protection against HPV strains 31, 33, 45, 52, and 58. Importantly, the immune responses triggered by the 9vHPV vaccine are as protective against HPV disease as those raised by the qHPV vaccine.

 

Yet we are all too familiar with the contention surrounding the original qHPV vaccine. And no doubt, this new 9vHPV vaccine will reignite the debate. Those who specifically oppose the HPV vaccine question its safety and usefulness. In terms of its safety, the HPV vaccine has been tested for over a decade prior to becoming commercially available and has been proven completely safe since its introduction a decade ago. Adverse effects include muscle soreness at the site of injection, which is expected for a vaccine delivered into the muscle…

 

As for its usefulness, don’t make me drag the Surgeon General and Elmo onto the stage. The qHPV vaccine has been shown to be safe and to significantly impact HPV-related genital warts, HPV infection, and cervical complications, “as early as three years after the introduction of [the vaccine]” in terms of curtailing the transmission and public health costs of HPV infections and related cancers.   “HPV related disease and cancer is common. It pays off to get vaccinated and even more importantly to protect the children,” noted Dr Elmar A. Joura.

 

Other opponents to the HPV vaccines raise concerns regarding the use of aluminium as the adjuvant in the formulation of the vaccine. This inorganic compound is necessary to increase the immunogenicity of the vaccine and for the appropriate immune response to be raised against HPV. Common vaccines that include this adjuvant include the hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTP), Haemophilus influenzae type b, as well as pneumococcal vaccines.

 

The only question we face is that given the availability of Gardasil, why do we need a nine-valent vaccine? In order to achieve even greater levels of protection in the population at large, extending coverage to additional high-risk HPV strains is of central importance for public health. The team of international scientists that contributed to the study underlined that the 9vHPV vaccine “offers the potential to increase overall prevention of cervical cancer from approximately 70% to approximately 90%.” Thus the novel 9vHPV vaccine offers hope in bringing us even closer to achieving this epidemiological goal. “With this vaccine cervical and other HPV-related cancers could potentially get eliminated, if a good coverage could be achieved. This has not only an impact on treatment costs but also on cervical screening algorithms and long-term costs,” highlighted Dr. Elmar A Joura.

One Flu Over the Cuckoo’s Nest: Has the New Avian Influenza Virus Achieved Human-to-Human Transmission?

 

By Asu Erden

Human cases of H7N9 – a new avian influenza A virus – were first reported in China between February and March 2013. It is believed that infection with this virus requires exposure to poultry but when and how the virus crossed the species barrier remains elusive. The Centers for Disease Control (CDC) originally estimated that up to 20% of the people that become infected with this virus die. There are currently no vaccines available against this avian flu virus, although clinical trials are under way with the help of the World Health Organization (WHO). The disease caused is severe and mainly affects the respiratory tract. Li et al. recently published a study in the New England Journal of Medicine that sheds light on the epidemiology of the disease caused by H7N9 and suggests that the virus might have achieved human-to-human transmission.

 

In their study, Li et al. investigated 139 confirmed cases of H7N9 from 12 different areas in China (including Shanghai and Beijing). Their aim was to better understand the epidemiology of the lower respiratory illness caused by this avian flu virus newly infecting humans. They were able to identify cases thanks to the Chinese surveillance system for pneumonia of unknown origin, which was put in place in 2004 at the time of the H5N1 avian influenza outbreak. The study confirmed that infection with H7N9 is most likely caused by exposure to live animals (poultry, birds, or swine). Most of the studied cases (77%) occurred in older individuals with the median age of patients being 61. Despite an older age distribution, the H7N9 virus seems to infect people from a broader age range than H5N1 did a decade ago.

 

This emerging zoonosis seems to be particularly virulent. After an incubation period of 7 days, H7N9 caused an acute illness characterized by severe lower respiratory symptoms – including pneumonia and respiratory failure – in all studied patients. The case fatality rate was also high, with 34% of patients dying. This rate is significantly higher than originally estimated by the WHO but remains lower than for H5N1. Further studies are required to establish the true case fatality rate of the disease caused by H7N9 in the overall population.

 

Li’s group also carried out family cluster analyses based on four families in which two or more individuals had confirmed cases of H7N9. In each cluster, one of the individuals became infected due to close contact with poultry (e.g. visits at poultry markets) but the other infected individuals never came in close contact with live animals. This suggests that the virus might have evolved to achieve human-to-human transmission. On the other hand, Li et al. also followed over 2500 close contacts of their 139 confirmed cases and only 1% developed respiratory symptoms, none of which tested positive for H7N9. Of note, however, is that these individuals were only followed for 7 days after contact and only single swabs were collected from them. This likely decreased the likeliness of detecting H7N9 cases among close contacts.

 

The most significant finding from this study also happens to be the only negative data that were presented:  Li et al. were unable to discard the possibility that H7N9 can transmit from human to human. Given the virulence, case fatality rate, and ongoing outbreak of the H7N9 avian influenza virus, the possibility of human-to-human transmission is cause for concern. The establishment of a putative human reservoir would allow for fast spread of the virus worldwide and should be scrutinized by public health officials.