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The Trans-Pacific Partnership and its Impact on Pharmaceutical Affordability

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By: Shakira M. Nelson, PhD, MPH

        For many, the Trans-Pacific Partnership (TPP) was a point of great debate during the 2016 Presidential primaries and election. As a simplified explanation, the TPP is a free-trade agreement involving the United States, Canada, Australia, Japan, New Zealand, Mexico, Chile, Peru, Brunei, Malaysia, Singapore and Vietnam, intended to “level the trading playing field” through the elimination of tariffs and other laws that create trade barriers. In its final form, the TPP would impact up to one-third of world trade and 40% of the global gross domestic product. Many who debated the ramifications of the TPP did so in the context of foreign policy interests. Although aligned with foreign policy, a major part of the TPP deals with intellectual property protection, and pharmaceutical drug development. If implemented, the effects of the TPP could greatly diminish public access to affordable medicines, both domestically and internationally. Moreover, the stronghold the TPP places on intellectual property could limit the development and marketing of less expensive options.

Intellectual property can be divided into two categories: industrial property and copyright. Patents, trademarks, and industrial design fall under industrial property. Patent development is a large part of scientists’ work, seen as almost a necessity to incentivizing innovation. Many argue that, without the ability to patent inventions and significant findings, scientists would not be able to generate profits used to sustain research and development; within the pharmaceutical industry, patents are the proverbial bread-and-butter. When in place, patents create a stronghold around the release of new chemical drugs, which prevents competition by generic brands. The standard length of time of a patent for a chemical drug is 20 years, which starts from the time the drug is invented.

Many new medicines under development today fall under the category of ‘biologics’. As the name suggests, biologics are treatments made from biological sources, and are very different from chemical drugs. Created to treat a multitude of diseases, including Ebola and cancer, biological sources include vaccines, anti-toxins, proteins, and monoclonal antibodies. Given their structural complexity compared to traditional drugs, and use of recombinant DNA technology, biologics are more difficult, and costlier to make. Moreover, manufacturers have a greater burden in ensuring product consistency, quality, and purity over time. This is done through certifying that the manufacturing process remains the same over time. Because of this, it is estimated that the price to manufacture biologics cost on average more than 22 times the price of chemical drugs. Current laws state that generic biologic development, known as biosimilars, cannot be approved until 12 years after the branded product has been approved – this is known as an exclusivity period. This was enacted under the Biologics Price Competition and Innovation Act of 2009, by the Food & Drug Administration (FDA).

The challenge with current policies is establishing a period-of-time that balances the need for companies to generate profits and cash flows, which will incentive them to conduct more research and compensate them for the extensive manufacturing processes, with the need to provide greater access through launching generic drugs and biosimilars. The trouble with the proposed policies of the TPP agreement is that they seem to embolden the pharmaceutical companies by introducing changes that would prevent competition from generics and biosimilars for longer periods of time than the current basic terms. The implications of this are far-reaching, as it may lead to a significant increase in the current costs of pharmaceutical drugs and biologics, hindering the health of the patients who rely upon these treatments.

Critics of the current system of patent length and biologic exclusivity periods fear that rather than incentivizing innovation, companies are being rewarded through their ability to charge higher amounts for drugs without the fear of competition on the market. Health policy experts concur, identifying policies such as the Hatch-Waxman Act of 1984 in allowing for the creation of drug monopolies, and “going too far in compensating the pharmaceutical industry at the public’s expense”. A report released in 2009 by the Federal Trade Commission stated that biosimilar development was more difficult to achieve than traditional generic drugs. For example, development requires comparisons to the original biologic, to prove efficacy and equivalence. Biosimilars must share the same mechanism of action, with no clinically significant differences in terms of safety or potency for the approved condition of use. The steps necessary to achieve this are significant, and therefore imposing a 12-year exclusivity period on biologics may be unnecessary. US Congressmen have pushed to compromise, floating an amendment to the TPP that would lower the exclusivity period to 8 years. However, critics and patients who rely upon drug competition to lower market prices, have protested this amendment stating that costs of new drugs and biologics are too high, and 8 years is too long of a length of time to wait for affordable generics and biosimilars to come on to the market.

The impact of decreasing the length of time it takes for biosimilars to come onto the market can be seen with Neupogen, a leukemia drug that was first approved by the FDA in 1991. Delivered via injection, Neupogen costs patients $3,000 for 10 injections. With injections needed daily, this drug could carry a price tag of well over $100,000 per year. It wasn’t until recently, however, that the first biosimilar was approved on the US market. The biosimilar, Zarxio, was approved as a leukemia drug and is priced at more than $1000 less than Neupogen. This pricing has the potential to decrease the yearly costs of this drug from $100,000 with Neupogen to $55,000-$75,000. Further evidence of these financial savings was provided by the Rand Corporation, which predicted a savings of over $44 billion over 10 years with an increased approval of biosimilars, for patients who rely upon these specific cancer treatments.

Internationally, the policies of the TPP also have far reaching effects on the availability and costs of pharmaceuticals. The 12-year exclusivity period would be imposed upon the other countries involved in the TPP, where currently for some, such as Brunei, there is no current exclusivity protection. By imposing the 12-year period, global competition could become restricted. Additionally, the TPP proposes other key patent protections that play a bigger role on the international market. One protection, known as evergreening, allows drug companies to request patent extensions for new uses of old drugs. The immediate effect of this is an extension of monopolies on drug sales for minor reasons. The second protection allows pharmaceutical companies to request patent extensions if it takes “more than 5 years for an application to be granted or rejected.” Advocacy groups fear that the price of drugs would undermine the efforts of health initiatives, such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria. These initiatives rely upon price competition to manage costs, with the availability of cheap generics helping drive costs down.

Although the current administration has ended the USA’s association with the Trans-Pacific Partnership, it is important to note that other countries may try to implement some of the policies, affecting the availability and affordability of drug treatments. To decrease this burden, the US could work to assist in negotiating exceptions for the poorer and smaller countries, to help them meet any challenges they may come up against. Within the US itself, it is important for policies, laws and any future trade agreements to be modified, with more of a focus on the affordability and regulation of drugs and biologics. Imposing price controls may offer a modest benefit, but may not be a long-term solution. A focus on lowering the patent length for new drugs and biologics can be an immediate step. Although the push back from pharmaceutical lobbyists will be substantial, alleviating the financial burden on families afflicted with cancer and diseases should be the focus.

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How to Make a Valuable Postdoctoral Experience: Updating the Model

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By: Aparna Kishor, MD, PhD

       To an outside observer, the scientific enterprise in the US appears to be thriving. The 2016 budget of the National Institutes of Health (NIH) was $31.3 billion. Of this, about 80% was distributed to research projects performed extramurally, pointing to the fact that hundreds of thousands of researchers nationwide, established scientists as well as trainees, benefit from the funding. Although the numbers are somewhat murky, it is likely that over 50% of graduate students and postdoctoral researchers (postdocs) receive some federal funds.

A more granular view of the reality of modern scientific training reveals its true complexity. In The Postdoctoral Experience Revisited, a report on postdoctoral training in the US, the National Academies argue that there are serious issues in the way we train our young scientists today, including those having to do with recognition and compensation, mentorship, and career advising. Fundamentally, although the US has more postdocs than ever before, does this serve the individuals involved?

First some context. For those committed to a career in the biological sciences, the first stage of training is graduate study to acquire technical and field-specific skills, culminating in a PhD. Traditionally, the second is the postdoctoral stage, which provides additional technical experience and preparation for a future career, ideally culminating in a research position. In the US, approximately 65% of those with graduate degrees in the life sciences continue on to a postdoc which is the field with the highest rate of entry. The second highest is in the physical sciences, with only 50%. Although the quotidian experiences of the two may be similar, the graduate and postdoctoral stages are actually quite different, particularly since graduate training tends to have formal requirements and expectations while postdoctoral training, does not. This framework also has distinct benefits for the principle investigators (PIs). A major one is economic: junior scientists are a willing, and in the case of postdocs, highly trained, source of cheap labor (more on this below). On occasion, the work may be done at no cost to the PI if the trainee has funding from another source, although this is becoming proportionally less common.

When the postdoctoral arrangement was established in the early part of the 20th century, the training periods were typically 1-2 year stints in a lab to learn additional skills and consolidate connections in the field. After this, the young researcher would generally transition into an academic position. In the 1970’s, close to 55% of postdocs held tenure or tenure track faculty positions 6 years after completion of their graduate studies. Now, when a postdoc plans for his or her next career move, the situation is not so simple and this has aroused the concern of the National Academies. Partly, the difficulty is due to the number of available academic positions being outstripped by the number of postdocs in the pipeline. Data from 2006 show that only 33% of postdocs had faculty positions 6 years after graduate school and only half of those were tenured or tenure-track. The rest of the explanation lies in the fact that the landscape of the scientific enterprise has evolved.

Most obviously, the demographics of the postdoc community are markedly different from those in the early 20th century resulting in different needs for trainees. As of 2014, women were receiving close to 50% of all life science doctorates awarded in the US. Gender parity at graduation has not carried through to the faculty level (where only approximately 25% of tenured faculty are women). Among the many potential causes for this decline, one is that many women leave the academic track due to the challenges in balancing a career with raising a family. Nonetheless, there are more women at all levels in the sciences than before, indicating that retention may be increased by supporting women during the time that their children are young. Holders of temporary visas comprise another important population, but there are very few concrete data pertaining to them. They obtain close to 25% of all doctorates in the biological sciences, and 80% of those who have jobs after graduation stay in the US. With this, there is significant flux into the system at the postdoc level. As a result, upwards of a third of all biomedical postdocs in the US are foreign nationals primarily from India and China. Since these people have never been counted, the best way to help them meet their goals and the role they play in the US scientific arena are undefined.

Another important change is that postdoctoral training periods have lengthened from 1-2 years to around 4 years. For those who want the training, this timeline extension is believed to be a necessary sacrifice in order to gain entry into the competitive world of academia. Unsurprisingly, the percentage of PIs under 36 has fallen from 18% from 1980 to 3% in 2010. For established investigators, the longer training times are advantageous. Postdoc salaries at research institutions generally amount to less than the combined tuition-plus-stipend package offered to graduate students. After a few years, a postdoc may conduct research at a level equivalent to that of permanent scientific staff but at a fraction of the cost – postdocs pull in anywhere from $40,000 to $49,000 a year, while staff will have full benefits and a salary closer to $80,000 a year. Given this, the challenge is to make a prolonged training period valuable, feasible, and non-exploitative for all who choose it.

Finally, there is growing evidence that a postdoc may not be the right choice for everyone. Most junior scientists feel limited by the now-classic dichotomy between pursuing research in academia and industry. The reality is that many other career options exist, although some are a step or two removed from pure research. These are in areas like consulting, intellectual property, and science policy. Some jobs will provide entry-level incomes greater than a postdoc, and may even lead to career prospects that are more secure than that in research. Entry level salaries for some careers in industry begin at $70,000 and mean salaries in industry can be $40,000 more than that in academia, and the age at first non-academic job is lower than that for academics. Critically, for those wishing to optimize some of these other aspects of their professional advancement, a postdoc may be unnecessary.

Taken together, these developments indicate a need to change the culture surrounding the postdoc. The essence of the National Academies’ recommendation to improve the postdoctoral experience is that the entire scientific community must treat it as a valuable training opportunity instead of basic employment. To this end, the minimum postdoctoral salary should be increased, even beyond the current $47,484.  The improved economics for trainees will have a number of benefits: it will place more value on these individuals, limit the number of postdocs an investigator may hire, perhaps encourage more women to stay in research, and make positions more competitive, lessening their use as a default employment option. Postdocs should also be encouraged to receive individual funds as proof of independence. There is some evidence that postdocs on their own fellowships are more satisfied than those funded by their lab, although it seems likely that people more committed to a career as a researcher are the ones most likely to apply for fellowships. Additionally, those who receive early career grants are more likely to receive independent investigator grants and faculty appointments. Finally, there is an argument for more staff positions as a measure to keep postdoctoral opportunities as dedicated training experiences.

For now, it is important for each researcher to decide whether it is in his or her best interest to embark on the postdoctoral route. Fortunately, career advising is increasingly available to trainees at all levels and the NIH and other groups have issued mentorship guidelines for postdocs. Overall, the entire scientific community must assist in returning value to a postdoc and in meaningful career development for all trainees.

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Written by sciencepolicyforall

March 10, 2017 at 9:56 am

Sickle Cell Disease in Sub-Saharan Africa: Using Science Diplomacy to Promote Global Health

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By: Steven Brooks, PhD

         Science diplomacy is an important conduit through which nations can cooperate with each other to help address issues of common concern. Establishing international collaborations based on scientific research and resource sharing can be a valuable tool to promote advances in global health and to help foster research communities in developing nations. In 2001, Nelson Mandela proposed a model for building and advancing a network of institutions investing in Science, Engineering, and Technology (SET) across sub-Saharan Africa (SSA) to enhance economic diversification, promote job growth, and improve living conditions for peoples across the region. Since then, significant strides have been made by many international organizations, including the World Health Organization, World Bank, and United Nations, to invest in SET institutions and researchers across SSA. Much work is still needed, however, to address the significant global health disparities affecting SSA. According to the United Nations Development Programme, life expectancy in SSA is on average only 46 years. Among the largest contributory factors to this gap is HIV/AIDS, but non-communicable diseases and genetic conditions such as Sickle Cell Disease (SCD) contribute as well. SCD in particular offers a stark geographic contrast in disease outcome: in the United States, childhood mortality (up to age 18) from SCD is below 10%, while in SSA the early childhood mortality rate is 50-90% by age 5. This drastic difference in childhood mortality from SCD raises an important question- why is the difference in mortality rates so large, and what can be done to eliminate it?

SCD represents a significant public health success in the United States. From the early 1970s, average life expectancy of people with SCD has substantially increased from 14 years of age to over 40 years, and childhood mortality rates have continued to decline. These vast improvements in SCD mortality in the US are attributable to improvements in screening and early diagnosis, as well as surveillance for early childhood infections and prophylactic treatments.  Availability of therapies like hydroxyurea and access to blood transfusions have also contributed to reducing childhood mortality, while several currently ongoing clinical trials in the US are testing the use of bone marrow transplantation as a curative procedure for patients with severe complications of SCD. While the best practices for diagnosing and treating SCD are well-established in developed nations, lack of global implementation has meant that these advances in treatment have had very limited effect on reducing mortality and improving quality of life in developing nations. More than 85% of all new SCD cases occur in SSA, with over 240,000 infants with SCD born in SSA annually (compared to less than 2,000 in the US). Many nations in SSA do not have the resources or personnel to implement protocols for screening and diagnosis, and many children are born outside of hospitals. As a result, most children born with SCD in SSA will go undiagnosed, and therefore untreated, leading to devastatingly high rates of early childhood mortality for children with SCD.

The disparity in health outcomes between children born with SCD in developed nations and developing nations in SSA should be addressed through science diplomacy. An opportunity exists for diplomatic cooperation between scientists and health officials from the US and their counterparts in SSA to build infrastructure and train researchers and healthcare professionals to diagnose, treat, and innovate new solutions for SCD. The crucial first steps towards improving outcomes in SCD – parental and newborn screening, early childhood nutrition standards, parental and community education, and anti-bacterial and anti-viral vaccinations and prophylaxis – are achievable through diplomatic efforts and collaboration with governmental health agencies across SSA. Proof of this concept has been demonstrated in Bamako, Mali, with the success of the CRLD (The Center for Sickle Cell Disease Research and Control), a SCD-specific treatment and research center that reflects an effort of the government of Mali, with funding and medical resources provided by the Foundation Pierre Fabre. The CRLD utilizes modern diagnostic techniques to screen for SCD. It also provides immunizations, hospitalizations, and access to preventive medicine, and provides education and outreach to patients and to the larger community. Historically, the infant mortality rate from SCD in Mali was estimated to be 50% by age 5. Since the opening of the CRLD in 2005, only 81 of the over 6,000 patients enrolled at CRLD have died, a mortality rate for this cohort that is comparable to rates in the US and UK. The CRLD also has modern laboratories that conduct research, with over 20 academic papers published from the CRLD so far. The ongoing success of the CRLD is proof that investment in, and collaboration with, governments and medical professionals in Africa can lead to equitable health outcomes in SCD. Similar investments by the US government and the National Institutes of Health (NIH), possibly through intramural research programs, and in cooperation with health-focused private foundations, could lead to similar success stories in communities across SSA.

The NIH supports and facilitates collaborations in global health research through the NIH Fogarty International Center (FIC), which currently sponsors projects in 20 countries across SSA. NIH has also invested intramural resources into collaborations in SSA to combat Malaria. The National Institute of Allergy and Infectious Diseases (NIAID) trains and sponsors investigators to independently conduct research in Mali (NIAID’s Mali ICER (International Centers of Excellence in Research)). Despite its significant history of investment in SSA, the NIH offers almost no international support for research related to SCD. The NIH FIC only currently funds one project related to SCD, preventing pediatric stroke in Nigerian Children. The Division of Intramural Research at the NIH is currently home to robust basic science and clinical-translational research on SCD. Intramural researchers can and should collaborate with clinicians and scientists from SSA who will lead the effort to combat SCD in their home nations. More broadly, the NIH could spearhead an initiative to bring together stakeholders from the US government, health ministries from nations in SSA, and private foundations that support efforts to reduce or eradicate global disease, to begin establishing a network of laboratory and clinical facilities for testing and treatment, as well as to train clinicians and researchers from SSA in diagnostic and research techniques specific to SCD, and to design and disseminate educational resources for increasing communal knowledge regarding SCD across SSA.

In addition to significantly improving SCD mortality and health outcomes in SSA, these efforts of science diplomacy will have substantial benefits in the US as well. The US is home to a sizeable, and growing population of people living with SCD. As life expectancy continues to increase, new challenges will arise for effectively treating serious complications associated with SCD, such as renal disease, stroke, cardiovascular disease, heart failure, cardiomyopathy, and pulmonary hypertension. By collaborating with researchers and healthcare leaders studying large populations of people with SCD in SSA, the NIH will foster innovation and generate new insights about SCD that are uniquely informed by the data and perspectives of African scientists and populations. The NIH and the US government can establish a mutually beneficial program of treatment, education, and research that will enable developing nations to treat their patients with the same methods available in the US. Investing in 21st century methods of diagnosis and treatment, as well as contributing funding, training, and infrastructure to clinicians and researchers in SSA, can strengthen diplomatic relationships between governmental leaders and scientists alike and lead to lasting collaborations that strengthens research and innovation into new treatments for SCD.

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Written by sciencepolicyforall

March 3, 2017 at 9:21 am

Synthetic Biology to Cure Diseases – Promises and Challenges

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By: Emmette Hutchinson, PhD

       Synthetic biology is an interdisciplinary field that utilizes an engineering approach to construct novel biological products, circuits and designer organisms. This field has the potential to revolutionize many aspects of society from chemical production to healthcare. Synthetic biology holds particular promise in the production of biological therapeutics or chemical compounds for the treatment of disease. Increased efficiency and stability of production can be especially beneficial when treating global diseases that are typically associated with poverty. Treatment for these conditions is typically funded by grants from large charitable foundations, sometimes leading to scarcity as funding recedes.

In 2015, 212 million cases of malaria were reported worldwide, predominantly among the poorest countries in the world. While major initiatives such as the President’s Malaria initiative and the Gates foundation focus on various aspects of combating the disease, such as the spread of the parasite and the eradication of the disease, respectively, cost-effective treatments for infections are still needed. The most efficacious treatments for malaria are artemisinin-based combination therapies (ACTs). The 2015 Nobel Prize in Medicine was awarded in part to Youyou Tu for her work demonstrating that artemisinin, an Artemisia annua (sweet wormwood) extract, was an effective anti-malarial treatment. Landmark research published in 2006 demonstrated synthetic production of artemisinic acid, a precursor to artemisin, in yeast. Prior to this study, the only source of artemisinin was tiny hairs found on the surface of the wormwood. The supply of artemisinin has previously been unstable, resulting in dramatic price fluctuations. These price spikes have resulted in both shortages and unattainable cost of treatment. The pharmaceutical giant Sanofi licensed the yeast strain with the hope of creating a more reliable source of artemisinin. In part, due to market forces pushing down the price of artemisinin (primarily a surge in world-wide Artemisia annua cultivation), Sanofi recently sold both its technology and production facilities to Huvepharma. Despite the potential of synthetic biology to disrupt the pharmaceutical industry, this is an example of how existing production methods can impede adoption of more efficient (and stable) synthetic approaches. An alternative to synthetic production of artemisinin in yeast, termed COSTREL (combinatorial supertransformation of transplastomic recipient lines), re-creates the enzymatic pathway necessary to produce artemisinin in tobacco. Although not as efficient as synthetic production of the chemical in yeast, this route offers a significant per-acre boost in artemisinin production over the native source and a potentially more open market to supply drug manufacturers.

Similar to malaria, snake bites predominantly affect impoverished regions of the world. This makes the use of life-saving anti-venoms particularly burdensome as they are both expensive and difficult to produce. The World Health Organization estimates that up to 2.5 million cases of envenoming occur each year, resulting in death, amputations and permanent disabilities. Antivenoms are typically produced using plasma from hyperimmune animals, an often expensive and time-consuming process. In some cases, the profit margins are considered too low to continue producing effective antivenoms such as FAV-Afrique, a polyvalent antivenom effective against 10 species of sub-Saharan snakes. Two recent approaches utilizing synthetic antibody fragments have shown promising effects for protection against specific snake venoms. In a screen for antibody fragments to snake venom, Prado and colleagues found two fragments that protected mice against muscle damage from Bothrops jararacussu and Bothrops brazili venom. Ramos and colleagues designed two synthetic DNA sequences encoding components of coral snake (Micrurus corallinus) venom. Serum obtained from animals immunized with these DNA sequences resulted in 60% survival of animals given a lethal dose of coral snake venom. This second approach eliminates the need for difficult-to-obtain venom when seeking to generate hyperimmune animals as anti-venom producers. It is possible that these or similar synthetic biology approaches could be utilized to produce FAV-Afrique or other polyvalent antivenoms in a faster, more cost-effective manner than hyperimmune animals.

While the possibility of artemisinic acid-producing yeast, high artemisinin-yielding tobacco, and more efficient sources of anti-venom are compelling, regulatory challenges and ethical dilemmas are abundant in the burgeoning field of synthetic biology. Both the US and the EU have recently held surveys and drafted opinions concerning the ethics and risks of synthetic biology. One potential issue with the use of synthetic biology approaches to industrial scale production of chemicals or recombinant proteins is the potential for uncontained spread of the recombinant organism or uncontrolled transfer of the modified genetic material. Another concern centers around the impact of synthetic biology on existing biological diversity. There are also concerns regarding the proliferation of synthetic biology capabilities and biosecurity. At the moment, the United States is in middle of an epidemic of opioid addiction. Synthesis of more complex chemicals in yeast also opens up issues with substance control. A research group has already demonstrated the ability to synthesize heroin in yeast, cheaply and effectively in much the same manner as one might brew beer, raising the possibility that new, designer substances of abuse could be produced in a similar manner. Approaches to the issue of biocontainment have varied, but as the control of synthetic transcriptional circuits becomes robust, more efficacious approaches to biocontainment can be developed. One recent approach to this problem implemented a two-part genetic version of a Dead Man’s Switch into E. coli, which will kill the synthetic organism when certain conditions are not met. As a standard operating procedure, this system would go a long way toward addressing containment of engineered organisms.

The engineering of novel biologicals, re-purposing of existing or development of new transcriptional circuits and entirely new organisms holds immense promise for all aspects of society. These technologies will likely impact the treatment of diseases typically associated with poverty initially, as the increased efficiency of production will lead to stability in price and decreased scarcity of therapeutics. Once concerns of containment and potential effects on existing ecosystems are sufficiently addressed, the broad application of these technologies becomes more reasonable. As the methodologies enabling the creation of designer organisms and novel biologicals improves, the market forces that impede adoption of more efficient synthetic sources of therapeutics may also have less of an impact.

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February 23, 2017 at 4:33 pm

Genetically Modified Animal Vectors to Combat Disease

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By: Sarah L Hawes, PhD

Mosquito larvae: ©ProjectManhattan via Wikimedia Commons

Diseases transmitted through contact with an animal carrier, or “vector,” cause over one million deaths annually, many of these in children under the age of five. More numerous, non-fatal cases incur a variety of symptoms ranging from fevers to lesions to lasting organ damage. Vector-borne disease is most commonly contracted from the bite of an infected arthropod, such as a tick or mosquito. Mosquito-borne Zika made recent, regular headlines following a 2015-2016 surge in birth defects among infants born to women bitten during pregnancy. Other big names in vector-borne disease include Malaria, Dengue, Chagas disease, Leishmaniasis, Rocky Mountain spotted fever and Lyme.

Vaccines do not exist for many of these diseases, and the Centers for Disease Control (CDC) Division of Vector-Borne Diseases focuses on “prevention and control strategies that can reach the targeted disease or vector at multiple levels while being mindful of cost-effective delivery that is acceptable to the public, and cognizant of the world’s ecology.” Prevention through reducing human contact with vectors is classically achieved through a combination of physical barriers (i.e. bed nets and clothing), controlling vector habitat near humans (i.e. dumping standing water or mowing tall grass), and reducing vector populations with poisons. For instance, the Presidential Malaria Initiative (PMI), initiated under President Bush in 2005, and expanded under President Obama, reduces vector contact through a complement of educating the public, distributing and encouraging the use of bed nets, and spraying insecticide. Now a 600 million dollar a year program, PMI has been instrumental in preventing several million Malaria-related deaths in the last decade.

But what if a potentially safer, cheaper and more effective solution to reduce human-vector contact exists in the release of Genetically Modified (GM) vector species? Imagine a mosquito engineered to include a new or altered gene to confer disease resistance, sterility, or to otherwise impede disease transmission to humans. Release of GM mosquitos could drastically reduce the need for pesticides, which may be harmful to humans, toxic to off-target species, and have led to pesticide-resistance in heavily-sprayed areas. Health and efficacy aside, it is impossible to overturn or poison every leaf cupping rainwater where mosquitos breed. GM mosquitos could reach and “treat” the same pockets of water as their non-GM counterparts. However, an insect designed to pass on disease resistance to future generations would mean persistence of genetic modifications in the wild, which is worrisome given the possibility of unintended direct effects or further mutation. An elegant alternative is the release of GM vector animals producing non-viable offspring – and this is exactly what biotech company Oxitec has done with mosquitos.

Oxitec’s OX513A mosquitos express a gene that interferes with critical cellular functions in the mosquitos, but this gene is suppressed in captivity by administering the antibiotic tetracycline in the mosquitos’ diet. Release of thousands of non-biting OX513A males into the wild results in a local generation of larvae which, in the absence of tetracycline, die before reaching adulthood. Release of OX513A has proven successful at controlling mosquito populations in several countries since 2009, rapidly reducing local numbers by roughly 90%. Oxitec’s OX513A line may indeed be a safe and effective tool. But who is charged with making this call for OX513A and, moreover for future variations in GM vector release?

Policy governing use of genetically modified organisms must keep pace with globally available biotechnology. Regulatory procedures for the use of GM vector release are determined by country, and there is a high degree of international policy alignment. The Cartagena Protocol on Biosafety is a treaty involving 170 nations currently (the US not included) that governs transport of “living modified organisms resulting from modern biotechnology” with potential to impact environmental or human health. The World Health Organization (WHO) and the Foundation for the National Institutes of Health (FNIH) published the 2014 guidelines for evaluating safety and efficacy of GM mosquitos.

Within the US, the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology was published this January in response to a solicitation by the Executive Office of the President for a cohesive report from the Food and Drug Administration (FDA), Environmental Protection Agency (EPA), and US Department of Agriculture (USDA). Separately, biotech industry has been given fresh guidance on whether to seek FDA or EPA approval (in brief):  if your GM product is designed to reduce disease load or spread, including vector population reduction, it requires New Animal Drug approval by FDA; if it is designed to reduce pest population but is un-related to disease, it requires Pesticide Product approval by EPA under the Federal Insecticide, Fungicide, and Rodenticide Act.

Thus, for a biotech company to release GM mosquitos in the US with the intent of curbing the spread of mosquito-borne disease, they must first gain FDA approval. Oxitec gained federal approval to release OX513A in a Florida suburb in August 2015 because of FDA’s “final environmental assessment (EA) and finding of no significant impact (FONSI).” These FDA assessments determined that the Florida ecosystem would not be harmed by eliminating the targeted, invasive Aedes aegypti mosquito. In addition, they affirmed that no method exists for the modified gene carried by OX513A to impact humans or other species. Risks were determined to be negligible, and include the accidental release of a few, disease-free OX513A females. For a human bitten by a rare GM female, there is zero risk of transgene transfer. There is no difference in saliva allergens, and therefore the response to a bite, from GM and non-GM mosquitos. In addition, as many as 3% of OX513A offspring manage to survive to adulthood, presumably by spawning in tetracycline-treated water for livestock. These few surviving offspring will not become a long-term problem because their survival is not a heritable loop-hole; it is instead analogous to a lucky few mosquitos avoiding contact with poison.

Solid scientific understanding of the nature of genetic modifications is key to the creation of good policy surrounding the creation and use of GMOs. In an updated draft of Guidelines For Industry 187 (GFI 187), the FDA advises industry seeking New Animal Drug Approval to include a molecular description of the intentional genetic alteration in animals, method for alteration, description of introduction to the animal, and whether the alteration is stable over time/across generations if heritable, and environmental and food safety assessments. Newer genomic DNA editing techniques such as CRISPR offer improved control over the location, and thus, the effect of genetic revisions. In light of this, the FDA is soliciting feedback from the public on the GFI 187 draft until April 19th, 2017, in part to determine whether certain types of genetic alteration in animals might represent no risk to humans or animals, and thus merit reduced federal regulation.

Following federal clearance, the decision on whether to release GM vectors rests with local government. Currently, lack of agreement among Florida voters has delayed the release of OX315A mosquitos. Similar to when GM mosquito release was first proposed in Florida following a 2009-2010 Dengue outbreak, voter concern today hinges on the perception that GM technology is “unproven and unnatural.” This illustrates both a healthy sense of skepticism in our voters, and the critical need to improve scientific education and outreach in stride with biotechnology and policy. Until we achieve better public understanding of GM organisms, including how they are created, controlled, and vetted, we may miss out on real opportunities to safely and rapidly advance public health.

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February 16, 2017 at 9:46 am

Containing Emerging and Re-emerging Infections Through Vaccination Strategies

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By: Arielle Glatman Zaretsky, PhD

Source: CDC [Public Domain], via Wikimedia Commons

           Throughout history, humans have sought to understand the human body and remedy ailments. Since the realization that disease can be caused by infection and the establishment of Koch’s postulates, designed to demonstrate that a specific microbe causes a disease, humans have sought to identify and “cure” diseases. However, while we have been successful as a species at developing treatments for numerous microbes, viruses, and even parasites, pure cures that prevent future reinfection have remained elusive. Indeed, the only human disease that has been eradicated in the modern era (smallpox) was eliminated through the successful development and application of preventative vaccines, not the implementation of any treatment strategy. Furthermore, the two next most likely candidates for eradication, dracunculiasis (guinea worm disease) and poliomyelitis (polio), are approaching this status through the use of preventative measures, via water filtration and vaccination, respectively. In fact, despite the recent pushback from a scientifically unfounded anti-vaxxers movement, the use of a standardized vaccination regimen has led to clear reductions in disease incidence of numerous childhood ailments in the Americas, including measles, mumps, rubella, and many others. Thus, although the development of antibiotics and other medical interventions have dramatically improved human health, vaccines remain the gold standard of preventative treatment for the potential of disease elimination. By Centers for Disease Control and Prevention [Public domain], via Wikimedia Commons

Recently, there have been numerous outbreaks of emerging or reemerging infectious diseases. From SARS to Ebola to Zika virus, these epidemics have led to significant morbidity and mortality, and have incited global panic. In the modern era of air travel and a global economy, disease can spread quickly across continents, making containment difficult. Additionally, the low incidence of these diseases means that few efforts are exerted to the development of treatments and interventions for them, and when these are attempted, the low incidence further complicates the implementation of clinical trials. For example, though Ebola has been a public health concern since the first outbreak in 1976, no successful Ebola treatment or vaccine existed until the most recent outbreak of 2014-2016. This outbreak resulted in the deaths of more than 11,000 people, spread across more than 4 countries, and motivated the development of several treatments and 2 vaccine candidates, which have now reached human trials. However, these treatments currently remain unlicensed and are still undergoing testing, and were not available at the start or even the height of the outbreak when they were most needed. Instead, diseases that occur primarily in low income populations in developing countries are understudied, for lack of financial incentive. Thus, these pathogens can persist at low levels in populations, particularly in developing countries, creating a high likelihood of eventual outbreak and potential for future epidemics.

This stream of newly emerging diseases and the re-emergence of previously untreatable diseases brings the question of how to address these outbreaks and prevent global pandemics to the forefront for public health policy makers and agencies tasked with controlling infectious disease spread. Indeed, many regulatory bodies have integrated accelerated approval policies that can be implemented in an outbreak to hasten the bench to bedside process. Although the tools to identify new pathogens rapidly during an outbreak have advanced tremendously, the pathway from identification to treatment or prevention remains complicated. Regulatory and bureaucratic delays compound the slow and complicated research processes, and the ability to conduct clinical trials can be hindered by rare exposures to these pathogens. Thus, the World Health Organization (WHO) has compiled a blueprint for the prevention of future epidemics, meant to inspire partnerships in the development of tools, techniques, medications and approaches to reduce the frequency and severity of these disease outbreaks. Through the documentation and public declaration of disease priorities and approaches to promote research and development in these disease areas, WHO has set up a new phase of epidemic prevention through proactive research and strategy.

Recently, this inspired the establishment of the Coalition for Epidemic Preparedness Innovations (CEPI) by a mixed group of public and private funding organizations, including the Bill and Melinda Gates Foundation, inspired by the suggestion that an Ebola vaccine could have prevented the recent outbreak if not for the lack of funding slowing research and development, to begin to create a pipeline for developing solutions to control and contain outbreaks, thereby preventing epidemics. Instead of focusing on developing treatments to ongoing outbreaks, the mission at CEPI is to identify likely candidates for future outbreaks based on known epidemic threats and to lower the barriers for effective vaccine development through assisting with initial dose and safety trials, and providing support through both the research and clinical trials, and the regulatory and industry aspects. If successful, this approach could lead to a stockpile of ready-made vaccines, which could easily be deployed to sites of an outbreak and administered to aid workers to reduce their morality and improve containment. What makes this coalition both unique and exciting is the commitment to orphan vaccines, so called for their lack of financial appeal to the pharmaceutical industry that normally determines the research and development priorities, and the prioritization of vaccine development over treatment or other prophylactic approaches. The advantage of a vaccination strategy is that it prevents disease through one simple treatment, with numerous precedents for adaptation of the vaccine to a form that is permissive of the potential temperature fluctuations and shipping difficulties likely to arise in developing regions. Furthermore, it aids in containment, by preventing infection, and can be quickly administered to large at risk populations.

Thus, while the recent outbreaks have incited fear, there is reason for hope. Indeed, the realization of these vaccination approaches and improved fast tracking of planning and regulatory processes could have long reaching advantages for endemic countries, as well as global health and epidemic prevention.

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Written by sciencepolicyforall

January 26, 2017 at 9:47 am

Biosurveillance: Can We Predict And Prevent Infectious Disease Outbreaks?

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By: Teegan A. Dellibovi-Ragheb, PhD

The increasing frequency and scope of infectious disease outbreaks in recent years (such as SARS, MERS, Ebola and Zika) highlight the need for effective disease monitoring and response capabilities. The question is, can we implement programs to detect and prevent outbreaks before they occur, or will we always be reacting to existing outbreaks, trying to control the spread of disease and mitigate the harm to people and animals?

In some cases, the science suggests that we can predict the nature of the public health threat. For instance, scientists at the University of North Carolina at Chapel Hill identified a SARS-like virus, SHC014-CoV, that is currently circulating in Chinese horseshoe bat populations. This virus is highly pathogenic, does not respond to SARS-based therapies, and can infect human cells without the need for adaptive mutations. Furthermore, there are thought to be thousands of related coronaviruses in bat populations, some of which could emerge as human pathogens. These findings suggest that circulating SARS-like viruses have the potential to cause another global pandemic, and resources need to be dedicated to surveillance and the development of more effective therapeutics.

What is biosurveillance?

In 2012 President Obama released the first-ever National Strategy for Biosurveillance, whose purpose is to better integrate the many disparate governmental programs and non-governmental organizations that collect and monitor public health data. The Strategy defines biosurveillance as “the process of gathering, integrating, interpreting, and communicating essential information related to ‘all-hazards’ threats or disease activity affecting human, animal, or plant health to achieve early detection and warning, contribute to overall situational awareness of the health aspects of an incident, and to enable better decision making at all levels”. The “threats” described by the Strategy include emerging infectious diseases, pandemics, agricultural and food-borne illnesses, as well as the deliberate use of chemical, biological, radiological and nuclear (CBRN) weapons.

The overall goal of the Strategy is “to achieve a well-integrated national biosurveillance enterprise that saves lives by providing essential information for better decision making at all levels”. This goal is broken down into four core functions: (1) scan and discern the environment; (2) identify and integrate essential information; (3) inform and alert decision makers; and (4) forecast and advise potential impacts.

How are these programs implemented?

A number of programs were launched in response to President Obama’s Strategy. For instance, USAID’s Emerging Pandemic Threats (EPT) program created four complementary projects (Predict, Prevent, Identify, and Respond) which together aim to combat zoonotic outbreaks in 20 developing countries in Africa, Asia and Latin America that are hotspots of viral evolution and spread. Predict focuses on monitoring the wildlife-human interface to discover new and reemerging zoonotic diseases. The Prevent project aims to mitigate risk behavior associated with animal-to-human disease transmission. Identify works to strengthen laboratory diagnostic capabilities, and Respond focuses on preparing the public health workforce for an effective outbreak response.

There are many other agencies besides USAID and the State Department that participate in biosurveillance and biosecurity, including the Department of Health and Human Services (through the Biomedical Advanced Research and Development Authority). The Department of Defense and the Department of Homeland Security both have biosecurity programs as well (the Defense Threat Reduction Agency and the National Biodefense Analysis And Countermeasures Center, respectively). These focus more on protecting the health of armed forces and combatting deliberate acts of terror, however there is still a lot of overlap with emerging infectious diseases and global health. A comprehensive disaster preparedness strategy requires coordination between agencies that may not be used to working together, and who have very different structures and missions.

What are the challenges?

Global disease surveillance is a critical aspect of our biosecurity, due to accelerated population growth and migration, and worldwide movement of goods and food supplies. Political instability, cultural differences and lack of infrastructure in developing countries all present obstacles to effective global biosurveillance. These are complex issues, but are critically important to address, as rural populations in low- and middle-income countries can become hotspots of infectious disease outbreaks. This is in part due to the lack of sanitation and clean water, and the close contact with both domestic and wild animals.

Another challenge is determining the most effective metrics with which to monitor public health data. Often by the time a new pathogen has been positively identified and robust diagnostic measures implemented, a disease outbreak is well under way. In some cases, the actions of health workers can make the situation worse, such as in the tragic mishandling of the 2010 cholera outbreak in Haiti by the United Nations. One approach that has been shown to be effective for early detection is the use of syndromic surveillance systems, such as aggregating data from emergency room visits or the sale of over-the-counter medication. When combined with advanced computing techniques and adaptive machine learning methods this provides a powerful tool for the collection and integration of real-time data. This method can alert public health officials much earlier to the existence of a possible outbreak.

Scientific research on high-consequence pathogens is a key aspect of an effective biosecurity program. This is how we develop new diagnostic and therapeutic capabilities, as well as understand how pathogens spread and evolve. However, laboratories can also be the initial source of an infection, such as the laboratory-acquired tularemia outbreak, and research with the most dangerous pathogens (Select Agent Research) must be carefully monitored and regulated. It has been an ongoing challenge to balance the regulation of Select Agents with the critical need to enhance our scientific understanding of these pathogens. Of particular concern are gain-of-function studies, or Dual Use Research of Concern (DURC). From a scientific standpoint, these studies are vital to understanding pathogen evolution, which in turn helps us to predict the course of an outbreak and develop broad-spectrum therapeutics. However this also poses a security risk, since it means scientists are deliberately increasing the virulence of a given pathogen, such as the experimental adaptation of H5N1 avian influenza to mammalian transmission, which could pose a significant public health threat if deliberately misused.

How well are we doing?

The International Security Advisory Board, a committee established to provide independent analysis to the State Department on matters related to national and international security, published a report in May of 2016 on overseas disease outbreaks. They make a number of recommendations, including: (1) better integration of public health measures with foreign policy operations; (2) working with non-governmental organizations and international partners to increase preparedness planning and exercises; (3) increase financial support and reform structural issues at the World Health Organization to ensure effective communication during crises; (4) bolster lines of communication and data sharing across the federal government, in part through the establishment of interagency working groups; and (5) strengthening public health programs at the State Department and integrating public health experts into regional offices, foreign embassies and Washington for effective decision making at all levels.

The RAND Corporation, an independent think tank, conducted a review of the Department of Defense biosurveillance programs. They found that “more near-real-time analysis and better internal and external integration could enhance its performance and value”. They also found funding to be insufficient, and lacking a unified funding system. Improvements were needed in prioritizing the most critical programs, streamlining organization and governance, and increasing staff and facility resources.

RAND researchers also published an article assessing the nation’s health security research. They found that federal support is “heavily weighted toward preparing for bioterrorism and other biological threats, providing significantly less funding for challenges such as monster storms or attacks with conventional bombs”. In a study spanning seven non-defense agencies, including the National Institutes of Health (NIH) and the Centers for Disease Control (CDC), they found that fewer than 10% of federally funded projects address natural disasters. This could have broad consequences, especially considering that natural disasters such as earthquakes, hurricanes or tornadoes can create an environment for infectious diseases to take hold in a population. More work needs to be done to integrate biosurveillance and biosecurity programs across different agencies and allocate resources in a way that reflects the priorities laid out by the administration.

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Written by sciencepolicyforall

January 13, 2017 at 10:00 am