Archive for March 2017
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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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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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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