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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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Science Policy Around the Web – February 17, 2017

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By: Thaddeus Davenport, PhD

Source: pixabay

CRISPR

Decision in the CRISPR-Cas9 Patent Dispute

This week, Heidi Wedford from Nature News reported that the United States Patent and Trademark Office (USPTO) made a decision on the disputed patents for the gene editing technology known as CRISPR-Cas9 in favor of the Broad Institute of MIT and Harvard. The CRISPR-Cas9 system has been widely publicized, and this publicity is arguably not out of proportion with the potential of this technology to simplify and accelerate the manipulation of DNA of both microbial (prokaryotic) and higher order (eukaryotic) cells for research and therapy. A simplified, programmable version of CRISPR-Cas9 for use in gene editing was initially described by Charpentier and Doudna, and it was rapidly translated for use in eukaryotic cells by Zhang and colleagues at the Broad Institute in parallel with Doudna, Charpentier, and others.

The USPTO decision follows a dramatic and ongoing dispute over whether the patent application submitted by the University of California on behalf of Doudna and Charpentier – which was submitted before that of the Broad Institute, and described the technology in broad terms as a method of cutting desired DNA sequences – was sufficient to protect the CRISPR-Cas9 intellectual property when the Broad Institute later filed a fast-tracked patent application describing the use of CRISPR-Cas9 for use in eukaryotic cells. Because the Broad Institute’s application was expedited, it was approved before the University of California’s application. In January of 2016, the University of California filed for an ‘interference’ proceeding, with the goal of demonstrating to the USPTO that Doudna and colleagues were the first to invent CRISPR-Cas9, and that the patent application from the Broad Institute was an ‘ordinary’ extension of the technology described in the University of California application.

On February 15th of this year, the USPTO ruled that the technology described in the Broad Institute’s application was distinct from that of the University of California’s. The importance of this decision is that the patents granted to the Broad Institute for the use of CRISPR-Cas9 in mammalian cells will be upheld for now. It also creates some complexity for companies seeking to license CRISPR-Cas9 technology. Because of the overlapping content of the CRISPR-Cas9 patents held by the University of California and the Broad Institute, it is possible that companies may need to license the technology from both institutions. The University of California may still appeal the USPTO’s decision, but this is a significant victory for the Broad Institute for the time being. For many scientists, this dispute is a dramatic introduction to the inner workings of the patent application process. We would do well to familiarize ourselves with this system and ensure that it works effectively to accurately reward the discoveries of our fellow scientists and to facilitate the transfer of technology to those who need it most, without imposing undue economic burden on companies and consumers. (Heidi Wedford, Nature News)

Scientific Publishing

Open Access to Gates Foundation Funded Research

Also this week, Dalmeet Singh Chawla reported for ScienceInsider that the Bill and Melinda Gates Foundation had reached an agreement with the American Association for the Advancement of Science (AAAS) that will allow researchers funded by the Gates Foundation to publish their research in the AAAS journals Science, Science Translational Medicine, Science Signaling, Science Immunology, and Science Robotics. This agreement follows an announcement in January in which the Gates Foundation decided that research funded by the foundation would no longer be allowed to be published in subscription journals including Nature, Science, and New England Journal of Medicine, among others, because these journals do not meet the open access requirements stipulated by the new Gates open-access policies. The new Gates Foundation policy requires its grant recipients to publish in free, open-access journals and to make data freely available immediately after publication for both commercial and non-commercial uses. A similar policy is being considered by the nascent Chan Zuckerberg Initiative.

In the agreement with AAAS, the Gates Foundation will pay the association $100,000 in order to make Gates-funded published content immediately freely available online. Convincing a journal as prominent as Science to make some of its content open-access is a step in the right direction, but it is perhaps more important as a symbol of a changing attitude toward publishing companies. Michael Eisen, co-founder of the Public Library of Science (PLoS) open-access journals, was interviewed for the ScienceInsider article and noted, “[t]he future is with immediate publication and post-publication peer review, and the sooner we get there the better.” This sentiment seems to be increasingly shared by researchers frustrated with the hegemony of the top-tier journals, their power over researchers’ careers, and the constraints that subscription-based journals impose on the spread of new information. Funding agencies including the Gates Foundation, Howard Hughes Medical Institute, and the National Institutes of Health are in a unique position to be able to dictate where the research they fund may be published. A collective decision by these agencies to push the publishing market towards an improved distribution of knowledge – through open-access publishing and post-publication peer review – and away from the historical and totally imagined importance of validation through high-tier journal publication would enrich the scientific ecosystem and accelerate innovation. In this regard, the efforts by the Gates Foundation are laudable and should be extended further. (Dalmeet Singh Chawla, ScienceInsider)

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Written by sciencepolicyforall

February 17, 2017 at 12:44 pm

Science Policy Around the Web – August 26, 2016

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By: Leopold Kong, PhD

Adipose Tissue  Source: Wikipedia Commons, by Blausen.com staff, “Blausen Gallery 2014“.

Health Policy

Is there such a thing as ‘fat but fit’?

Nearly 70% of American adults are overweight or obese, raising their risk for health problems such as heart disease, diabetes, and high blood pressure. However, about a third of obese individuals appear to have healthy levels of blood sugar and blood pressure. Whether these ‘fat but fit’ individuals are actually “fit” has been controversial. A recent study published in Cell Reports has sought to dissect differences in the fat cells of the ‘unfit’ obese versus the ‘fit’ obese using tools that probe the patterns of genes being turned on or off. Fat from non-overweight people were also examined in the study. Interestingly, fat of non-overweight individuals and obese individuals differed in over 200 genes, regardless of ‘fitness’. However, the fat of ‘fit’ versus ‘unfit’ obese individuals only differed in two genes. Dr. Mikael Rydén, the lead author of the study commented: “We think that adds fuel to the debate. It would imply that you are not protected from bad outcomes if you are a so-called fit and fat person.” The study also highlights the complexity of fat’s influence on health, and raises the possibility of ‘fat’ biopsies. For example, fat from normal weight individuals following an unhealthy lifestyle may have marked differences that are diagnostic of future obesity. With the rising cost of treating chronic diseases associated with being overweight, further studies are warranted. (Lindzi Wessel, Stat News)

Biomedical Research

Half of biomedical research studies don’t stand up to scrutiny

Reproducible results are at the heart of what makes science ‘science’. However, a large proportion of published biomedical research appears to be irreproducible. A shocking study by scientists at the biotechnology firm Amgen aiming to reproduce 53 “landmark” studies showed that only 6 them could be confirmed. The stakes are even higher when it comes to pre-clinical cancer research. In fact, they are $30 billion higher, according to a recent study, suggesting that only 50% of findings can be reproduced. Primary sources of irreproducibility can be traced to (1) poor study design, (2) instability and scarcity of biological reagents and reference materials, (3) unclear laboratory protocols, and (4) poor data analysis and reporting. A major stumbling block may be the present culture of science, which does not reward publishing replication studies, or negative results. Higher impact journals generally prioritize work that demonstrates something new and potentially groundbreaking or controversial. When winning grant money and academic posts hinges on impact factor, reproducibility suffers. However, with such high potential for wasting substantial funds on medically significant areas, radical changes in science policy towards publishing, peer review and science education is urgently needed. The recent reproducibility initiative aiming “to identify and reward high quality reproducible research via independent validation” may be a step in the right direction. However, a paradigm shift in scientists’ attitudes towards what constitutes important research might be necessary. (Ivan Orannsky, The Conversation)

Biotechnology

In CRISPR fight, co-inventor says Broad Institute misled patent office

The intellectual property dispute over the multibillion-dollar CRISPR gene editing technology has grown increasingly heated in the last months. With the FDA giving the go-ahead for the first U.S. clinical trial using CRISPR and with China beginning a clinical trial this month using this technology, the tension is high. On one side of the dispute is University of California’s Jennifer Doudna whose initial work established the gene-editing technology in a test tube. On the other side is Broad Institute’s Feng Zhang, who within one year made the technology work in cells and organisms, and therefore broadly applicable for biotechnology. Was Zhang’s contribution a substantial enough advance to warrant its own patents? Was Doudna’s work too theoretical and basic? This week, a potentially damning email that emerged from the legal filings of the dispute was made public. The email is from a former graduate student of Zhang’s, Shuailiang Lin, to Doudna. In addition to asking for a job, Lin wrote that Zhang was unable to make the technology work until the 2012 Doudna publication revealed the key conceptual advances. Lin adds: “I think a revolutionary technology like this […] should not be mis-patented. We did not work it out before seeing your paper, it’s really a pity. But I think we should be responsible for the truth. That’s science.” A spokesperson for the Broad Institute, Lee McGuire, suggested that Lin’s claims are false, and pointed out that Lin was in a rush to renew his visa, and had sent his explosive email to Doudna after being rejected for a new post at the Broad Institute. With CRISPR technology promising to change the face of biotechnology, the drama over its intellectual property continues to escalate. (Antonio Regalado, MIT Technology Review)

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Written by sciencepolicyforall

August 26, 2016 at 9:00 am

Science Policy Around the Web – March 11, 2016

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By: Sophia Jeon, Ph.D.

Photo source: pixabay.com

Patent law and Intellectual Property

Accusations of errors and deception fly in CRISPR patent fight

Clustered regularly-interspaced short palindromic repeats, better known as CRISPR, is getting a lot of attention as a promising molecular engineering technique that can easily edit genes in laboratories and potentially, for therapeutic uses. Last year, Chinese researchers successfully used the technique in human embryos, raising serious ethical concerns. Perhaps designing your own pets or human babies won’t happen in the immediate future but before CRISPR can even be considered for any commercial use, two research teams at UC Berkeley and at the Broad Institute will have to settle the issue of who gets to benefit financially from its use.

In May 2012, a team led by UC Berkeley’s Jennifer Doudna submitted a patent application for CRISPR-Cas9 technology. Several months later in December 2012, Feng Zhang’s research team at the Broad Institute also initiated the process to file for a patent but ended up getting the patent before Berkeley team since they used the expedited review program. The Berkeley team requested a patent interference, which will determine who actually invented the technology first. However, the issue becomes a bit more complicated by the fact that in March 2013, the U.S. patent law was switched to a system in which whoever files first gets the patent from a system that awarded patent to whoever invented first.

So how does one go about proving that someone invented or thought of something first, especially in this age of open access journals and public data sharing? The investigation process could be messy and could take months, or even years. However, both sides seem to have a number of strategies to weaken each other’s arguments, revealing mistakes in the application process and pointing fingers at insufficient data or misrepresented information in the application. Patent fights like this aren’t too rare with biotechnologies that could be used commercially (e.g. the recent lawsuit surrounding DNA sequencing technique between Oxford Nanopore Technologies and Illumina, Inc.) but it is interesting to see such a huge legal dispute between researchers from academia. (Kelly Servick, ScienceInsider)

Abortion law and Social Science

The Return of the D.I.Y. Abortion

In the recent years, abortion clinics have been vanishing from certain states (e.g. Texas, Mississippi, Missouri, North Dakota, South Dakota, Wyoming, Florida etc.) at a record pace. Planned Parenthood facilities are many of those clinics and these closures are partially due to passage of the bill to defund Planned Parenthood and other abortion restrictions in those States. However, the more important question is whether these restriction laws have actually result in lower abortion rates. Social scientists and health experts say there are multiple factors to consider. Some argue that abortion rates were going down even before clinic closings accelerated in the first place, due to increasing acceptance of single motherhood, the recession, and more effective birth control use.

How does law affect public health or more specifically, personal decisions regarding women’s bodies? Does limited access to abortion clinics make women turn to alternative methods such as self-induced abortion? It turns out that Google searches may provide some insight. Because there aren’t large enough surveys to track behavior in different states and also because surveys often don’t tell the real story (since people can lie), Seth Stephens-Davidowitz did an interesting study using Google searches to find correlation between the number of abortion clinics and interest in self-induced abortion. Sadly, the search terms he found related to self-induced abortion methods indicated that women might be driven to risky methods such as purchasing abortion pills online, punching one’s stomach, bleaching one’s uterus, or abortion using a coat hanger.

A previous study found that a vast majority of women would be willing to travel to other states with legal abortion if needed. However, underage girls or low-income women with unwanted pregnancy could be googling for and trying alternative abortion methods that could lead to adverse health outcomes. This June, the Supreme Court is expected to make a decision about a Texas law that restricts access to abortion clinics and whether or not it places an “undue burden” on women’s rights to abortion. The justices should make decisions based on hard evidence and well-balanced research. The study using Google search methods may be limited in certain ways as it is difficult to find out about their health outcomes or whether they actually succeeded in abortions, but it is one way to look at human behavior and how law could affect public health. (Seth Stephens-Davidowitz, New York Times)

Clinical Trials and Data Sharing

STAT investigation sparked improved reporting of study results, NIH says

The results of clinical trials are required by a federal law to be publicly reported on clinicaltrials.gov at the end of the trial. The goal is to promote transparency in any clinical research and to share data among the research community and physicians, as well as enhance patient empowerment by returning the results to the participants. However, according to a 2014 analysis published in JAMA, “a recent analysis of 400 clinical studies revealed that 30% had not shared results through publication or through results reporting in ClinicalTrials.gov within 4 years of completion.”

Last December, STAT also did a quite extensive investigation looking at clinical trials led by companies, universities, hospitals and even NIH-led trials to determine who actually reported their findings and how long after study completion. Many top research institutions failed to report on time and the federal government has not imposed fines on a single trial, which was “very troubling” according to the NIH director, Francis Collins said. Possible reasons for the delay in reporting are that the investigators continue to analyze data which can take a long time even after the trial has ended, that investigators wait until they publish their findings in a peer-reviewed journal and that in some cases drug companies intentionally want to hide negative results. Whatever the reason is, there should be consequences for withholding data that could be useful for doctors and patients.

The STAT investigation has named names and it seems to have worked. The data released by NIH showed that between December 2015 and January 2016, there was a 25 percent rise in new submissions and a 6 percent increase in reporting of corrected results for trial findings that had previously been submitted. Deborah Zarin, director of Clinicaltrials.gov, said the agency’s own outreach to researchers and training efforts are paying off as well. NIH is currently working on developing a new policy to clarify, expand, and enforce the requirements for clinical trial registration and results submission. (Charles Piller, STATnews)

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Written by sciencepolicyforall

March 11, 2016 at 9:00 am