Biotechnology

Xenotransplantation: Ethics and Public Policy Need To Catch up to the Science

March 5, 2022
Bioethics, Biotechnology, Discrimination, Ethics, FDA, Health, Medical Devices, New Technology, Personalized Medicine

Claire Colby, MJLST Staffer

In early January, surgeons at the University of Maryland Medical Center made history by successfully transplanting a genetically altered pig heart to a human recipient, David Bennett.  The achievement represents a major milestone in transplantation. The demand for transplantable organs far outpaces the supply, and xenotransplantation–the implantation of non-human tissue into human recipients–could help bridge this gap. In the U.S. alone, more than 106,000 people are on the waiting list for transplants. Legal and ethical questions remain open about the appropriateness of implementing xenotransplants on a large scale. 

The FDA approved the January transplant through an emergency authorization compassionate use pathway because Bennett likely would have died without this intervention. Larger clinical trials will be needed to generate enough data to show that xenotransplants are safe and effective. The FDA will require these trials to show xenotransplantations are non-inferior to human organ transplants. IRB requirements bar interventions where risk outweighs benefits for patients, but accurately predicting and measuring risk is difficult. 

If xenotransplantation becomes standard clinical practice, animal rights proponents may balk at the idea of raising pigs for organs. Far before that point, pre-clinical trials will make heavy use of animal models. Institutional Animal Care and Use Committees (IACUCs) which oversee animal research in universities and medical entities apply a “much lower ethical standard” for animals than human research subjects. Bioethicists apply a “3R” framework for animal subjects research that stresses replacing animal models, reducing animal testing, and refining their use. Because of the inherent nature of xenotransplantation, applying this framework may be near impossible. Ongoing discussions are needed with relevant stakeholders.  

If both human and animal organs are approved for widespread transplant, but human organs prove superior, new allocation policies are needed to determine who gets what. Organ allocation policy is currently dictated by the Organ Procurement and Transplantation Network (OPTN). As it stands, organ transplantation shows inequality across racial groups and financial status. New allocation policies for organs must not reinforce or worsen these disparities. 

Like all medical interventions, patients must be able to provide informed consent for xenotransplantation. The recipient of the altered pig heart had previously been deemed ineligible for a human heart transplant because his heart failure was poorly managed. Reserving experimental interventions, like xenotransplantations, for the sickest patients raises serious ethical concerns. Are these desperate patients truly able to give meaningful consent? If xenotransplantation becomes a common practice, the traditional model of institutional review boards may need updating. Currently, individual institutions maintain their own IRBs. Xenotransplantation of altered animal organs may involve several sites: procurement of the organ, genetic editing, and transplantation may all take place in different locations. A central IRB for xenotransplantation could standardize and streamline this process. 

In all, xenotransplantation represents an exciting new frontier in transplant medicine. Responsibly implementing this innovation will require foresight and parallel innovation in ethics and public policy. 

You Wouldn’t 3D Print Tylenol, Would You?

October 12, 2021
3-D Printing, Administrative Law, Bioethics, Biotechnology, FDA, Food and Drug Law, Health, Healthcare, Healthcare Reform, Medical Devices, Personalized Medicine, Pharmaceuticals, Uncategorized

By Mason Medeiros, MJLST Staffer

3D printing has the potential to change the medical field. As improvements are made to 3D printing systems and new uses are allocated, medical device manufacturers are using them to improve products and better provide for consumers. This is commonly seen through consumer use of 3D-printed prosthetic limbs and orthopedic implants. Many researchers are also using 3D printing technology to generate organs for transplant surgeries. By utilizing the technology, manufacturers can lower costs while making products tailored to the needs of the consumer. This concept can also be applied to the creation of drugs. By utilizing 3D printing, drug manufacturers and hospitals can generate medication that is tailored to the individual metabolic needs of the consumer, making the medicine safer and more effective. This potential, however, is limited by FDA regulations.

3D-printed drugs have the potential to make pill and tablet-based drugs safer and more effective for consumers. Currently, when a person picks up their prescription the drug comes in a set dose (for example, Tylenol tablets commonly come in doses of 325 or 500 mg per tablet). Because the pills come in these doses, it limits the amount that can be taken to multiples of these numbers. While this will create a safe and effective response in most people, what if your drug metabolism requires a different dose to create maximum effectiveness?

Drug metabolism is the process where drugs are chemically transformed into a substance that is easier to excrete from the body. This process primarily happens in the kidney and is influenced by various factors such as genetics, age, concurrent medications, and certain health conditions. The rate of drug metabolism can have a major impact on the safety and efficacy of drugs. If drugs are metabolized too slowly it can increase the risk of side effects, but if they are metabolized too quickly the drug will not be as effective. 3D printing the drugs can help minimize these problems by printing drugs with doses that match an individual’s metabolic needs, or by printing drugs in structures that affect the speed that the tablet dissolves. These individualized tablets could be printed at the pharmacy and provided straight to the consumer. However, doing so will force pharmacies and drug companies to deal with additional regulatory hurdles.

Pharmacies that 3D print drugs will be forced to comply with Current Good Manufacturing Procedures (CGMPs) as determined by the FDA. See 21 C.F.R. § 211 (2020). CGMPs are designed to ensure that drugs are manufactured safely to protect the health of consumers. Each pharmacy will need to ensure that the printers’ design conforms to the CGMPs, periodically test samples of the drugs for safety and efficacy, and conform to various other regulations. 21 C.F.R. § 211.65, 211.110 (2020). These additional safety precautions will place a larger strain on pharmacies and potentially harm the other services that they provide.

Additionally, the original drug developers will be financially burdened. When pharmacies 3D print the medication, they will become a new manufacturing location. Additionally, utilizing 3D printing technology will lead to a change in the manufacturing process. These changes will require the original drug developer to update their New Drug Application (NDA) that declared the product as safe and effective for use. Updating the NDA will be a costly process that will further be complicated by the vast number of new manufacturing locations that will be present. Because each pharmacy that decides to 3D print the medicine on-site will be a manufacturer, and because it is unlikely that all pharmacies will adopt 3D printing at the same time, drug developers will constantly need to update their NDA to ensure compliance with FDA regulations. Although these regulatory hurdles seem daunting, the FDA can take steps to mitigate the work needed by the pharmacies and manufacturers.

The FDA should implement a regulatory exception for pharmacies that 3D print drugs. The exemption should allow pharmacies to avoid some CGMPs for manufacturing and allow pharmacies to proceed without being registered as a manufacturer for each drug they are printing. One possibility is to categorize 3D-printed drugs as a type of compounded drug. This will allow pharmacies that 3D print drugs to act under section 503A of the Food Drug & Cosmetic Act. Under this section, the pharmacies would not need to comply with CGMPs or premarket approval requirements. The pharmacies, however, will need to comply with the section 503A requirements such as having the printing be performed by a licensed pharmacist in a state-licensed pharmacy or by a licensed physician, limiting the interstate distribution of the drugs to 5%, only printing from bulk drugs manufactured by FDA licensed establishments and only printing drugs “based on the receipt of a valid prescription for an individualized patient”. Although this solution limits the situations where 3D prints drugs can be made, it will allow the pharmacies to avoid the additional time and cost that would otherwise be required while helping ensure the safety of the drugs.

This solution would be beneficial for the pharmacies wishing to 3D print drugs, but it comes with some drawbacks. One of the main drawbacks is that there is no adverse event reporting requirement under section 503A. This will likely make it harder to hold pharmacies accountable for dangerous mistakes. Another issue is that pharmacies registered as an outsourcing facility under section 503B of the FD&C Act will not be able to avoid conforming to CGMPs unless they withdraw their registration. This issue, however, could be solved by an additional exemption from CGMPs for 3D-printed drugs. Even with these drawbacks, including 3D-printed drugs under the definition of compounded drugs proposes a relatively simple way to ease the burden on pharmacies that wish to utilize this new technology.

3D printing drugs has the opportunity to change the medical drug industry. The 3D-printed drugs can be specialized for the individual needs of the patient, making them safer and more effective for each person. For this to occur, however, the FDA needs to create an exemption for these pharmacies by including 3D-printed drugs under the definition of compounded drugs.

Intellectual Property in Crisis: Does SARS-CoV-2 Warrant Waiving TRIPS?

February 21, 2021
Bioethics, Biotechnology, COVID-19, Food and Drug Law, Health, Healthcare, Intellectual Property, Patents, Regulatory

Daniel Walsh, MJLST Staffer

The SARS-CoV-2 virus (which causes the disease COVID-19) has been a massive challenge to public health causing untold human suffering. Multiple vaccines and biotechnologies have been developed to combat the virus at a record pace, enabled by innovations in biotechnology. These technologies, vaccines in particular, represent the clearest path towards ending the pandemic. Governments have invested heavily in vaccine development. In May 2020 the United States made commitments to purchase, at the time, untested vaccines. These commitments were intended to indemnify the manufacture of vaccines allowing manufacturing to begin before regulatory approval was received from the Food and Drug Administration. The United States was not alone. China and Germany, just to name two, contributed heavily to funding the development of biotechnology in response to the pandemic. It is clear that both private and public institutions contributed heavily to the speed with which biotechnology has been developed in the context of the SARS-CoV-2 pandemic. However, there are criticisms that the public-private partnerships underlying vaccine manufacturing and distribution have been opaque. The contracts between governments and manufacturers are highly secretive, and contain clauses that disadvantage the developing world, for example forbidding the donation of extra vaccine doses.

Advanced biotechnology necessarily implicates intellectual property (IP) protections. Patents are the clearest example of this. Patents protect what is colloquially thought of as inventions or technological innovations. However, other forms of IP also have their place. Computer code, for example, can be subject to copyright protection. A therapy’s brand name might be subject to a trademark. Trade secrets can be used to protect things like clinical trial data needed for regulatory approval. IP involved in the pandemic is not limited to technologies developed directly in response to the emergence of SARS-CoV-2. Moderna, for example, has a variety of patents filed prior to the pandemic that protect its SARS-CoV-2 vaccine. IP necessarily restricts access, however, and in the context of the pandemic this has garnered significant criticism. Critics have argued that IP protections should be suspended or relaxed to expand access to lifesaving biotechnology. The current iteration of this debate is not unique; there is a perennial debate about whether it should be possible to obtain IP which could restrict access to medical therapies. Many nations have exceptions that limit IP rights for things like medical procedures. See, e.g., 35 U.S.C. 287(c).

In response to these concerns the waiver of a variety of IP protections has been proposed at the World Trade Organization (WTO). In October 2020 India and South Africa filed a communication proposing “a waiver from the implementation, application and enforcement of Sections 1, 4, 5, and 7 of Part II of the TRIPS Agreement in relation to prevention, containment or treatment of COVID-19.” The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) sets minimum standards for IP standards, acquisition, and enforcement and creates an intergovernmental dispute resolution process for member states. Charles R. McManis, Intellectual Property and International Mergers and Acquisitions, 66 U. Cin. L. Rev. 1283, 1288 (1998). It is necessary to accede to TRIPS in order to join the WTO, but membership in the WTO has significant benefits, especially for developing nations. “Sections 1, 4, 5, and 7 . . .” relate to the protection of copyrights, industrial designs, patents, and trade secrets respectively. Waiver would permit nation states to provide intellectual property protections “in relation to prevention, containment or treatment of COVID-19” that fall below the minimum standard set by the TRIPs Agreement. At time of writing, 10 nations have cosponsored this proposal.

This proposal has been criticized as unnecessary. There is an argument that patents will not enter effect until after the current crisis is resolved, implying they will have no preclusive effect. However, as previously mentioned, it is a matter of fact that preexisting patents apply to therapies that are being used to treat SARS-CoV-2. Repurposing is common in the field of biotechnology where existing therapies are often repurposed or used as platforms, as is the case with mRNA vaccines. However, it is true that therapies directly developed in response to the pandemic are unlikely to be under patent protection in the near future given lag between filing for and receiving a patent. Others argue that if investors perceive biotech as an area where IP rights are likely to be undermined in the event of an emergency, it will reduce marginal investment in vaccine and biotech therapies. Finally, critics argue that the proposal ignores the existing mechanisms in the TRIPS Agreement that would allow compulsory licensing of therapies that nations feel are unavailable. Supporters of the status quo argue that voluntary licensing agreements can serve the needs of developing nations while preserving the investments in innovation made by larger economies.

The waiver sponsors respond that a wholesale waiver would permit greater flexibility in the face of the crisis, and be a more proportionate response to the scale of the emergency. They also assert that the preexisting compulsory licensing provisions are undermined by lobbying against compulsory licensing by opponents of the waiver, though it is unlikely that this lobbying would cease even if a waiver were passed. The sponsors also argue that the public investment implies that any research products are a public good and should therefore be free to the public.

It is unclear how the current debate on TRIPS will be resolved. The voluntary licensing agreements might end up abrogating the need for a wholesale waiver of IP protections in practice rendering the debate moot. However, the WTO should consider taking up the issue of IP protections in a crisis after the current emergency is over. The current debate is a reflection of a larger underlying disagreement about the terms of the TRIPS Agreement. Further, uncertainty about the status of IP rights in emergencies can dissuade investment in the same way as erosion of IP rights, implying that society may pay the costs of decreased investment without reaping any of the benefits.

 

Orange Book, Purple Book, Complex Products, and Process Patents

December 23, 2019
Biotechnology, Intellectual Property, Patents

Philip E. Alford, Ph.D., MJLST Staffer

Complex Products and Process Claims

The most economically important pharmaceutical innovations of the past decade have centered around biologics and complex non-biologic products. Biologics are a diverse class of therapeutic products, typically produced via biotechnology or obtained from biological sources. Biologics often contain complex mixtures or large, elaborate molecules that are intricately folded into a specific desired conformation. In many respects, we do not yet have the technology to characterize all the functional elements of these products fully, and sometimes it is not possible to make the products synthetically or according to alternative processes. Even minor variations in biologic manufacturing can result in a product having different properties. Since the manufacturing process may be one of the most accurate ways to describe a biologic, patent strategies for biologics typically give extra emphasis around process patents. Indeed, biologic process claims have proven to be a powerful tool, and process patents have been at the core of the first waves of biosimilar litigation.

Non-biologic drugs can also be so complex as to defy characterization and reproduction. Such products are now referred to as complex products or non-biological complex drugs (NBCDs), as well as “nanomedicine” or “synthetic biologics.” Like biologics, many complex products have the challenge that different manufacturing processes can result in the product having divergent properties. Thus, manufacturing aspects are uniquely important to both complex products and biologics. Where the patent system is involved in the regulatory framework, process patents should play a central role in protecting complex products from generic entry. Yet for complex drug products, FDA does not integrate process patents into the generic entry process.

Despite being difficult to truly reproduce, complex products are nonetheless susceptible to market pressure under Hatch-Waxman-type generic entry 21 USC 355(b)(2) and 355(j), i.e., via Food Drug & Cosmetic Act 505(b)(2) and 505(j) applications. The Hatch-Waxman Act, discussed in more detail below, ingeniously incorporated the patent system as a secondary gatekeeper in FDA’s generic drug approval process. The so-called Orange Book is the nexus uniting two separate regulatory regimes. However, FDA has interpreted that the Orange Book and Hatch-Waxman provisions invoke only on the types of patents that were important for determining infringement of traditional, small molecule drugs, namely, drug and therapeutic use claims. The Orange Book expressly excludes process patents. 21 C.F.R. §314.53.

Although product-by-process claims can be permitted, the resulting product must be novel, and product-by-process claims are not interchangeable with process claims. (For example, see, MPEP 2113 and Judge Newman’s dissent in Abbott Labs. v. Sandoz, Inc, suggesting that process claims and product-by-process claims are held to different validity standards.)

Hatch-Waxman as a political bargain.

When Congress passed the Hatch-Waxman Act was passed in 1984, the Act represented a classic political bargain. The hope was to strike a balance between innovation and competition by strengthening the golden years of brand drugs while facilitating subsequent generic entry. Pioneers of approved new drugs were given up to 5 years of data exclusivity during which FDA would not approve a generic of the drug. Additionally, one of the pioneer’s patents could be extended up to 5 additional years to compensate for lost patent term consumed while seeking FDA approval. In turn, the Act provided a new, streamlined process for drug makers to obtain approval of generic drugs.

A key provision of the Act directs the drug pioneer to identify its patents in the Orange Book. The listed patents must (1) claim the new drug, or (2) claim a method of using the drug, in so far as a claim of infringement could reasonably be asserted if another engaged in the manufacture, use, or sale of the drug. 21 U.S.C. §355(b)(1)(G). The Orange Book thus represents an essential part of the Hatch-Waxman political bargain. Process (manufacturing) patents are expressly excluded from the Orange Book, as are patents relating to packaging, metabolites, or intermediates. 21 C.F.R. §314.53.

The Orange Book lists these patents alongside each FDA approved drug. Before obtaining approval of a generic, the generic drug maker must certify to FDA that the patents listed in the Orange Book are expired, invalid, or will not be infringed by its generic. 21 U.S.C. §355(b)(2)(A) and 21 U.S.C. 355(j)(2)(vii). Under 35 U.S.C. § 271(e)(2), such certifications of invalidity or non-infringement constitutes an act of infringement permitting the pioneer to sue the generic drug maker before the generic ever reaches the market. Prompt litigation can trigger a stay on the generic’s approval. In this manner, the Orange Book serves not only as a mechanism for transparency (informing the public of patent and regulatory exclusivities), but also as a mechanism for litigation. The Orange Book has served both causes well.

As blockbuster biologics began to approach the end of the foreseeable patent life, FDA created a compendium of BLA-approved biological products loosely mirroring the Orange Book, but for biologics instead of drugs. Reverently, FDA named this volume the Purple Book. Unlike the Orange Book, the Purple Book has had no reason to list patents because the generic drug provisions of the Hatch–Waxman Act apply only to drug approvals under 21 U.S.C. §355(b) and 21 U.S.C §355(j). The Biologics Price Competition and Innovation Act of 2009 (BPCIA) provides a framework for approving biosimilars and resolving patent disputes. Instead of referring to a book of approvals and patents, the BPCIA invokes a so-called patent dance exchange of patent information. 42 USC § 262 (l). This patent information includes not only composition and use claims, but also process of manufacture claims. Conceptually, the dance was expected to lead the parties to agree on an initial set of patents to litigate and thus control the tempo and scope of litigation. However, the parties soon recognized that dancing is optional. Sandoz Inc. v. Amgen Inc., 137 S. Ct. 1664. Dance or no dance, the parties ultimately litigate their patent disputes, which often center the methods of manufacturing the biologic product.

As new biologics and complex drug products come to market, process claims are likely to be increasingly important.

Possible Legislation to the Orange Book and Purple Book

This year, Congress considered legislation sponsored by members of the House Committee on Energy and Commerce proposing changes to the way the Purple Book and Orange Book function.

The Purple Book Continuity Act of 2019 proposes that the purple book be updated to list patents generated during the ‘patent dance’ of 42 USC § 262 (l), which would include process patents or any other patent likely to be important in an infringement claim. Any such patents listed in the Purple Book would not function as a regulatory gatekeeper for generics since no mechanism yet exists for the Purple Book to do so. Still, from a transparency point-of-view, it seems like a reasonable choice to have the Purple Book act at least as a compendium of relevant patents. The Orange Book Transparency Act of 2019 proposes a requirement to list the drug substance, drug product, and method of use patents, while also requiring removal of any patents that are improperly listed (presumably including process patents absent any change to 21 C.F.R. §314.53). Although the House Committee on Energy and Commerce sponsored both acts, each take differing approaches to process patents. It seems illogical to insert process patents into the Purple Book, while more tightly excluding process patents from the Orange Book at a time when process claims are increasingly more important to modern therapeutics.

Indeed, FDA has expressly focused on the manufacturing process when trying to understand how a generic relates to a reference complex product. For example, FDA explained that a central part of their inquiry was whether the generic is made according to the same process as the original®, a non-biologic complex product, FDA explained that a central part of their inquiry was whether the generic is made according to the same process as the original. See, also, Bell et al., which discusses FDA’s criteria for approving a generic even when there is no physicochemical or biological characterization technique to establish active ingredient sameness. If such an inquiry is part of FDA’s analysis for permitting the sale of a generic drug, then it should be more than enough to justify listing process patents in the orange book.

If Congress revisits either of these matters, it should adjust the code to include process patents in both the Orange Book and the Purple Book. Listing process patents in the Orange Book would serve a public good, namely, that of transparency, but also would notify competitors of the manufacturing space the pioneer drug company intends to protect. Delaying such litigation until after a possible generic approval is messy for all parties involved. As more medications become too complex to manufacture by alternative routes, the importance of process patents in complex biologic and nonbiologic drugs will only increase.

 

Treating Depression with Ketamine? How The Investment Was Made

March 15, 2019
Biotechnology, FDA, Food and Drug Law, Health

Hunter Moss, MJLST Staffer

Depression is a serious mental disorder that afflicts millions of Americans each year. One in three of these individuals struggles to find a treatment method that alleviates their condition, and are aptly said to suffer from treatment-resistant depression. In the most severe cases, treating depression can be a life or death decision—depression is the leading cause of over 41,000 suicides every year. For those dealing with depression, every day is a struggle to persevere and try to regain a sense of normalcy.

A new therapy for treatment-resistant depression was approved by the Food and Drug Administration (FDA) earlier this week, one that could help those that have been unable to find relief elsewhere. The unexpected source of the therapy is esketamine. If the name of this drug sounds familiar, it is because the name is based on, and molecularly similar to, the street drug named ketamine. While originally synthesized in the 1960’s as an anesthetic and first used widely in the Vietnam War, ketamine is now known as a party drug, providing the user with mild hallucinations and a sense of euphoria. Due to its dangerous side-effects and potential for abuse, ketamine was placed on the Schedule III of the United States Controlled Substance Act in August of 1999.

In the early 1990’s, researchers at Yale University first recognized the potential for ketamine to treat the symptoms of depression. Since then, scientists sought to confirm the viability of ketamine as a treatment option for individuals who did not experience relief from other treatment methods. A 2012 study out of Baylor College of Medicine proved just that: 85% of patients with severe depression reported the treatment to be effective. Unlike selective serotonin reuptake inhibitors (SSRIs), which are most commonly prescribed to treat depression and can take weeks to build in a patient’s system before becoming effective, ketamine can provide nearly immediate relief with its full effect being felt in as little as two days.

With the science firmly in place, the next hurdle advocates of ketamine faced was of perception—in the eyes of the FDA and the public alike. Radical clinics began to emerge across the country to provide patients suffering from treatment-resistant depression with a safe, heavily-monitored environment to undergo care. Because ketamine had yet to be recognized as a potential aid for depression by the FDA, clinic physicians would often have to prescribe the drug under the guise of using it as an anesthetic. The “don’t ask, don’t tell” approach to a new treatment for a severe mental disorder created some inevitable quandaries for both doctors and patients, who would be unable to receive insurance coverage for a non-FDA approved treatment program.

While the medical community was well aware of the healing potential of ketamine, pharmaceutical companies were reluctant to make the investment. The average price-tag of a clinical trial for the FDA is $19m. There is certainly a market for the drug with countless Americans suffering from depression. The issue holding pharmaceutical companies back is related to patent law. In order to receive a patent, the proposed invention must be novel—and considering that ketamine has been around for nearly sixty years, that would be an impossible claim to make. Without patent protection, the multi-million dollar investment is bad economics for big pharma, even if the trials could provide relief for millions of Americans.

So why did Janssen Pharmaceuticals, the developer of a treatment method for depression based on ketamine, make the investment and receive FDA approval for its new drug Sprovato? The answer is because Sprovato is esketamine, a sufficiently different molecule from ketamine to be patentable. Certain molecules can be left-handed and have right-handed doppelgangers. While it is beyond the scope of this blog piece (and the ability of its author) to explain the difference between the two, esketamine is the left-handed version of ketamine’s right hand. The deviation between the molecules is a significant enough difference to pass the novelty requirement necessitated by the U.S. Patent and Trademark Office (USPTO). While there is some debate as to whether esketamine is as effective as its counterpart, esketamine passed the FDA’s clinical trials and, for the most part, has been received as a viable alternative to ketamine treatment. This development could help legitimize the countless ketamine clinics that have emerged across the United States over the last few years, yielding a promising new alternative for those struggling with severe depression. At the same time, the story of ketamine raises questions about the roles of several actors in the health care system, specifically pharmaceutical companies, the FDA and the USPTO, in delaying the introduction of life saving medication in order to adhere their respective financial and regulatory requirements.

Happy Mother’s Day to all the Moms!: Law, Science, Technology and Beagles

May 7, 2017
Biotechnology, Drug Policy, Ethics

Angela Fralish, MJLST Guest Blogger

Beagles are well-known as a quintessential family dog because they love humans and listen to their owners (most of the time). What is less known, is that those same traits are the primary reasons they are used in 95% of canine medical experimentation. Although, beagles are not biologically comparable to humans, they are compliant people-pleasers, making them ideal subjects for scientific experiments.

This reality is a hard pill to swallow for animal lovers and scientists alike. To scientists, research beagles are a necessary evil decreasing the pain and suffering of humans. To advocates, beagles are victims of unspeakable cruelty.

One law bridges the divide between these opposing views to help the beagles. The Beagle Freedom Bill, created by the Beagle Freedom Project (BFP), forges a compromise between animal rights lawyers, scientists and medical technologists. The Bill asks that ”tax-payer funded laboratories offer up the “experimentally-spent” dogs and cats for public adoption through rescue organizations.” In other words, once the beagle is no longer used for research, the dog is given a home instead of euthanasia. Minnesota was the first state to sign the Bill into law in 2014, and since then, 5 more states have joined. Currently, 5 additional states are considering adopting this law as well.

In addition to legislative measures, the BFP has found other ways to help research beagles. They have created new technology such as the Cruelty-Cutter app which helps shoppers easily scan products for humane animal testing, and sued the USDA demanding restoration of scrubbed animal records. The Beagle Freedom Project is a leader in animal science law and a great example of how lawyers, scientists and technologists can work together for the greater good of both humans and animals.

Scientists are working to replace this “necessary evil” as well. According to Dr. Teresa Arora’s article Substitute of Animals in Drug Research: An Approach Towards Fulfillment of 4Rs, research methods are being developed that are “superior to using animals to learn about human disease or predict the safety of new drugs [and include] stem cells, microdosing, DNA chips, microfluidics chips, human tissue, new imaging technologies, and post-marketing drug surveillance.” There is even a Center for Alternatives to Animal Testing at John Hopkins University and the NC3R in the UK.

For an employee of medical research looking to carve out meaning in their every day workweek, helping research animals through new collaborative measures is one way to answer the call. As a lawyer, scientists or technologist, you can help develop policy, arbitrate between groups, hold violators accountable, assist in medical technology development, vote for the Beagle Freedom Bill or adopt a research beagle. According to Congressman Earl Blumenauer, “members of Congress are realizing that protecting animals is not just the right thing to do, it’s also developing to become potent politically.” Congress will need help understanding the relationship between animal models and science in order to make improvements. That help will come from people who work in these fields on a daily basis.

The Beagle Freedom Bill highlights the plight of animals languishing in labs and promotes cruelty-free lifestyle choices everyone can make. Now that BFP has opened the door, it is time for all of us to show a little gratitude to the beagles for their sacrifice in advancing medical science such as chemotherapy and insulin. We can do this in our own unique ways, and although we can’t change the world for all beagles, for some beagles, we can change the world.

As Mahatma Ghandi stated, “The greatness of a nation and its moral progress can be judged by the way its animals are treated.” I hope ours is one of progress.

Is there a Reasonable Pot of Gold at the End of the Rainbow?: Legal Ethics, Brain Stimulation and Neuroprosthetics

March 3, 2017
Biotechnology, Ethics, Neuroscience

Angela Fralish, MJLST Invited Blogger

As expert bioethicist Dr. Walter Glannon remarks, “Interventions in the brain raise general ethical questions about weighing the potential benefit of altering neural circuits against the potential harm from neurophysiological and psychological sequelae.” Laws governing human subject research for these interventions mandate that “risks to subjects are reasonable in relation to anticipated benefits.” Modern brain technologies in neuroprosthetics make the harm/benefit analysis challenging because there are many unanswered questions surrounding neuroprosthetic implementation.

So what is a neuroprosthetic? Neuroprosthetic devices use electrode muscle and nerve stimulation to produce muscle contraction and restore motor function. Basically, since the brain controls the body, a device is put on the brain telling it to make the body work. Through neuroprosthetics devices, a person may restore movement by bypassing nervous system damage which allows greater independence in daily living. To someone whose dependence is caused by non-working body parts such as blindness, Parkinson’s or spinal cord paralysis, this technology holds great potential for a higher quality of life.

However, the use of a neuroprosthetic may involve negative side effects. Some are more behavioral such as gambling and addiction while others are biological like pain from overstimulation. For instance, Steffen K. Rosahl discusses how “relatives and friends sometimes complain of personality changes in the patient, ranging from transient confusion and bradyphrenia to euphoria or depression.” Further, implanting the device is not an exact science and if done incorrectly, a completely different result may occur such as loss of speech or other unknown changes. Research also indicates that an autonomy-capable neuroprosthetic can influence the brain if its actions go unchecked, making it a threat to the user and his or her surroundings. There are serious risks and concerns associated with the use of neurprosthetic technology.

The juncture of law, science and research is especially prevalent in modern neurological research. The cochlear implant is one such example. While the implant has allowed many children all over the world to hear for the first time, it has also led to shock and convulsions. In Sadler v. Advanced Bionics, Inc., the plaintiffs won a $7.25 million verdict in a negligence action when the manufacturer failed to adequately test or obtain approval for a new material in one of their implant designs. The unanswered legal questions in this case evolved around product recalls for implants, overcoming federal preemption, regulatory laws governing research submissions and product liability. Exactly how does a business recall an implant in someone’s brain!?

Clearly, legal-science partnerships are in high demand in advancing neurological research. Scientists need to understand the law and lawyers need to understand science. This principle is critically important when research institutions weigh the risks and benefits to subjects before that device ever hits the market. As Stephen Breyer, associate justice of the U.S. Supreme Court, stated, “In this age of science, we must build legal foundations that are sound in science as well as in law. Scientists have offered their help. We in the legal community should accept that offer.”

Bet on Science: Transplantation Without Human Donation

February 17, 2017
Biotechnology, Healthcare

Rhett Schwichtenberg, MJLST Staffer

There is no question that the American organ donor process is flawed. An individual makes the selfless decision to become an organ donor, but upon death their organs remain in their body.  Although the law states that the donor is the only person that can revoke an anatomical gift, hospital practice will almost never harvest an organ without the family’s consent. A recent article published in the Minnesota Journal of Law, Science & Technology has proposed a solution to the 120,000 Americans waiting for organs: paying the donor $5,000 per organ. This solution could have many positive impacts, but many negative ones as well.

First, this solution will have a strong influence on the socio-economically poor, as an individual could make up to $40,000 for their family by donating the eight organs currently eligible for donation (not including hands and face, added in 2014). This amount of money would put low-income families in a horrible position where they might choose to forego medical treatment in order to provide for their family. This reward manages to take the decision away from the socio-economically poor by incentivizing death. Though middle-class individuals might also elect to choose money over treatment, the decision is based more on want than on need.

Second, with advancing technologies, organs harvested from fatalities will become less frequent. Take, for instance, the new technology of self-driving cars. In the near future, self-driving cars will dominate the automotive industry. Given that in 2016, 13.6 percent of organ donors died in a road accident, the number of available organs will only decrease in years to come. In a very recent article, Elon Musk stated that nearly all new cars will be self-driving within ten years.

Although self-driving cars might be farther down the road than Musk declared, scientists have made a major breakthrough in the biological field. Researchers have successfully used an enzyme to integrate human stem cells into developing pig embryos. This technology makes it possible to edit a pig’s DNA sequence coding for a certain organ, and insert code that would “theoretically grow a human organ for patient transplantation.” Artificially creating human organs would single-handedly eliminate the need for organ donation.

In addition to biological advancements, the tech industry has been a major player in organ creation. The use of 3D printing in the medical industry was instantly commercialized for its ability to create prosthetics and fake organs to practice surgical procedures. Today, Wake Forest Institute for Regenerative Medicine has developed a 3D printer capable of “print[ing] tissues and organs by utilizing cells as the main filament or component of the 3D printer.” Using an individual’s own cells to 3D print new organs for them would also eliminate the need for organ donation.

With such large advancements in science and technology, I do not believe there is a need to incentivize organ donation. This would result in a disparity between rich and poor and create situations where an individual has to choose between life or death for all the wrong reasons. Until science reaches the point where human organs can be created, individuals who wish to donate their organs upon death need to take steps to ensure their wish is fulfilled. Such steps include preparing an advance directive or a living will, signing a donor card, obtaining a health care power of attorney, and informing family members of their decision. Paying someone for their organs is simply not the solution.

Exploring the Final Frontier—The Relevance of Brain Imaging in Litigation

February 15, 2017
Biotechnology, Litigation, Neuroscience

Mary Riverso, MJLST Staffer

Human curiosity and technological advancements have led to the exploration of the ends of the earth, the deep seas, even outer space. We have learned so much about the animals we live amongst, the nooks and crannies of planet Earth, and our role in the universe. But as we continue to explore farther and farther outward, we often overlook how little we actually know about ourselves.

The human brain remains predominantly mysterious and unknown. Neuroscientists continue to attempt to map the brain, to assign different functions and behaviors to the different regions of the brain supposedly responsible for them. However, a thorough understanding remains nearly impossible given the intricate circuitry of brain functioning. While certain areas of the brain are sometimes responsible for discrete tasks, complex functions are not exclusively localized. It is more accurate to think of the brain as composed of neuron circuits – the different regions constantly connecting with one another via neuron circuits to work together to process information and complete tasks. Technological advancements now allow for many groundbreaking and non-invasive means of observing the functioning brain. For example, devices administering scans for functional magnetic resonance imaging, or fMRI, monitor blood flow to detect areas of activity. Whereas an electroencephalogram, or EEG, is a test that measures and records the electrical activity of your brain. Finally, magnetoencephalography, or MEG, captures the magnetic fields generated by neural activity. As the capacity and means to monitor brain functioning expand, the potential for successful brain mapping increases. As a result, using brain images resulting from these scans as evidence in litigation becomes more tempting.

The potential for brain imaging to be used as expert evidence in litigation is already being explored. Criminal defendants, such as Herbert Weinstein, want to use the results from brain scans and tests to show that they are not responsible for their criminal actions due to a physical mental disease or defect. Other defense teams see the potential of brain imaging to aid in assessments of truth-telling. Physicians who administer the tests must be willing to testify as expert witnesses to the results and their medical conclusions. Often times, the physicians probe brain function and analyze energy utilization of the brain and then administer tests of human behavior and mental representations to provide a basis for their medical conclusions. However, a major hurdle for potential neuroscientific evidence is its relevance under Federal Rule of Evidence 401 (“FRE 401”). FRE 401 demands that before such evidence be admitted, it must have a tendency to make a fact of consequence more of less probable. But because the brain remains so misunderstand, it is difficult, or arguably impossible, to draw any exact conclusions that a physical disease or defect in fact caused a behavioral or mental defect.  As a result, courts have come out on either side of the threshold issue in FRE 401 – some have found that the neuroscientific evidence is appropriate for consideration by a jury who can decide what inferences to draw from it, while others find that this kind of evidence is too prejudicial while being only minimally probative and exclude the evidence under FRE 403, and still others allow the evidence but only for limited purposes, such as the sentencing phase of proceedings instead of the guilt phase. As technology continues to advance and neuroscientists continue to learn more about brain functioning, this kind of evidence may become commonplace in litigation. But for now, the admissibility decision seems to be fact-and-circumstance dependent, based on the case, the expert, the evidence, and the judge.

Genetically Modified Foods And The Consumer Quest For Disclosure

February 14, 2017
Biotechnology, Food and Agriculture, Regulatory

Nicholas Ratkowski, MJLST Staffer

In 2000, the Minnesota Journal of Law, Science, and Technology (MJLST) proudly published its first issue, spanning a variety of issues between Patent Protection of Computer Programs to an analysis of the First Amendment through the lens of Jesse Ventura. One Note addressed how genetically modified foods (GMOs) should be labeled, if at all. In the seventeen years since MJLST’s inception, much has changed – how has the landscape of GMO labeling progressed?

In 2000, the principal argument was whether or not GMOs should be specially labeled as such; the author references unexpected concomitant protein allergies and environmental effects as prime concerns. As of 2000, scientists had not identified any negative effects from consuming GMOs. The Note notes different approaches between Europe and the United States, with the former relying on strict disclosure requirements, and the latter ignoring the issue (for the most part). At the time of authorship, “[m]ore than 4,500 GM plants ha[d] been tested, and at least 40 ha[d] passed government reviews” and “as much as 70% of processed foods contain[ed] GM components. The Note “propose[d] that the most appropriate method of resolving the labeling issue involves developing a new, international, voluntary labeling standard for products that have not been developed through genetic engineering techniques or do not contain genetically engineered ingredients.”

Now to the fun part – has anything changed? The short answer is not really. In 2013, Connecticut became the first state to “successfully enact a law requiring food containing genetically modified ingredients to be labeled as such, though it comes with the unusual requirement that four other states must pass similar legislation.” As of 2017, more than 70 bills across 30 states have been proposed in an effort to require labeling of GMOs. Only two states (Vermont and Maine) have joined Connecticut’s lead in forcing disclosure of genetically modified foods. Maine’s disclosure law requires disclosure, but is subject to a litany of exceptions. Vermont’s seems a bit more stringent, but is also easily circumvented. See §3043(d) and §3044 (for example, “Any processed food that would be subject to subsection 3043(a) of this title solely because it includes one or more materials that have been produced with genetic engineering, provided that the genetically engineered materials in the aggregate do not account for more than 0.9 percent of the total weight of the processed food”).

It is perhaps surprising then that GMOs remain mostly invisible to the average consumer in the United States, considering “[m]ore than 70 percent of Americans say they don’t want genetically modified organisms in their food” and “92 percent of Americans want genetically modified foods to be labeled,” according to a 2014 Consumer Reports survey. I’m not smart enough to tell you whether or not eating GMOs has any effect on health, much less whether that effect would be positive or negative. I can, however, posit a theory to explain this paradox, albeit not a novel one – the Pro-GMO lobby is simply too powerful for states to butt heads with in the courts on the taxpayers’ dime. With Monsanto leading the charge, the pro-GMO lobby has spent tens of millions of dollars to fight state-level labeling initiatives. In 2013, lobbyists spent $9,300,000 to prevent GMO disclosure requirements. In just the first quarter of 2014, lobbyist spent another $9,000,000. How can states compete?

If the U.S. ever makes the policy decision to implement widespread labeling requirements for GMOs, doing so will require federal legislation; states have been shown to lack the resources necessary to fight the purveyors of incomplete information that are GMO lobbyists. On the other hand, would labeling have any discernable effect on consumers? Maybe not, but I believe consumers should have the choice to pick what they eat, and how their food is sourced.

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