FDA Approval of New Alzheimer’s Drug May Harm More Than It Helps

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This post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

On June 7, 2021, the United States Food and Drug Administration (FDA) approved a controversial new Alzheimer’s Disease drug—aducanumab—to be sold by Biogen under the name Aduhelm. Alzheimer’s disease is estimated to currently be affecting over 6 million Americans plus their families, who must watch the mental decline of their loved ones and provide increasing levels of care as the disease progresses.

Controversy

Unfortunately, the approval of Aduhelm has generated a large amount of controversy because the FDA approval came despite the rejection of the studies of the drug’s efficacy by the FDA advisory committee. The opposition to the FDA’s approval has been so heated that three of the eleven-person advisory committee have resigned.

Detailed discussions of the science behind Alzheimer’s disease and the Aduhelm clinical studies can be found elsewhere. In summary, as Alzheimer’s disease progresses, protein plaques—amyloid and tau—build up in the patients’ brain. The progression of these plaques correlated with decreased mental acuity in patients. Therefore, drug candidates that target these plaques have been of interest to scientists for many years.

While the clinical data associated with Aduhelm supported a decrease in brain plaques in early-stage Alzheimer’s patients, the data did not show that decreasing plaques by the drug resulted in slowed progression of Alzheimer’s disease. In addition, the data showed that some patients have brain swelling as a result of the drug. Using this data, the FDA approved Aduhelm for broad use for all Alzheimer’s patients.

FDA Approval Process

Generally, to gain approval to sell a new drug, a company will complete a series of clinical trials to determine if a drug candidate is safe and effective for a given disease. Safety and efficacy are balanced against each other and consideration is given to the severity of the disease to determine if approval will be granted. As an example, a highly effective drug that is also highly toxic would not be approved as a simple headache remedy but may be approved as a treatment against a fast-growing, inoperable form of brain tumor. Conversely, an ineffective drug should never be approved no matter how safe it is—such are the wares of snake-oil salesmen of the past.

The FDA also has an Accelerated Approval pathway to allow drugs for diseases that have few treatments to proceed to market more quickly. It is under this accelerated path that the FDA approved Aduhelm. The accelerated pathway allows companies to use biomarker changes rather than disease improvement to show efficacy in the drug approval process. The FDA used the decrease in amyloid plaques as the biomarker for approval of the new Alzheimer’s drug—despite the fact that the clinical trial studies were submitted to show efficacy against disease progression. Moreover, the advisory committee was not informed of potential accelerated approval. Only after the clinical trial data was found unacceptable by the advisory committee did the FDA switch to the accelerated approval pathway. Perhaps most importantly, other drug candidates have been abandoned after amyloid plaque removal did not halt progression of the disease, so biomarkers may not be effective ways to judge the halt of Alzheimer’s progression.

The accelerated approval is, in effect, a contingent approval. Biogen will be allowed to sell Aduhelm, but it must gather data as to whether the drug is actually effective. If clinical data does not eventually support reduced disease progression, then the FDA can rescind the approval, and Biogen will no longer be able to sell the drug. The FDA’s approval of the Aduhelm may be harmful in the long run for several reasons.

Medicine IV infusion
Image description: A close-up photo of an IV drip containing clear liquid. Image source: stux/Pixabay.

Trust in FDA

The move by the FDA to approve Aduhelm could lead to a decrease in trust in the agency. First, the controversial nature of its approval over the recommendations of the scientists who reviewed the data created a controversy that is playing out across the news media as people wonder why an ineffective drug has been approved.

In fairness, the accelerated approval process is contingent, but due to the way the accelerated approval was used scientists did not have the opportunity to weigh-in on the use of biomarkers in that approval. That way in which the accelerated approval process was tapped, only after the regular approval process seemed doomed to fail, may well erode trust that the FDA evenly applies its own rules. Additionally, it is very difficult to rescind these accelerated approvals, and if the drug approval is rescinded public perception will likely be highly negative. Finally, according to Biogen it may take up to nine years to gather the data to complete the required studies.

New Drug Development

Aduhelm is not the only drug candidate in its class in clinical trials for Alzheimer’s disease treatment. Other drug candidates that include patients who receive a placebo rather than the drug candidate are undergoing clinical trials. Since these studies tend to be double-blinded—neither the doctor nor the patient knows if the drug or the placebo has been administered—patients will likely drop out of these other studies in order to be assured of receiving some drug. Thus, Alzheimer’s drug development will be slowed, in favor of a drug that has no demonstrable efficacy. Additionally, these new drug manufacturers may also ask for similar approval, based on biomarkers that may not be indicative of clinical effectiveness.

False Hope

Patients and Alzheimer’s advocates pushed for approval of this drug. But a drug with contingent approval may give these patients and their families false hopes. We have seen in Right to Try legislation–legislation allowing patients to use un-approved drugs in the FDA approval pipeline–both a fundamental lack of understanding of the FDA approval process as well as the desperation of patients for whom there are no clear treatment options. I have argued before that Right to Try laws prey on the emotionally fragile. Here the FDA’s controversial accelerated approval may have the same result—patients clamoring for a drug that does not work.

In addition, the cost of the drug will be borne by insurance companies that may well decide not to cover the drug. While the drug is approved for all stages of Alzheimer’s, clinical studies were only aimed at early-stage disease. In effect, the FDA has shifted its responsibility as gatekeeper for effective drugs to insurance companies for whom profit is a driving force.

Drug Cost

The cost of Aduhelm in light of the lack of efficacy data presents its own problems. Biogen has indicated that the average yearly cost of Aduhelm will be $56,000, not including the cost of doctors, hospital or clinic visits, and supplies to receive the infusions, or the cost of brain scans to monitor for swelling and brain bleeds as side effects. This cost, like most drugs, will be passed on to consumers through direct payments, increased insurance premiums, and higher budget expenditures for Medicare and Medicaid. One study reported that if 500,000 people on Medicare are prescribed the drug, it would cost $29 billion per year with copays of over $11,000 per year.

Biogen defends its pricing of the drug. According to its own press release, Biogen “established the price of Aduhelm based on the overall value this treatment is expected to bring to patients, caregivers, and society.” This expected value seems high for a drug that may not work but admittedly reflects normal drug company calculations in a system where insurance covers most prescriptions and the uninsured either do without or rely on the generosity of the drug company.

Because FDA approval is contingent, the FDA can remove the drug from the market if the required data do not show efficacy. However, the money paid for the failed treatment regime will not be refunded. Patients are paying to take this risk.

In the end, the FDA’s approval of Aduhelm will impact the way the agency is perceived, and the way other companies approach the drug approval process. Neither of these changes will be for the better.

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Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law at the Michigan State University College of Law.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Monday, July 5, 2021. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

Continue reading “FDA Approval of New Alzheimer’s Drug May Harm More Than It Helps”

CRISPR Dangers Highlight the Need for Continued Research on Human Gene Editing

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This post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

The excitement and potential of CRISPR to treat severe genetic conditions by editing disease-causing DNA has taken an unexpected hit. A recent Wall Street Journal article highlighted the unexpected results from a CRISPR study in which attempts to edit a human gene responsible for blindness resulted in the loss of the entire chromosome from the cells in the embryos. These results echo another study conducted in human cell lines published earlier in 2019.

CRISPR is a targeted gene editing process that allows scientists to direct genetic modifications with far more precision than prior procedures. CRISPR has been touted as a gigantic leap in the ability to modify DNA by creating or repairing pinpoint DNA mutations without affecting other areas of the chromosome on which the gene resides. The recent study indicates that the technique might not be as straightforward in humans – and thus neither will be its use to fight disease.

Blue DNA double helix puzzle with missing pieces
Image description: A partially assembled puzzle that is an image of blue double helix DNA molecule structures. Image source: Arek Socha/Pixabay

CRISPR Technology – Promise and Problems

The value in CRISPR mediated genetic modification can be seen in a wide variety of biotechnology products, such as genetically modified crops and new biologics. But perhaps the most exciting and most controversial potential for CRISPR can be found in the desire to modify embryonic genomes to remove genetic abnormalities for which we currently have no cure.

This promise of embryonic gene editing is appealing not only because it would remove the condition from the child born from the gene-edited embryo, but also because the offspring of that child would also be free of the condition. CRISPR gene editing – because it is done at the embryonic stage – creates germline mutations that are passed to future generations. In a therapeutic use of CRISPR, those mutations would be cures for often untreatable diseases.

However, it is this very promise that raises many of the problems with CRISPR embryonic gene editing. Much debate has surrounded embryonic gene editing. Until this recent news, there were fears that CRISPR may make gene editing too easy. The technological development of CRISPR in embryonic gene editing is moving at a breakneck pace as scientists around the world are working on procedures. Biohackers work in their garages and livestream the use of CRISPR to edit their own genomes.

Many are debating which genes should be targeted and how fast the research into actual trials should proceed. Most agree that severe diseases would be the best place to start, but should the technology be deployed for cosmetic benefits such as eye color, or diseases for which a treatment exists? The dangers of CRISPR editing are unclear, and there has been an informal moratorium on the use of the technology to create children. Despite that, there has been at least one rogue scientist who has created genetically modified embryos and brought them to full term birth.

International Policy on Human Gene Editing

The scientific research is not occurring in a vacuum. Each country decides how CRISPR can be used in its medical system – both when the technique is safe enough and on which diseases it should be used.

An international commission recently pronounced that the technology is not ready for clinic implementation because scientists don’t understand the full safety issues surrounding its use in human embryos. The commission described some of the potential clinical uses in the future and outlined a basic safety protocol for approval.

One of the creators of CRISPR, Jennifer Doudna, has also spoken out against applying CRISPR too hastily to embryonic gene editing. 

Based on the recent studies showing loss of chromosomes, the international commission and other scientists are correct to call for a moratorium on clinical embryonic gene editing.

Blue and green DNA double helixes and binary code
Image description: An abstract image of blue and green double helix structures and binary code (zeros and ones) against a black background. Image source: Gerd Altmann/Pixabay

CRISPR – The Path Forward

The setback in CRISPR gene editing does not mean that the technology and research should be discarded. The potential to change lives is too great; however, the dangers of use with our current understanding are even greater. So how do we move forward with CRISPR in embryonic gene editing? The answer must include balance – in research strategies and in voices.

While the technology is not ready for clinical use, and we have not yet determined which uses would be appropriate if it were available, the science should not stand still. The research surrounding CRISPR gene editing will yield insights into human biology that we cannot predict. For example, the loss of chromosome length in human embryonic cells undergoing CRISPR treatment seems to be different than the response of other species of embryonic cells. And debates about the appropriate use of the technology will allow us to discover more about ourselves as humans. 

As we debate the best way to develop and deploy CRISPR technology, we should look to a variety of stakeholders. Scientists have a solid track record in understanding when recombinant DNA technology has potentially hazardous implications. In the 1970s, the Asilomar Conference allowed scientists to put together research guidelines that allowed the technology to be developed without harming public health. In fact, the international scientific consensus not to use the technology such as described above indicates that scientists are beginning that work. Such a moratorium on clinical uses gives us time to understand how to deploy the technology in the safest manner.

Additionally, there is a role for the voices of the patients whose lives could be changed by the technology. Patients may not be in the best place to judge when the technology should be deemed safe enough to deploy, but they certainly will have input about which mutations cause hardships that merit the risk of germline editing. Many of these patients already work with scientists on potential treatments for their diseases. CRISPR discussions may open another avenue for many.

Finally, there is a role for legal regulation of the use of CRISPR. Governments should listen to the voices of scientists and potential patients in drafting these regulations. But as shown by the example of at least one rogue scientist, there needs to be teeth to the moratorium on CRISPR clinical use at this time. CRISPR and its use in human gene editing raise complicated issues and hold great promise as a powerful tool to defeat genetic diseases. The development of those technologies will not be straightforward or without risk and will require more basic science research to achieve clinical efficacy. But with proper planning, we may learn more about ourselves as humans on the path to a cure.

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Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law in the Michigan State University College of Law. Dr. Carter-Johnson is a member of the Michigan State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Tuesday, December 15, 2020. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

More Bioethics in the News from Dr. Carter-Johnson: Biohacking: How a DIY Approach to Biology Can Shape Our FutureWeb of Interests Surrounding Medicines Makes Patient Access Increasingly DifficultHumanity in the Age of Genetic ModificationDefining The Spectrum of “Normal”: What is a Disease?Dawn of False Hope: Spread of “Right To Try” Laws across the U.S.

Continue reading “CRISPR Dangers Highlight the Need for Continued Research on Human Gene Editing”

Biohacking: How a DIY Approach to Biology Can Shape Our Future

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

In 2017, Josiah Zayner live-streamed himself injecting a gene therapy construct designed to edit the DNA in his muscle cells to give him bigger muscles. This moment was noteworthy because the gene therapy construct had been created entirely by Zayner in his garage laboratory. Such work is called biohacking or DIY biology.

These actions do not come without consequences. He has recently been investigated for practicing medicine without a license, and the state of California recently passed a law to require all such kits to include a notice “stating that the kit is not for self-administration.”

What is Biohacking?
Zayner is not alone; in fact, the biohacking movement is growing across the country. Zayner also sells kits that allow other biohackers to experiment with DNA and gene editing from his website, The Odin. There are also laboratories across the country that allow interested people to have space to conduct biology experiments without having to build a home laboratory.

Biohacking at its core is bringing science out of the laboratories of academia and industry and into grasp of citizen scientists. But the exact definition of what is included in biohacking differs among people. Biohacking includes a diverse variety of science experiments such as tracking of sleep and diet, under-skin implantation of computer chips and other technology, ingestion of “smart drugs” and sub-clinical levels of LSD, transplantation of gut and skin microbiomes, infusion of “young blood” to reverse aging, and genetic modification of bacteria, yeast and human cells.

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Image description: an equipment setup called a “makerbay” in a Hong Kong biohacking makerspace. Image source: Athena Lam/Flickr Creative Commons.

Each type of biohacking brings its own risks and rewards. This blog post will focus on genetic modification of cells using new gene editing techniques such as CRISPR. Advances in gene editing technology over the past five years have made accessible science that was once confined to expensive, high-technology laboratories. For a broader look at CRISPR and gene editing by researchers and bio-hackers, Netflix has a new documentary series, Unnatural Selection.

Benefits of Biohacking
First and foremost, the benefit of biohacking is access to science. Not everyone can afford an advanced degree biology or wants to work full time in a laboratory. Biohacking democratizes science for people who have a passion for learning about the world and how it works. It also has the potential to increase access to medicine. One endeavor, the Open Insulin Project, attempts to find a cheaper and intellectual property-free way to produce and distribute insulin to make it available to people who have a hard time affording the drug.

In addition to access, biohacking communities are also hubs of outreach and education. The laboratory spaces often hold classes and meeting spaces for like-minded individuals to network. There are competitions that bring together student and citizen scientist teams who work on using synthetic biology to create biological solutions to local and international problems.

Biohackers are taking these responsibilities seriously as a whole. The community has even developed its own code of ethics emphasizing open access, transparency, education, safety, environment, and peaceful purposes.

Risks of Biohacking
Although biohacking has many benefits, there are risks of which the world and individual citizen scientists should be aware. Perhaps the largest potential threats are the lack of education and regulation within the biohacking community.

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Image description: two people are gathered at a table containing various types of scientific equipment. Image source: Martin Dittus/Flickr Creative Commons.

While Josiah Zaynor holds a PhD in biopohysics, not all biohackers are so well educated. Community laboratories help with classes and mutual support, but home-based biohackers must rely on their own knowledge and understanding, though websites are available for questions and discussions. Education and outreach to biohackers is also the strategy of the FBI in recent years, though many biohackers are reticent to accept its help. Additionally, while the community does have a code of ethics, there is little formal ethics training in concepts such as informed consent or using animals in research.

Due to the open definition and decentralized structure of biohacking, regulation is almost impossible. Lack of regulation leaves laboratory safety in the hands of the biohackers. As with any scientific endeavor involving genetic engineering, accidents can occur that could lead to the release of environmentally destructive organisms. Biohackers injecting themselves or others could cause any number of infections or adverse reactions. Additionally, the risk of the development of dangerous or ineffective gene therapies and other products by biohackers has led the Food and Drug Administration to issue warnings to the public about untested products. This risk is especially relevant in an era of rising drug costs.

Other dangers, such as specific threats to biosecurity, are real but attenuated. While it is possible biohackers could genetically engineer a bacteria or virus, there are far easier ways for a small-scale terrorist group to attack.

Future of Biohacking
Highly technical equipment and processes are becoming more accessible. People are looking for ways to take control of their health and provide access to medicines. Curiosity about the natural world should be encouraged.

The risks are real, but we can deal with them by working together. By having community leaders willing to confront the risks and help develop community norms, we can shape the application of biohacker energies. Zayner himself has realized that other biohackers may seek to emulate his self-experimentation and get hurt.

In the end, biohacking is here to stay.

Jennifer Carter-Johnson photo

Jennifer Carter-Johnson, PhD, JD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, November 14, 2019. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

More Bioethics in the News from Dr. Carter-Johnson: Web of Interests Surrounding Medicines Makes Patient Access Increasingly DifficultHumanity in the Age of Genetic ModificationDefining The Spectrum of “Normal”: What is a Disease?Dawn of False Hope: Spread of “Right To Try” Laws across the U.S.

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Bioethics for Breakfast: Biobanking Tissue: Trash or Treasure?

Bioethics for Breakfast Seminars in Medicine, Law and SocietyJennifer Carter-Johnson, PhD, JD, and Tom Tomlinson, PhD, presented at the Bioethics for Breakfast event on December 6, 2018, offering their perspectives and insight on the topic “Biobanking Tissue: Trash or Treasure?”

“Big data”—repositories of biological, medical and demographic information about large numbers of people—is a critical platform for discovery of the causes of disease and potential new avenues for its treatment.

This data must come from us, the general public. Data about you might end up in a biobank because you’ve generously agreed to provide it, perhaps by agreeing to join the National Institutes of Health’s All of Us project that aims to recruit a broad representative sample of one million Americans.

Or it might already have been provided for use in research without your knowledge or consent. Research using specimens and medical information collected during your clinical care, once de-identified, doesn’t count as research on a “human subject” under the Federal regulations. Thus, your consent is not required. This source probably provides the great majority of information used in big data research, and acquiring and distributing it has become a multimillion dollar business.

This practice raises a host of questions. Doesn’t my specimen and my medical information belong to me, rather than to the hospital or clinic that collects it? Or have I thrown it away like my trash sitting on the curb each week? Although many people may feel comfortable providing this information for research, others might not. So isn’t it a simple act of respect to ask first? Or are researchers simply the medical equivalent of college students dumpster diving for cheap furniture that has been thrown away? Additionally, if we ask, and too many people say “no,” won’t critical research be hampered, to the detriment of all of us?

Dr. Tomlinson asked attendees to consider this question: Should clinically-acquired specimens and other medical information be treated like the trash that you have no control of once it has left your curb?

Dr. Tomlinson referred to a national study that his research team conducted in 2014 regarding willingness to give blanket consent, focusing on the fact that people care about more than risk – they have concern about how their materials may be used, and they worry about how much they should trust the research establishment. Dr. Tomlinson’s overarching argument was that respect for persons, a fundamental bioethics principle, requires informed consent.

Dr. Carter-Johnson also offered a question: whose treasure is it? Biospecimens and related data can be donated by patients and the public, can be clinically collected de-identified materials, and they can be samples given to private companies like 23andMe or Ancestry.com. Dr. Carter-Johnson also discussed a new startup offering to sequence your genome for free, and highlighted the variety of health and fitness apps that we give our data too. “When something is free, you are the product,” she said. A show of hands revealed that a minority of the attendees had gotten their DNA sequenced.

Dr. Carter-Johnson offered a legal perspective on tissue and genetic data in relation to property and privacy rights. She explained that individuals do not own their own tissue, citing the cases Moore v. Regents of California and Greenberg v. Miami Children’s Hospital Research Institute. However, there have been exceptions, and there are legal ways to “sell” your body (think plasma, bone marrow, sperm, or clinical trials).

When discussing privacy, Dr. Carter-Johnson used 23andMe and Ancestry.com’s privacy policies as examples. These policies are contractual, they are updated frequently, and they are often ignored by the consumer. However, push from consumers as well as bioethicists have led to these policies being more available and accessible.

Audience discussion brought up the famous Henrietta Lacks case, the future of biobank donor policies, and newborn screening programs and biobanks.

Jennifer Carter-Johnson, PhD, JD
Jennifer Carter-Johnson is an Associate Professor of Law at the Michigan State University College of Law and holds both a JD and a PhD in Microbiology. Professor Carter-Johnson uses her interdisciplinary training to study the intersection of law and scientific research.

Tom Tomlinson, PhD
Tom Tomlinson was Director of the Center for Ethics and Humanities in the Life Sciences from 2000 to 2018, and is a Professor in the Department of Philosophy. He chairs the Ethics Committee at Sparrow Health System, and has published widely on the ethics of biobank-based research.

About Bioethics for Breakfast:
In 2010, Hall, Render, Killian, Heath & Lyman invited the Center for Ethics to partner on a bioethics seminar series. The Center for Ethics and Hall Render invite guests from the health professions, religious and community organizations, political circles, and the academy to engage in lively discussions of topics spanning the worlds of bioethics, health law, business, and policy. For each event, the Center selects from a wide range of controversial issues and provides two presenters either from our own faculty or invited guests, who offer distinctive, and sometimes clashing, perspectives. Those brief presentations are followed by a moderated open discussion.

Web of Interests Surrounding Medicines Makes Patient Access Increasingly Difficult

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

A recent New York Times article described the problems that patients are having gaining access to a new class of cholesterol reducers, called PCSK9 inhibitors. This difficulty extends not just to the uninsured but also to patients with insurance. The drug costs are exorbitant, listing as more than $14,000 per year for a drug that may need to be taken indefinitely. Insurance companies are balking at paying so much for the new drug when cheaper cholesterol reducers are available. Patients for whom the old cholesterol reducers do not work are forced to jump through many time-consuming hoops – mountains of paperwork, proof that other drugs have failed, and appeals after initial denials of coverage – before drug coverage approval for the PCSK9 inhibitors.

It is easy to blame the drug companies in this situation. Why must they charge so much?!?! This question has become more common considering recent news stories about drug company price increases designed only to increase profits. But high drug costs are only one obstacle for patients to access drugs. Insurance coverage dictates cost of drugs to patients from nominal co-pays to out-of-pocket self-funding. Attempts to address one issue without addressing the entire web of interests is doomed to failure.

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Image description: A close-up photograph of a spider web that is covered in water droplets. The web takes up the entire frame and is in focus, the background is blurred and includes green and purple tones. Image source: nils.rohwer/Flickr Creative Commons

Drug Companies and Federal Regulations

Drugs cost money and time to develop and produce. All drugs must undergo scrutiny from the U.S. Food and Drug Administration, where drug developers must prove both the safety and efficacy of the potential drug before it is sold. The process takes on average 12 years between lead compound identification and final approval, and often costs close to a billion dollars absent streamlined approval processes for certain rare diseases. The billion-dollar cost estimate includes the cost of research for the failure of the many compounds that enter clinical trials but are deemed either unsafe or ineffective for the disease to be treated.

Thus, drug companies charge prices to recoup this huge research investment. Prices also pay for manufacturing and advertising as well as profit margins of close to 20% to fuel further investment. While there are mechanisms in place to incentivize generic drug manufacturers to enter the market and decrease prices through competition, branded drug companies have strategies to delay generic entry that have come under recent legal scrutiny.

Private Insurance and Federal/State Medical Programs

While drug costs are high due to the myriad factors described briefly above, patients are often insulated from some of those costs by insurance companies that cover the cost of drugs. Insurance comes in a variety of forms. Private insurance may be procured on the open market or through employer coverage. In the latter, the employer may cover some or all the costs of the insurance. Senior citizens rely on the Federally-sponsored Medicare program for medical coverage, though private supplements insurance policies are also the norm. Those too young for Medicare and too poor for private insurance (with or without an employer subsidy) are forced to rely on state Medicaid programs.

Unfortunately, not every insurance plan covers every drug. Insurance companies produce a formulary of covered drugs for each plan. The insurance plan negotiates a price, often significantly cheaper than the drug’s list price, that it will pay the drug manufacturer. More expensive drugs may require insurance pre-approval and multiple rounds of paperwork from the prescribing doctor.

Insurance companies have an incentive to reduce the usage of expensive drug alternatives. For private insurance companies, that incentive is profit. In fact, for-profit insurance companies know how to play this game quite well; many have profits in excess of 6 billion dollars. Medicaid and Medicare programs have limited budgets for all medical costs including drugs. While increased Medicaid funding for states offered through the Affordable Care Act was effective in decreasing uninsured rates, government funding is always in flux due to political pressures.

Doctors and Pharmacists

Doctors have great discretion in prescribing drugs. While doctors hold their patients’ health as the highest goal, knowledge of insurance (or its lack) may influence the doctor’s choice of drugs. Denial of a drug may well mean many, many more forms for a doctor who wants to make sure her patient has the best, most expensive drug. Doctors who do this for multiple patients could soon find themselves spending as much time on drug paperwork as medical care. Many doctors have taken to giving samples of drugs – left by drug companies as part of their advertising budgets – to patients who cannot afford the drug but need it.

Pharmacists exist at the epicenter of the patient’s dilemma. Patients often find out that insurance is not covering the drug when the pharmacist explains the situation. More troubling is the fact that drug prices are sometimes cheaper for a patient without insurance. For instance, a patient may have a twenty-dollar co-pay, but the drug may only cost ten dollars. For years, pharmacists have been subject to “gag clauses” in contracts between pharmacies and pharmacy benefit managers that prevent them from disclosing to the patient the cheaper alternative. Recent legislation signed this month has banned this practice.

Patients

Caught in this web of diverse and conflicting interests are the very people for whom drugs are created and vetted and prescribed – patients. Drug manufacturers must be able to recoup costs, but if no one can afford the drug how will they make sales? Additionally, drug pricing is a convoluted process that varies between insurance policies, pharmacies, and branded or generic formulations. Insurance coverage is often dictated by employer, age, or resources. Lack of coverage for a specific drug might mean the patient is faced with choosing a different drug or a different job. But asking about insurance formularies during a job interview would be quite difficult even if switching jobs in the midst of a medical crisis were possible. On the other hand, determining drug needs in advance is almost impossible. Finding a doctor with the time to work with a patient on an involved approval process is becoming more difficult given the increasing shortage of doctors in the United States.

Sitting in the center of this web of interests, patients have the most to gain and the most to lose from any overhaul of our drug system. It is impossible to fix all the problems by focusing only on the problems in one area. Unfortunately, patients are also a very small voice in the web that includes pharmaceutical companies, insurance companies, and medical professionals.

Jennifer Carter-Johnson photo

Jennifer Carter-Johnson, PhD, JD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar and the Washington State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, November 1, 2018. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

More Bioethics in the News from Dr. Carter-Johnson: Humanity in the Age of Genetic ModificationDefining The Spectrum of “Normal”: What is a Disease?Dawn of False Hope: Spread of “Right To Try” Laws across the U.S.Designing Children: Patents and the Market are not Sufficient Regulation

Click through to view references

“Where does responsibility lie if a person acts under the influence of their brain implant?”

Laura Cabrera photoJennifer Carter-Johnson photoVisit The Conversation to read “It’s not my fault, my brain implant made me do it,” a collaborative article from Center Assistant Professor Dr. Laura Cabrera and College of Law Associate Professor Dr. Jennifer Carter-Johnson. They combine their neuroethics and legal expertise to address questions such as: “Where does responsibility lie if a person acts under the influence of their brain implant?” The article was also published in Scientific American.

In November 2017, Drs. Cabrera and Carter-Johnson participated in a Brews and Views event of the same name, “It’s not my fault: my brain implant made me do it.” Brews and Views events, moderated discussions addressing the most fascinating and provocative areas of bioscience and engineering, are a collaboration between the Institute for Quantitative Health Science and Engineering and the Center for Ethics and Humanities in the Life Sciences at Michigan State University.

Bioethics in the News from Laura Cabrera:

Bioethics in the News from Jennifer Carter-Johnson:

Humanity in the Age of Genetic Modification

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

Scientists have recently announced that they had used the new gene editing technique, CRISPR, to remove remnants of ancient viruses that had integrated into the pig genome. An amazing feat of genetic engineering to be sure—but the article is notable as a first step in “humanizing” pig organs for use in organ transplant by removing pig-specific viruses before they can infect human organ recipients. The idea of humanizing pigs should make us wonder—what does it mean to be human? How much genetic modification can pigs undergo and still be pigs? How do we define humanity for our neighbors and ourselves? How much genetic modification would it take to remove the label of humanity?

These questions are not asked in a vacuum nor is the research being conducted solely for philosophical inquiry. We need organs to save lives. There are over 116,000 people on the organ donor list and only 33,611 organ donations each year. About 20 people die every day in the U.S. waiting for a match so that they can receive a new heart, kidney or lung. Additionally, not everyone who actually receives a transplant has a successful outcome.

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Image description: a Lego figurine of a person dressed in a pig costume is shown in the foreground against a yellow and white background. Image source: clement127/Flickr Creative Commons.

Transplant rejection occurs because each person has a fairly unique set of signal markers on their cells that allow the immune system to identify “self.” Bacterial or viral infections trigger immune responses in part because they change the infected cell’s signal markers from “self” to “foreign.” A transplanted organ also looks “foreign” to the recipient’s immune system due to the difference in signal markers, and this immune response leads to transplant rejection. For instance, identical twins would have very little risk of transplant rejection, while two unrelated people of different backgrounds would likely be unable to donate to each other. Thus, doctors search for the greatest amount of match between recipient and donor, and then suppress the recipient’s immune system to further decrease the risk of transplant rejection.

Using animal organs introduces yet more foreign signals to the organ recipient, leading to the desire to humanize those organs with markers that signal “human” and “self” to the recipient. In fact, doctors have been using pig heart valves in transplants since the 1970s. These hearts valves are extracted and then stripped of live cells to decrease the risk of rejection. This preparation procedure limits types of transplants that can be performed, and even with preparation, rejection issues may eventually arise.

Therefore, today’s scientists are working to use genetic engineering to modify pig organs to express the same cell markers that signal “self” to a human recipient. The referenced article described the development of pigs without endogenous retroviruses that some fear could infect recipients. From that basis, scientists could use several different techniques to develop pigs with humanized organs. One technique would be to genetically modify an embryo such that the pig’s cells express more “human” markers and less “pig” markers. Another technique that has been pioneered recently would be to inject human cells into a pig embryo such that the resulting chimeric pig would grow a genetically human organ.

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Image description: three pigs are shown outside through metal fencing. The main pig appears to be smiling. Image source: Peppysis/Flickr Creative Commons.

Both of these techniques raise the question of what it means to be human. Merriam-Webster defines the noun human as “a bipedal primate mammal (Homo sapiens) : a person.” Furthermore, the adjective definition of the word human, “having human form or attributes,” broadens that definition in an ambiguous way that leaves us no closer to an answer than before. After all, the point of humanizing cells is to give them human attributes for organ transplantation. Surely, that isn’t enough to make the pig a human? Pigs with genomes edited to have organs that look more “human” will likely still act like pigs. But we don’t truly know how multiple genetic changes will present. Looking to the chimera technique, would a chimeric pig with the heart and kidneys of a human still be a pig? What if some of those human cells colonized the brain and some percentage of neurons were human? How do we answer the question of humanity? Do we ask what percentage of the body is human? Do we see if the animal still acts like a pig or test its skills on the SAT?

In contrast, does a person who receives a pig heart transplant cease to be human and become a pig? Humans do not have a great track record of recognizing humanity in others. Perhaps in recent times, we in the United States have not had to consider what qualifies as human. A baby born from a human mother is a human. But this concept has not always been so straightforward. Constitutional definition of a slave as 3/5 of a person and the idea of blood quantum to limit Native American rights go back to the beginning of our country. More broadly, Hitler wanted to develop a master race and viewed Jews as subhuman – leading to horrific abuses and mass murder. Today, some countries still view women as property rather than humans with rights.

Genetic technologies will challenge how we view ourselves, our neighbors, and the next generation. Genetic testing has revealed Neanderthal genetic code in many of us due to interbreeding thousands of years ago. CRISPR-based tools will eventually allow parents using artificial reproductive technologies to select genetic traits for their children. How many modifications would it take for a child to cease to be human? Perhaps super strength or gills to breathe under water sound like fantastic science fiction now, but so too did the tablets and communicators of Star Trek in the 1960s and the watch phone/TV from Dick Tracy in the 1940s. Returning to the idea of organ transplants, would a skin bag full of organs derived from a human’s cells but with no brain be considered a human? Would your answer differ if there was a brain but no higher order brain function? Such an option could reduce organ rejection to nil if a person’s cells could be used to create their own replacement organs.

The dangers of relegating a population to second tier status because they are genetically different from the norm have been explored across fiction from Animal Farm to the X-Men. Humanity’s history suggests that those stories are rooted in our inability to see humanity in those we deem as other. Advances in science mean that we need to define what it means to be human in order to avoid abuses equal to slavery or Nuremberg. Our world is changing and so too will humanity – whether or not we are prepared.

j-carter-johnsonJennifer Carter-Johnson, JD, PhD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar and the Washington State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, November 9, 2017. With your participation, we hope to create discussions rich with insights from diverse perspectives.

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Designing Children: Patents and the Market are not Sufficient Regulation

Bioethics-in-the-News-logoThis post is a part of our Bioethics in the News series. For more information, click here.

By Jennifer Carter-Johnson, PhD, JD

In an October report entitled “Breeding Out Disease,” 60 MINUTES correspondent Nora O’Donnell reported on the use of pre-implantation genetic diagnosis (PGD) to screen embryos produced during in vitro fertilization (IVF) procedures.i PGD allows doctors to determine if an embryo contains a gene that will lead to disease or increased risk of disease after birth. PGD currently can be used to screen for diseases caused by a single defective gene. Examples of such diseases include cystic fibrosis, Tay-Sachs, muscular dystrophy, sickle-cell anemia, hemophilia, and Huntington’s disease as well as certain types of cancer and some types of early onset Alzheimer’s. For parents who know that they carry a family risk of these diseases, PGD can relieve fear about some of the diseases that their child will face.

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Source: Flickr Creative Commons

The report also described a relatively newly developed patented process that can be used in concert with PGD. The process, and the company that sells the service, is called GenePeeks. GenePeeks uses DNA profiles from a potential set of parents to determine the likely genetic profiles of children from that couple. Couples can then use that information to determine the diseases towards which to direct any PGD screening. However, the patent for the GenePeeks process is written quite broadly and contemplates screening for not only diseases but also over 500 other traits such as eye shape and color, sex, the ability to roll one’s tongue, social intelligence and cognitive abilities.ii While prospective parents don’t quite have the technology to specifically pick and choose the traits, à la the movie Gattaca,iii they would be able to predict and select either for, or against, genetic traits that the child might possibly naturally inherit.

In spite of the peace of mind many prospective parents receive from using these two technologies, a host of ethical and regulatory issues surround them. For instance, the extent to which parents should have the ability to tailor the genetic traits of their children is completely unregulated. Additionally, the disposition of unused embryos is controversial; embryos with disease-causing mutations are usually discarded, and excess embryos are often frozen indefinitely. Other uses for excess embryos, such as stem cell research, are equally fraught with controversy. Beyond such embryonic issues, a cycle of IVF and PGD will cost around 20,000 dollars, making access to this aspect of reproductive technology and disease-screened offspring a luxury. Also, once the DNA of a parent or child is sequenced, the potential exists for insurance companies and employers to discriminate based on genetic profile, and databases of DNA profiles could additionally be matched against forensic data from crime scenes.

In light of these potential problems, Nora O’Donnell interviewed two of the developers and patent owners related to the technology. She independently asked each one what regulations should be in place to keep PGD and GenePeeks limited to disease testing. The responses of the two men interviewed were essentially the same – and essentially wrong. Each explained that due to patent exclusivity few can practice the technology. Both doctors promised to act as gatekeepers for the technology and use it exclusively for screening for disease in embryos and conducting related disease research, rather than crafting designer children – even though such designer activities were explicitly described in the GenePeeks patent. “Trust us,” seemed to be the echoing cry.

However, the number of people who can sell a technology at a given moment has little bearing on whether a technology will need to be regulated. The number of patients GenePeeks and the PGD firm see each year number in thousands. Moreover, patents can be licensed broadly fairly quickly, increasing the reach of the technology even further. Once the patents expire, twenty years after filing, everyone will be free to offer the service for sale. More importantly, and problematically, the issuance of a patent does not indicate that a technology is being used ethically.

Patent law is technologically neutral. In 1980, in the case of Diamond v. Chakrabarty, the Supreme Court determined that “anything under the sun that is made by man” can be patented so long as the new technology is useful, novel and non-obvious. The Chakrabarty case dealt with the patentability of genetically modified bacteria and is credited with ushering in the biotechnology industry.

Furthermore, the same Chakrabarty Court recognized that patents may incentivize technology that needs regulation. In the discussion of the technology underlying genetically modified bacteria, the Chakrabarty Court contemplated a “parade of horribles” that could result if this underlying genetic technology were patented and encouraged. Among the potential problems discussed were the spread of pollution and disease, loss of genetic diversity and a devaluation of human life. The Chakrabarty Court then invited legislatures to pass any laws to regulate this new biotechnology by a “balancing of competing values and interests.”

Congress and various administrative agencies have answered that invitation in a myriad of circumstances and in as many distinct ways. Concerns over cloning and human ownership led Congress to forbid any patents directed toward a human organism.v The development of genetically modified crops and animals resulted in a multi-agency co-operative regulatory regime encompassing the Food and Drug Administration (FDA), the US Department of Agriculture and the Environmental Protection Agency.vi The Genetic Information Nondiscrimination Act (GINA) of 2008 prohibited discrimination in health coverage and employment based on genetic information.vii The FDA has promulgated rules for DNA research and the safety and efficacy of the resulting new biologics as well as the informed consent of volunteers for related clinical trials.  This oversight has not been limited to Federal laws and regulations as state legislatures have dealt with family law issues such as surrogacy agreementsviii and ownership of frozen embryos.ix

As the PGD and GenePeeks technologies develop, so too must the laws and regulations surrounding their use. Recently, the FDA announced new guidelines for proving the safety and accuracy of genetic tests. However, testing accuracy does not address whether the tests should be used in a capacity beyond disease diagnosis. As these technologies demonstrate, inventors and patent owners may be smart, and ethical, but they do not necessarily speak for all segments of society and they are at least in part generally profit-driven. Society needs to consider precisely potential problems beyond technical ability and rather than waiting to react, judiciously guide a growing industry.

References:

Breeding Out Disease, 60 MINUTES. Last accessed at http://www.cbsnews.com/news/breeding-out-disease-with-reproductive-genetics/.

ii  Method and system for generating a virtual progeny genome, Patent #8620594 (filed Aug 22, 2012).

iii Gattaca, Sony Pictures Entertainment (1997).

iv  Diamond v. Chakrabarty, 447 U.S. 303 (1980).

America Invents Act of 2011 (Pub. L. 112–29, § 33,Sept. 16, 2011, 125 Stat. 340(enacted September 22, 2011).

vi Emily Marden, Risk and Regulation: U.S. Regulatory Policy on Genetically Modified Food and Agriculture, 44 B.C.L. Rev. 733 (2003).

vii Genetic Information Nondiscrimination Act of 2008 Pub.L. 110–233, 122 Stat. 881 (enacted May 21, 2008).

viii Guide to State Surrogacy Laws. Last accessed at https://www.americanprogress.org/issues/women/news/2007/12/17/3758/guide-to-state-surrogacy-laws/.

ix  See, e.g., Szafranski v. Dunston, 993 N.E.2d 502 (2013).

Jennifer Carter-Johnson, PhD, Jj-carter-johnsonD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar and the Washington State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, December 4, 2014. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.