Policy & Law Archives - Philosophy of Biology and Health

Critical Disconnect, PBH Assessment, and Emerging Lessons

I have shared in earlier blogs my excitement and optimism for biomedical innovation across broadly applicable biotechnologies such as gene therapy, immunotherapies, mRNA vaccines. I have also discussed the critical role biomedical innovation has played in the global response to the pandemic: from rapid genome sequencing of the virus, to novel diagnostics, monoclonal antibody therapy, of course the first mRNA vaccines, and hopefully soon, antiviral pills. All this biomedical innovation at this rapid pace has been breathtaking to follow.

Why then do we, in the US, have more people dead from this pandemic in 18-months than we had US casualties in all of World War II? What good is all this innovation if more people died from COVID-19 than did from the Spanish Flu pandemic a 100 years ago?

Concept and Illustration by Rama Bhagwat

When I launched this blog site in spring of 2020, in the early days of the pandemic, I had articulated my underlying premise that our great societal challenges can not be solved by science alone. While scientific innovation is often necessary to solve these great challenges, it is not sufficient. Effective solutions need to be multidisciplinary and based on science, ethics, policy & law, and economics; my four PBH Lenses. Over time I added leadership as another important dimension to envision and then implement effective solutions.

Can I apply my PBH framework to the US response to the COVID-19 pandemic? I think it is worth testing.

This is indeed a sobering assessment. How can it be constructively used? We are still in the midst of the pandemic, especially in low and middle income countries. As I have said before, we are not truly safe, unless all of us are protected from this virus. Since the past is prologue, surely COVID-19 will not be the last global pandemic. We have already had MERS, SARS, Zika and Ebola threaten the health and well-being across countries and continents just in the past couple of decades. I believe the honest PBH assessment of our response to the current pandemic can help identify important learnings and lessons. The lessons that can help us, as a society, to be proactive – avoiding potential pandemics, limiting them to local epidemics – while also being better prepared for the inevitable next pandemic or global public health crisis.

Broadly speaking, I find myself organizing the PBH lessons learnt into two buckets:

Keep doing, further strengthen, and build on what we are doing well especially in the areas of scientific and biomedical innovation, and economics.
Aggressively and diligently fix those areas that have been lacking, especially in the areas of ethics and policy and law. The need to strengthen our public health infrastructure, capacity, and governance should be high on the list. So should the need to adopt Bioethics as a core value around which we build our public health systems.

Perhaps I will elaborate in more detail the specific lessons from the pandemic in a subsequent post. For now, I am happy that I was able to apply my PBH framework for this assessment, and that it has pointed me in the direction of potential answers to the question I raised. The reason the US has had more deaths from COVID-19 than from the Spanish Flu, in spite of all the incredible biomedical innovations over the past century, is that, we as a country, have neglected the PBH lenses of Ethics and Policy & Law while over indexing on Science and Economics. Narrow focus on science and economics alone cannot make up for the weakness in ethics, policy & law. This assessment makes the case for more comprehensive and lasting solutions, that cover ALL PBH dimensions, to effectively address our great societal challenges such as the global pandemic.

Finally on the PBH Leadership dimension: who is accountable for this tragic disconnect? I think, as a society, this Critical Disconnect represents a collective failure of leadership. Previously, in my Perspectives on Leadership, I have written of my admiration for Presidents Lincoln and FDR, who built coalitions and steered the country, and even the world, during times of crises. Can we even imagine the outcome of the Civil War or World War II without the leadership of a President Lincoln or FDR? As we face new, complex and deadly challenges, my unanswered question is: where are the Lincolns and FDRs of our time? Are we doing enough to educate and develop the next generation of multidisciplinary, transformational leaders who can comprehensively address the Critical Disconnect, and prevent it from recurring? To do so would be the most valuable lesson of all.

Gene Therapy – Connecting Three Exciting New Developments

Three very different, recent developments related to Gene Therapy caught my attention. One was a company specific announcement, another a national funding decision, and the third a global policy recommendation. In the spirit of PBH, I will share how I connected these distinct developments – from Cambridge, MA; Bethesda, Maryland; and Geneva, Switzerland – and along the way discuss their broader implications.

In the last week of June, two biotech companies – Inetllia and Regeneron – announced a landmark development in the application of CRISPR Cas-9 technology in humans. They had demonstrated the first safe and effective in-vivo application of this novel technology in a Phase 1 clinical trial to treat Transthyretin (ATTR) Amyloidosis. This is the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR. (Intellia). How incredibly exciting!

Transthyretin (ATTR) Amyloidosis is a “monogenic disease,” meaning it is caused by the mutation of a singular genetic mutation. A genetic mutation hinders the correct protein folding process for the protein Transthyretin. Now, this is taking me back to my Science Olympiad events on Designer Genes and Protein Modeling – Proteins have four key structures: the primary and secondary structures focus on the base amino-acid chain and resulting alpha helix or beta strand bonds formed along the chain. The tertiary structure folds the excess amino-acid chains into the final protein, cementing its properties and purposes. The connection of multiple protein tertiary-structures to each other is what makes up the quaternary structure.

The hereditary ATTR Amyloidosis occurs when a person is born with mutations in the TTR gene. This causes the liver to produce the protein Transthyretin with a tendency to misfold, thus changing its tertiary structure and inhibiting the protein’s function. Accumulation of the misfolded protein leads to the buildup of amyloid deposits in the body causing complications in the patient’s nerves, bone marrow, heart and kidney. If untreated, life expectancy of patients is 2-15 years after the onset of symptoms.

Intellia’s therapy (NTLA-2001) to treat ATTR Amyloidosis targets the Transthyretin (TTR) proteins. The therapy includes a lipid nanoparticle – similar to the mRNA vaccines (PBH) – and a two part gene editing system: a guide RNA specific to the disease causing gene, and the Cas-9 mRNA that encodes the enzyme that does the precision editing.

*Illustration by Rama Bhagwat – based on information at Intelliatx.com*

While additional clinical trials are underway, this exciting development opens the door to the possibility that in-vivo, single dose, gene therapy may be able to treat or cure other monogenic diseases. In order for this to come to fruition, we now have a proven safe and effective CRISPR Cas-9 platform, what is needed then is basic scientific research to identify the specific genes that cause each of the monogenic diseases.

This brings me to the second development: On July 15th, 2021 – less than a month after this breakthrough in in-vivo gene therapy – the NIH announced almost $80 million in new funding to support research efforts to discover the cause of single-gene diseases and disorders. There are 7000 Mendelian gene diseases affecting several hundred million individuals in the world. The current pace of identifying the genes that cause each of these diseases is about 300 a year. This new NIH funding has the potential to significantly accelerate the pace of these discoveries. The speedy discovery and availability of data surrounding specific mutations and mutagenic causes of disorders will be vital for researchers to better understand, identify, and ultimately develop new gene therapies, faster.

Yes, economic and affordability factors ultimately need to be considered. Especially given the vital role public funding, such as NIH grants, has played in the development of the science that is the basis of so many of these innovations. I will continue to learn and think about ways that these exciting innovations are made broadly affordable and accessible. Perhaps sharing my thoughts and learnings in a subsequent blog.

Beyond science, policy and economics, the other big question is – what are the ethical guardrails for gene editing in humans? There seems to be a growing consensus around the ethics of somatic gene editing, but what about human germline gene editing? More than a year ago, as I discussed in my earlier blog, A Look Back… Eugenics to CRISPR (PBH), I began to explore the ethical implications of novel gene editing technologies. As new advancements are made, and as our understanding evolves, there is an even more urgent need for global collaboration to evaluate and establish ethical guardrails and legal standards for the application of gene editing.

That brings me to the third recent development out of Geneva, Switzerland. On July 12, 2021- the WHO released its first global recommendations on human gene editing for the advancement of public health (WHO). The recommendations are based on over two years of consultations and hundreds of diverse perspectives. They cover both somatic gene editing – modifying a patient’s DNA to treat or cure disease – much like the Intellia therapy; as well as germline and heritable human gene editing. More needs to be done to generate a global consensus, build capacity across countries and establish some mechanism of enforcement. However, this WHO announcement is an important step towards ensuring that humanity can benefit from the immense potential of gene editing to diagnose, cure and treat disease, while still protecting our universal human values.

I hope this blog has brought to life the connections I saw across these three very different developments. Reflecting on these developments, I began to better understand how these various pieces fit into kind of a jigsaw puzzle, or an ecosystem. As I pictured this ecosystem, I observed a couple of virtuous cycles further accelerating the discovery and development of gene therapies.

Finally, these developments reinforce my belief in the need for, and the power of, public-private partnerships and global collaboration to address shared challenges especially in the area of bioethics, and for the prudent advancement of innovations that can improve the health of all our peoples. As a high school student, I am excited about these promising developments. I continue to be fascinated by what I am learning and the personal insights I am able to gain as I research and reflect on these developments through multidisciplinary lenses. This is my PBH at work!

TRIPS Debate + Reframing The Question: Should The US Waive COVID-19 Vaccine Patents?

It is good to see that the United States is effectively bridging the chasm from vaccines to vaccinations. Almost 50% of the US population has been fully vaccinated. In the US, vaccines are now freely available and authorized not only for adults but also for children over the age of 12. Additionally, the CDC has recently announced that individuals do not need to wear masks in most instances; two weeks after they are fully vaccinated. Many restaurants and local businesses are now open and resuming business indoors. Even Disneyland in California is once again open for out-of-state visitors. Schools and universities have announced plans for in-person sessions, starting in Fall. As a rising high school senior, whose sophomore and junior years have been disrupted by the pandemic, this means my friends and I may actually have a normal senior year of high school! I may even be able to visit a few college campuses in-person, and meet college students and professors, before I send in my application. What a wonderful feeling it is to see life in the US starting to return to normal!

Vaccines and vaccinations have been the turning point in this recovery. This progress to overcome the COVID-19 pandemic has been possible not just because of science, but by combining breakthrough scientific discoveries with thoughtful and ethical public policies, laws, and economic relief. In addition to the US, several other developed countries such as the UK, Canada and Israel have also made good progress in getting their citizens vaccinated, and are starting to reopen businesses and institutions. However, many of the less developed countries – the ones that the World Bank describes as developing and Low and Middle Income Countries (LMICs) – have not yet bridged the chasm from vaccines to universal vaccination.

In the graph above, based on Our World In Data, I have selected 20 countries including developed and developing countries and LMICs. The graph shows, as of May 29, 2021, the percent of the total population with at least one dose of an authorized COVID-19 vaccine. The chart reveals a stark contrast between the developed countries and the rest of the world. Countries such as Israel, UK, United States, Canada, and France have all vaccinated over 35% of their total population. There’s a clear break between these countries and the less developed countries such as Brazil, India, Indonesia, and South Africa, which range from 27% vaccinated to just under 1% of the population having received even a single dose of the vaccine.

Such stark contrast and disparity are so disheartening and unfair. This should not be acceptable. Period. While the level of infections, hospitalizations, and deaths have gone down dramatically in the developed world, they are still rising in much of the underdeveloped world. This humanitarian crisis persists, and is even accelerating in underdeveloped countries. This is a global pandemic that knows no boundaries. No one country is truly safe unless all countries are vaccinated. That we must not lose sight of. The world must urgently find effective ways to provide access to COVID-19 vaccines for the developing countries and LMICs.

It is in this context that TRIPS has been in the news over the past month. Developing countries, such as India and South Africa, have proposed to the World Trade Organization (WTO) a plan to temporarily suspend certain aspects of the WTO Agreement on Trade Related Aspects of Intellectual Property (TRIPS); especially those related to COVID-19 vaccines. In early May, 2021, during the two-day meeting of the WTO General Council, the United States government announced that it would support temporarily waiving the COVID-19 vaccine patents. Soon thereafter countries such as Germany and the UK announced that they would not support suspending the TRIPS provisions. There has been a lot of media coverage of this topic. Given my interest in both Biotechnology as well as in Business Law and Ethics, I wanted to further study and reflect on this topic in my blog.

Intellectual property (IP) – including patents, know-how, and research – are vital for innovation. Protection of intellectual property allows for companies and individuals to reap the rewards for their work, giving the ability to focus on future research, ideas, and development. In the current context, intellectual property is vital for pharmaceutical companies who are investing heavily, at risk, to develop new and promising therapies and vaccines. While some have succeeded there are dozens of companies that have not. At its core, IP laws give research institutions, individuals and companies the right to the creations of their own minds and efforts. It is also important to note that availability of patents alone are not sufficient to develop complex vaccines and therapies. A lot of the “secret sauce” is in the scientific and technical “know-how” that individual companies have developed. The WTO TRIPS agreement is an important trade agreement between all 164 WTO members. Established in 1994, TRIPS plays an important role in facilitating global trade and providing increased legal clarity on matters of global trade and economic relations. TRIPS does allow for compulsory licensing at times of public health emergencies, and the COVID-19 pandemic certainly qualifies as one.

Both sides in the TRIPS debate have been making their case over the past month. Those in favour of suspending TRIPS and waiving the patents make the arguments that it would remove some of the primary obstacles in the way of an equitable access and distribution of vaccines: production bottlenecks, financing, and patents. They argue that the TRIPS waiver and thereby giving access to vaccine patents will make it possible for LMICs to produce the vaccines themselves. They claim that this would cut both production bottlenecks as well as financing issues for the country, and allow LMICs to produce their own generic form of the COVID-19 vaccines. Each country could then produce the vaccines needed to support their populations, as opposed to relying on developed countries such as the United States, the UK, and Germany. A secondary benefit, they argue, is that by formally waiving the patents, it won’t set or encourage the wrong precedent of countries simply ignoring intellectual property rights in order to get access to effective vaccines. Those against suspending TRIPS point to the negative future implications of the proposal. They argue that such waivers would set a bad precedent, not address the current supply limitations, and create less incentives for innovation in the future.

I think there is a need to reframe the question and the discussion on this topic. All the focus and debate on whether or not to suspend TRIPS and waive patents may be misplaced and distracting from the overarching objective. I believe the main objective is to overcome the COVID-19 pandemic globally, as fast as possible, by vaccinating a vast majority of the global population and giving all countries, including those less developed, access to effective vaccines in massive quantities. I think the right question to ask then, is not whether the US should waive COVID-19 vaccine patents, but what can the US and other rich countries do to ensure that all countries have access to safe, effective and affordable vaccines as rapidly as possible and in massive quantities? This will help move beyond the current debate, from a particular tactic to focusing the world on achieving the overall objective. From villainizing rich countries and innovative companies that have given us these effective vaccines in record time, to effective global engagement. From an us-versus-them mindset to one of collaboration for the greater good.

What then is slowing down the massive scale of vaccine manufacturing and access? My reading and research suggests that just suspending the TRIPS provisions and waiving the COVID-19 vaccine patents, while antagonizing the innovative companies that developed these vaccines, will not be effective in addressing this supply and access shortfall. Expecting massive availability of vaccines within a year from now to meet the vaccine supply needs of all countries merely by waiving the patents would be like a high school swimmer hoping to win an olympic medal in a year, soley by reading a book and practice log on the current olympic champion. The probability of this approach succeeding is infinitely low. I certainly would not be depending on such an approach with thousands of lives, mostly in the less developed world, at stake. The challenges to rapidly increasing vaccine production go well beyond just access to patents. They revolve around having enough supplies of raw materials and key ingredients, access to validated and approved vaccine manufacturing sites, quality control, and manufacturing and technical know-how, beyond just the patents.

So while the debate around TRIPS and suspending the vaccine patents makes for interesting headlines and media debates, I believe that the most effective way to provide access to vaccines in large quantities, quickly, is for the developed world and philanthropic organizations to work with all the companies that have efficacious, authorized vaccines to massively scale-up manufacturing and supply chains so that there are enough vaccines to immunize the global populations. This would be the fastest, safest, and most effective path to overcome the pandemic; not just in the developed world, but also globally.

As I reflect on this blog and proposed solution, I think there is one critical PBH (Philosophy of Biology and Health) lense that warrants further study: the Economics Lense. How would the economics of this proposed solution work; is the solution I am suggesting even feasible? I will plan to cover the economics separately in a subsequent blog.

Racial Inequalities in Healthcare, Drug & Vaccine Development

In the summer of 2020, the country surged with support for the Black Lives Matter (BLM) movement, in protest of the systemic racism that unfortunately still occurs in our country. Through peaceful protests, widespread donations and petitions, and increased media coverage, the world’s eyes were opened to the various social and political disparities that affect many minority groups. In this blog, I will look through my Philosophy of Biology and Health (PBH) lenses to discuss the health disparities faced by many people of color (POC) in terms of disease prevalence and under representation in the clinical trials used to develop drugs and vaccines.

Health disparities between different demographic groups is commonly defined as the “attainment of full health potential” for individuals, and is measured through differences in incidence rates, mortality rates, severity of the disease, and future side effects (NCBI). While health disparities can occur due to a variety of demographic factors such as gender, sexuality, age, and socioeconomic status, one of the predominant determinants of this disparity is race.

Like so many other healthcare related challenges, this discrepancy has become much more evident in light of the COVID-19 pandemic. Currently, as of February 18, 2021, the CDC reported that the risk of COVID-19 infection, hospitalization and death was substantially higher for many racial and ethnic minority groups. The table below summarizes the current CDC findings.

These health disparities did not begin with the current pandemic, they have long represented a challenge to our healthcare system across many disease areas. As an example, a 2018 study showed that asthma, a lung-condition that causes inflammation of the lungs, is 42% more likely to impact African Americans than white individuals. While white individuals had a 7.7% chance of receiving the disease, African Americans had a rate of 10%, and Native American groups were even higher at a rate of 12% (Lung.org). Regarding overall respiratory disease prevalence in the United States, African Americans and Hispanics made up 12% and 16% of the population, respectively (Journal of Women’s Health). Type 2 Diabetes is another disease that illustrates this disparity. Those of Hispanic heritage, both white and black, were reported to be 1.56 and 2.64 times more likely to contract adult-onset Type 2 Diabetes, respectively, in comparison to their non-hispanic counterparts (NHIS). Perhaps cancer represents the most significant health disparity based on race. African Americans are the most likely racial group to contract Breast, Lung, Colon, and Prostate cancer (RCCA). In addition to contracting the disease, African Americans have been found to have higher mortality rates across these different forms of cancer, on average, in comparison to other racial or ethnic demographics (Cancer.gov).

That these trends have been in place for so long is very disturbing to me. I think a lot needs to be done to understand the causes of these disparities and also to effectively address them. As a start, pharmaceutical companies should make sure that the clinical trials that are conducted to test the safety and efficacy of new treatments – drugs or vaccines – are representative of the population suffering from that underlying disease. In the United States, new drugs and vaccines must go through a series of clinical trial phases in order to be approved. These trials allow scientists, researchers, and doctors to test the safety and efficacy of the new medicines. Each study is conducted with clinical trial participants, usually patients previously diagnosed with the disease and sourced from various hospitals and medical programs. Upon completion, companies and scientists submit their research to the FDA for safety approval. The end goal is a medication that can be used across all patients of the disease, safely and effectively.

I have spent hours going through data on the FDA and related websites. I had assumed, before I began researching some of the data, that a critical requirement for the design of clinical trials would be the fair representation of the underlying patient population by race and ethnicity. However, over the past decades, many drugs and vaccines have been developed and approved based on clinical trials that do not correctly represent the racial and ethnic diversity of the underlying patient population. This is especially problematic for diseases that disproportionately impact POC and underrepresented racial minorities. For example, despite respiratory illnesses being predominant in African American and Hispanic populations, as of 2015, only 1.9% of clinical trials included a representative number of minority subjects (The Editors). In other respiratory disease studies, African Americans made up only 5% of the clinical trial subjects and Hispanics only made up 1%.

Another challenge is perhaps that the effectiveness of approved drugs and vaccines is not reported based on the race and ethnicity of the patients treated. Also, the adverse event data that are reported to the FDA to document the undesired effects of the medications do not require companies to report this information by race and ethnicity.

As I think about this issue from the PBH lenses, I believe there is much that can be improved to make our drug and vaccine development process more representative of the racial diversity of the affected patient population, and as a result make the new drugs and vaccines more effective and safer for all people. A few starting thoughts on potential improvements that I will continue to explore in the future include:

FDA updating guidelines and requiring companies to design clinical trials that represent the racial diversity of the affected patient population
Eliminating barriers (social, economic, trust, awareness, etc.) to the low representation of POC in clinical trials
FDA requiring companies to report the effectiveness and adverse events of their drugs and vaccines by race and ethnicity

Bridging the Chasm: From Vaccines to Vaccinations

8 months ago when I started this PBH blog, my underlying premise was that scientific breakthroughs and science alone, while necessary, are not sufficient, for solving many of the health-related challenges facing our society. I believe that nowhere is this more true than in bridging the chasm from the discovery and development of the COVID-19 vaccines, to the vaccinations in large numbers sufficient to achieve herd immunity. Effectively addressing significant challenges, such as the COVID-19 pandemic, requires multi-faceted solutions that include considerations across Science, Ethics, Policy & Law, and Economics.

In my last blog, I shared my excitement about the tremendous accomplishment of utilizing novel mRNA technology to develop safe and effective COVID-19 vaccines in record time. Recent headlines have tempered that excitement. It has been disheartening to see the recent reports about vaccines not being used, sitting in freezers, or even going to waste. As of mid-January, on average across the US, only 35% of the distributed vaccines have been administered (CBS News). California, which according to the John Hopkins Covid Tracker has nearly 40,000 new daily cases and over 700 daily deaths, has only administered 26% of the vaccines they have received. Georgia has only administered 20% of the vaccines received. How is this acceptable in our country, one of the richest and most developed in the world?

Many other countries are doing a lot better at vaccinating their citizens (OurWorldData). As of mid-January, Israel, for example, has vaccinated approximately 25.8% of their population, as compared to 3.7% in the United States! Even the United Kingdom is doing much better, at 5.9% of their population.

More people are dying in the US, in a single day, than died from the terrorist attacks on 9/11. That day transformed the way the US deals with intelligence gathering and terrorism threats. This pandemic must be the crisis that transforms healthcare in the US. Clearly just scientific and technological advances, such as mRNA vaccines, are not sufficient. My hypothesis is that we need a multifaceted approach. We need continued contributions from science and technology to now develop effective, 1-dose vaccines that are more stable and easier to store and distribute.

From a Policy & Law Lense, short-term, I think that the United States needs to develop a much stronger and more streamlined vaccination plan. Currently, there is little coordination between federal and state governments on the most effective method for COVID-19 vaccinations. Each state is responsible for administering their allocated vaccines, developing priority groups, maintaining lock-downs, and scheduling the second-dose appointments. Developing a national plan that’s congruent across all states and territories, developed by heads at the HHS, FDA and CDC, and consistently implemented using say the national guard in each state would provide the structure needed to maximize the timely use of all available vaccine doses. Looking at learnings from countries like Israel and the UK, both the countries seem to have benefited from a national health system. Perhaps it is time for the US to establish an effective national health system.

From an Ethical Lense, we need to continue to make sure that the vaccines for this pandemic are available for free to all citizens. Some recent reports claim that elite medical schools have received an excessive number of vaccines, and people socially well-connected and rich have found ways to receive the vaccine early. Could the HHS or CDC establish a special office, not just to provide consistent ethical guidelines for vaccine distribution, but also to track their implementation, and, through the influence of the federal government that is supplying these vaccines, ensure compliance to these fair and ethical vaccination policies across all states? Beyond the US, the world must come together to make it easier for all countries to have the option to manufacture the COVID-19 vaccines in their own country, at a lower cost. An important step will be to make a one-time ethical and humanitarian exception for the IP associated with the COVID-19 vaccines.

From an Economics Lense, it is good that this first round of vaccines is being given for free in the United States. Given the shared public health implications of this pandemic, we need to ensure that the COVID-19 vaccines will continue to be available for free even if we find out that our entire population needs to be vaccinated for multiple years to come. Governments need to budget for this while also working with pharmaceutical companies to reduce the cost to manufacture the vaccines and the price the governments have to pay for them. Hopefully, economies of scale and increased competition with multiple safe and effective vaccines will help reduce the price over time.

These are my early thoughts based on reactions to recent news headlines. The COVID-19 pandemic has given us a real-life view into why focusing solely on scientific and technological innovations doesn’t automatically solve our greatest health challenges. By looking at all four of my PBH lenses – Science, Ethics, Policy & Law, and Economics – I am optimistic that with time and dedication, the United States and the world can bridge the chasm from vaccines to vaccinations, and a safer, healthier society.