Reviving the Pharmaceutical Industry, Reality Check: Lessons from Overseas

Recently, The Sankei Shimbun and JAPAN Forward highlighted Japan’s “lag” in discovering and developing novel drugs. The articles called for a revival of Japan’s pharmaceutical industry.

The editorial writers for the series might get more than they bargained for. While they focused on vaccines, the Cabinet’s 2021 “Plan for Strengthening Vaccine Development and Production Systems” cited in the series could be copied and pasted for the development of all drug classes.

Just replace “vaccines” with “therapeutics”. Domestic drug companies, big and small, will be more than willing to go along with that plan.

Chasing After Small Fish

Given the full-court press by governments around the world to vaccinate everyone against COVID-19, global sales of Pfizer’s COVID-19 vaccine, Comirnaty, brought in almost $37 billion USD in 2021. For 2022, Pfizer predicts sales of Comirnaty will be around $32 billion USD. Perhaps the Government of Japan saw these sales figures and wondered how it could get in on the action.

A reality check is needed, however. Billion-dollar vaccines are uncommon.

Merck’s biggest selling drug in 2020, Keytruda, a biologic used in cancer treatment, brought in $43 billion USD. But RotaTeq, Merck’s vaccine against rotavirus (which causes severe diarrhea in children) brought in $797 million USD in 2020. (As a humanitarian gesture, Merck sells RotaTeq to third-world countries, where rotavirus-induced illness in children can be particularly lethal, at a 95% discount, since the vaccine is not a significant source of income.)

Japan’s Medical Conditions Without Cures

Disease epidemics wax and wane, as they always have throughout human history. But one should always remember that the leading causes of death in Japan — cancer, heart disease and senility — are still without effective cures. Complications accompanying aging, such as chronic pain, will also need to be addressed.

Vaccines are therefore neither a panacea nor even a reliable source of revenue. Nor are vaccines necessarily what Japan needs most.

Consider that even with the all-hands-on-deck response to COVID-19, the National Institutes of Health (NIH), a United States government agency, increased funding for basic research for cancer, heart disease and senility in 2021, compared to 2019. Even higher levels of funding are expected for 2022. Indeed, the US has a wide-focus, long-term approach for elaborating the biology of human health and illness.

Show Me the Money!

The usual government response to a problem is to set up a committee and then entrust it with a lot of public money to solve that problem, and the Government of Japan is no exception.

In March of 2022, for instance, the Cabinet approved over ￥150.4 billion JPY (about $1.24 billion USD) for the establishment and operation of the Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA). (Conversions from JPY to USD are taken from the cited articles.)

An increase domestic vaccine development is the Cabinet's aim. The plan is to allocate ￥51.5 billion JPY ($420 million USD) to “prepare major development sites” and another ￥150.4 billion JPY ($1.13 billion USD) for vaccine research and development. According to the The Sankei Shimbun and JAPAN Forward, grants of up to ￥3 billion JPY ($22 million USD) will go to universities to facilitate the development of new vaccines.

Large pharmaceutical companies (“Big Pharma”) have a prominent role to play, according to the series, as they have the capacity to manufacture and market drugs on a global scale. However, the extent of the Japanese government’s commitment to small biotechnology companies is not entirely clear.

Getting Small Businesses Into the Act

In the United States, biotechs are the tip of the spear when it comes to new therapeutics, including COVID-19 vaccines.

Take Cambridge, Massachusetts-based Moderna. Moderna received over $1.5 billion USD from Operation Warp Speed, the US government’s crash effort to produce a COVID-19 vaccine. BioNTech, Pfizer’s German biotech partner that developed Comirnaty, received $445 million USD from the German government.

Per capita US gross domestic product is double that of Japan and the United States population is almost three times larger than that of Japan. Even taking these factors into account, US spending on new COVID-19 vaccines alone is grossly disproportionate to that of Japan’s initial foray into new vaccines.

Japan is spending far too little to make a dent in the global competition to produce vaccines.

Every year the NIH sets aside over $1 billion USD for American small businesses (defined as businesses with fewer than 500 employees) to pursue nonclinical and early-stage clinical studies for new biomedical technologies with commercial potential. What the Japanese government is offering in terms of overall financial support to the pharmaceutical industry is hardly a blip on the radar screen.

Innovation: Can the Brain Drain be Stopped?

There are barriers other than financial ones that Japan needs to overcome before fully reviving its pharmaceutical industry. The Sankei Shimbun and JAPAN Forward series boasts that “Japan is one of the world’s leading countries in the discovery of new drugs.” Overall, however, compared to other countries, Japan is not very competitive in the sciences.

In the top 10 rated countries for life science research, Japan is fifth, behind the US, the UK, Germany — and China

Many Japanese scientists leave Japan, most with no intention of returning. One reason Japanese scientists leave is that “they could not find the kind of job they wanted in Japan.” Others point to problems within Japan’s academic environment, including “age-based seniority,” recognition based on institution or head professor rather than individual merit, and the “closed nature and lack of diversity of research labs” which stymies “free discussion.”

Interestingly, those who do want to return will do so if there is a “research position at a Japanese university or public institution,” rather than a biotechnology or pharmaceutical company wherein basic science is applied to improving human health.

The Japanese government has yet to state what it plans to do to stop the exodus of scientific talent and to promote applied science as a career.

Stifling Curiosity-Driven Research

At the same time, there are those who believe that Japanese government policies are stifling basic science research. Syukuro Manabe of Princeton University, co-awardee of the 2021 Nobel Prize in Physics, stated that Japan is generating “less and less curiosity-driven research.” Professor Manabe left Japan for good after obtaining his Doctor of Science degree.

Dr Manabe has suggested that underlying all of the problems of Japanese academia identified earlier is the “lack of dialogue between scientists and policy makers.”

*2021 Nobel Prize in Physics co-awardee Syukuro Manabe.*

Perhaps current problems facing Japanese academia and the brain drain could be ameliorated if scientists directly confront policy makers—those who control funding.

Then again, however, perhaps there are those who like things just the way they are now.

Clasping the Asp to the Bosom

Collaboration between Big Pharma and the Japanese government is crucial to get drugs from laboratories to patients. However, The Sankei Shimbun and JAPAN Forward series did not mention a mechanism to ensure transparent interaction.

American Big Pharma has produced numerous, spectacular drugs that have improved and extended lives. But this does not come without cost, including regulatory hurdles. Pre-marketing approval by the US Food and Drug Administration (FDA) is mandatory for sale within the United States and facilitates obtaining marketing approval in most countries.

It is at this stage that ethical issues arise — along with the temptation to sacrifice ethics for profit. If trillions of yen are at stake, then Japan must learn hard lessons from the US to ensure accountability as well as transparency.

For example, in the US, a revolving door relationship exists between government regulators and the pharmaceutical industry. That is, there is a free flow of corporate executives and key government personnel involved in drug approvals.

The revolving door relationship is clearly illustrated by the controversy surrounding various branches of the US government and Purdue Pharma, which manufactured and marketed the opioid analgesic OxyContin. (Reckless prescribing of OxyContin has been cited as the trigger for the current opioid epidemic in America.)

The OxyContin Case

Curtis Wright was acting Director of the FDA division that oversaw OxyContin’s approval in 1995. Director Wright along with Purdue Pharma officials wrote the package insert for OxyContin. The package insert accompanies every prescription drug and contains dosing and safety information. Rather than objective statements, however, OxyContin’s package insert was basically “promotional and marketing material.”

Purdue Pharma officials also “helped” the Director compose reviews for their drug. Following OxyContin’s approval, Wright was later hired by Purdue Pharma.

Purdue Pharma used its attorneys, some “veterans of tobacco litigation,” others politically well-connected, to quash lawsuits directed at it. Then Purdue hired former deputy Attorney General Eric Holder and former US Attorney Mary Jo White as legal counsel. Holder went on to become President Obama’s Attorney General, and White would later serve as President Obama’s Chair of the Securities and Exchange Commission.

Author Patrick Keefe explained Purdue’s tactic: “If you were appealing to current prosecutors, it could be very helpful to send someone they recognized… perhaps, someone they might admire.”

Purdue Pharma also hired former US Attorneys who had in the past called out Purdue Pharma for its role in the opioid epidemic as consultants. The company used its political connections to try and terminate a federal investigation, telling then-Deputy Attorney General James Comey, who later served as President Obama’s Director of the Federal Bureau of Investigation (FBI), to “rein in the Western District of Virginia (US Attorney John Brownlee)”. This ploy failed.

Full Disclosure to Overcome Problems

It appears a collusion of sorts between the Japanese government and pharmaceutical industry is in the making. Dr Junichi Koga, the Provost of SCARDA, “hit it off with Dr [Michinari] Hamaguchi, the leader of SCARDA, after having drinks on the night of April 19th [2022].” “We will promote change by taking advantage of Dr Hamaguchi’s experience in academia and my experience in industry,” Dr Koga said, according to the series.

Koga was a former managing director of Daiichi Sankyo and also served as the head of research and development there. Dr Hamaguchi has served as the president of Nagoya University and director of the Nagoya University Faculty of Medicine.

There is nothing wrong with colleagues having drinks. But remember that these two are key government decision makers with control over who is allowed into the SCARDA network and who receives funds.

It is unlikely that these men have abandoned their network of past contacts. Those networks may play a crucial role in shaping the character of the SCARDA network of the future. To retain public confidence in SCARDA and its eventual products, full disclosure is imperative.

The Invisible, Omnipresent Hand of Government

The series of articles in The Sankei Shimbun and JAPAN Forward does not mention specific regulatory changes that could help to boost innovation and eventual marketing of Japanese therapeutics worldwide. One area of regulation that the Japanese government should seriously consider is its control over the pricing of pharmaceuticals.

Every year, in an effort to keep health care costs low, the Japanese government reviews drug prices and slashes them. Pharmaceutical companies, both within and outside of Japan, naturally take a dim view of the government’s annual price cuts. Why bother to market a drug in Japan at all if profit margins are guaranteed to decrease over time?

One other reform the Japanese government should undertake is to meld clinical data and experience with public health policy. Moral panic has no place in deciding public health policy. Clear facts must hold sway.

The urgency of this need becomes apparent when one considers the one vaccine that has managed to surpass the billion-dollar annual sales threshold: Gardasil, Merck’s vaccine against the human papillomavirus (HPV). (HPV causes cervical cancer.) This therapeutic brought in just under $4 billion USD in 2020.

Gardasil was approved for use in Japan in 2011 and was recommended by the government in April 2013 for routine immunization. But in June of the same year, after media-driven hysteria fueled by claims of adverse effects following immunization, the government, already hypersensitized to its responsibility for previous vaccine-related problems, indefinitely suspended the use of HPV vaccines.

It was not until April of 2022 that the government lifted its suspension. Rather than allow fear and ignorance dictate public health policy, cooler heads must prevail.