Topics Held the Pharmaceutical Manufacturers Association of Japan (PMAJ) Media Forum. Considering the Diverse Values of Pharmaceuticals - For the Rich Daily Lives Desired by Patients and Their Families

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On June 7, 2022, the "Pharmaceutical Manufacturers Association of Japan Media Forum" was held at Nihonbashi Hall (Chuo-ku, Tokyo). Twenty-seven journalists from 20 companies attended the forum at the venue and via webcast. The theme of the forum was "Considering the various values that pharmaceuticals bring - for the affluent daily lives that patients and their families desire. Executive Director of the Pharmaceutical Manufacturers Association of Japan (PMAJ), Mr. Kazuhiko Mori, facilitated a panel discussion among the three speakers.

Background of the Forum

As Japan faces a declining birthrate and aging population, and the number of "supporters" in the social security system continues to decline, pharmaceuticals are expected to contribute to increasing the number of "supporters" by extending healthy life expectancy. For example, by curing diseases or inhibiting the progression of disease, pharmaceuticals can improve the quality of life (QOL) of patients, improve productivity loss, and contribute to their reintegration into society. In addition, it also brings various values, such as reducing the workload of not only patients but also healthcare professionals and the burden of caregiving for patients' families.

In this issue, we will focus on specific diseases such as novel coronavirus infection (COVID-19), rheumatoid arthritis, and migraine headaches to clarify the current situation and issues of reduced quality of life and loss of productivity, and then we will discuss how pharmaceuticals contribute to the lives of patients and their families, The forum will also discuss how pharmaceuticals contribute to the lives of patients and their families and what is expected of pharmaceuticals in the future, and will serve as an opportunity to consider the various values that pharmaceuticals possess.

The following is a transcript of the lectures.

Subject 1

What is the "value" of pharmaceuticals? Beyond cost-effectiveness...

Associate Professor, Health and Social Medicine Unit, Yokohama City University School of Medicine
Dr. Naka Igarashi, Visiting Associate Professor, Pharmaceutical Policy, Graduate School of Pharmaceutical Sciences, The University of Tokyo

Today, I will introduce the value of pharmaceuticals, focusing on various factors that cannot be captured by cost-effectiveness (cost = money/QALY [quality-adjusted life year] *1) alone.

The "optimal allocation" of medical resources

In the field of health economics, resources (money) are limited, but when the situation becomes untenable, it has been possible to respond by raising budgets from other fields or by taking measures such as increasing co-payment rates and insurance premiums. However, the Corona Disaster made it widely recognized that health care has limited physical resources, creating the need for a more balanced approach with other fields ( Fig. 1 ). It has also become clear over the past two years that the relationship between health health care and the economy must be considered relatively, as they strongly influence each other.

Figure 1 Changes in optimal allocation theory in medical resources

What are the elements of value?

It is important to recognize that the elements of value are not only the so-called COST and QALYs, which may include the following

(1) Productivity loss due to new coronavirus infection (COVID-19) (1) Loss of productivity due to new coronavirus infection (COVID-19)

Productivity loss includes both the loss of being "unable" to work due to illness or its treatment and the loss of being "unable to get by"; in the case of COVID-19, until 2021, the patient himself was on home leave for 10 days and the concentrated contact person for about 14 days. Comparing the medical costs and productivity losses by month, assuming two persons per patient for each concentrated contact, the scale of productivity losses was estimated to be 5 to 6 times larger than medical costs after the Delta and Omicron strains ( Figure 2 ). While the number of infected patients expands, the impact of productivity loss is inevitably larger than medical costs because the hospitalization rate declines significantly. It can be said that this confirms the fact that the value of COVID-19 drugs and vaccines cannot be evaluated if only medical costs are assessed.

Figure 2 Comparison of medical costs and productivity losses

(2) Impact of dementia on family members

It has been suggested that as a patient's own quality of life declines due to disease, the quality of life of caregivers and family members also declines. The best example of this is dementia. Although medical costs do not change much as the disease becomes more severe, social costs such as nursing care and family care increase significantly, so that evaluation based on medical costs alone still fails to capture the burden of the disease ( Figure 3 ).

Figure 3 Social costs rise with increasing severity

(3) Effects of treatment and prevention of infection

The treatment and prevention of infectious diseases has benefits (group immunity) beyond those of the target population, and also has the effect of alleviating anxiety about infectious explosions. In addition, based on the concept of stewardship (meaning management and operation, etc.), the UK has responded by introducing measures such as "subscription," in which the government pays a certain amount to pharmaceutical companies for drug-resistant (AMR) antimicrobial agents, not limited to the amount used, to maintain development incentives. As part of this proper use, it is significant that in the UK, the value of drugs is also evaluated, even when they are not "used".

(4) Value according to the severity of the disease

The idea is that "plus one year" in critically ill or terminally ill patients may have a different level of value than those who are not. There is also the idea that it should be weighted according to life-saving principles, past contributions, future expectations, etc. There is still room for debate on these issues, but at the very least, this element is missing from the current HTA (Health Technology Assessment).

What is the value of pharmaceutical products?

In November 2020, a web-based survey was conducted jointly with the Institute of Pharmaceutical and Industrial Policy, targeting men and women aged 20-69 (2,155 respondents) on the "value of medicines and the way general consumers think about receiving medical examinations, etc.". What caught our attention in this survey was that the item "reduction of medical burden" rose to the top of the survey results. We believe it is very important that after the Corona Disaster, the value of reducing the burden on medical professionals was recognized ( Figure 4 ).

Figure 4 Items that are important as the value of new drugs

What is a price commensurate with value?

I have recently heard many people say that the price should be commensurate with the value. Hepatitis C drugs are often cited, but hepatitis C drugs are administered in a short period of time and are extremely effective. Since existing drugs (interferon), which are expensive in their own right, are no longer needed, cost reductions can be expected. And various domestic data on QOL, medical costs, etc., had been developed well before the drug was launched...this is a rare case. Therefore, even if the trial calculation for hepatitis C is successful (high price), there is no guarantee that the same results will be obtained in other areas. For example, in the area of molecular targeted drugs for cancer, if the prices of the currently quantified data are used, the prices will be much lower than the drug prices at the time of the analysis. This is an issue that needs to be addressed when evaluating various values of drugs in the future. It is necessary to take qualitative values into account, rather than only accumulating values that are already quantified now, and how to reflect these values is an important theme to be considered in the future.

Abstract 2

Advances in Rheumatoid Arthritis Treatment and Health Economic Challenges

Eiichi Tanaka, Associate Professor, Department of Internal Medicine, Tokyo Women's Medical University

What is rheumatoid arthritis?

Rheumatoid arthritis is a familiar intractable disease. If the swollen joints are not treated properly, joint destruction progresses and deformity occurs in the joints. This often occurs in the joints of the hands, and as the deformity progresses, it becomes inconvenient to use the hands in daily life (eating with chopsticks, getting change, etc.). The estimated number of patients in Japan is approximately 600,000 to 700,000, with a male-to-female ratio of 1:4, and the most common age of onset is 30 to 60 years old ( Figure 5 ). Once the disease develops, there is no cure, and treatment must be continued for the rest of one's life. Remission is a state in which the disease has largely ceased to gain momentum and the patient can live without pain, which can only be achieved with medication or injections.

Figure 5 What is rheumatoid arthritis

Effectiveness of treatment

According to our database, the percentage of "remission" was less than 10% in 2000, but it will increase to 64% in 2022. The total of "remission" and "mild disease," which is a relatively good condition, exceeds 80%, and many patients are coming to the hospital in good condition ( Fig. 6, right).

Figure 6 Advances in rheumatoid arthritis treatment

Drugs Contributing to Treatment and Patient Burden

The current status of rheumatoid arthritis treatment is that patients can now do almost the same things as healthy people by treating their joints well before they break down. There are two drugs that have contributed to treatment in the last 20 years: one is methotrexate. It is the first-line drug, known as the anchor drug, and 70% of our patients are treated with this drug. The other is a biologic agent. These are used when methotrexate is not effective enough or cannot be used due to side effects. In our hospital, biologics are used in 1 out of 3 patients ( Figure 6 left ).

Rheumatoid arthritis is a disease with no known underlying cause, but it is believed that the joints are destroyed by factors that destroy bones and cytokines that aggravate inflammation due to an abnormal immune system in the body. Biologics can be expected to suppress cytokines, thereby halting inflammation and preventing the destruction of bone and cartilage.

The co-payment for patients using biologics is 700,000 yen per year (according to a survey conducted in 2007). In the 2020 survey, the co-payment for patients using biologics was still as high as 450,000 yen per year, about three times the co-payment for those not using biologics. While stopping the progression of the disease is important, we need to consider whether it is worth it to use a drug that requires a high out-of-pocket expense.

1/3 of patients experience work restrictions

In 2008, a survey on the working conditions of rheumatoid arthritis patients revealed that 1/3 of those who worked experienced work restrictions and 40% of those who did household chores experienced restrictions ( Figure 7 ).

Figure 7 Working conditions of rheumatoid arthritis patients

Suggested that biologics allow patients to work like the general public

In the U.S., a 5-year follow-up study of salary increases and decreases for rheumatoid arthritis patients showed that salaries increased by 15% for patients who used biologic agents. This result is comparable to the general salary increase in the U.S. and suggests that treatment with biologics allows patients to work as well as the general population. On the other hand, patients not treated with biologics had a 3% salary increase, suggesting that they are not working enough due to absenteeism and productivity impairments ( Figure 8 ).

Figure 8 Wages and Survey on wage and salary increase

Thus, while the drug cost of biologics is high, their value in ameliorating productivity loss is a significant benefit from an economic standpoint as well as improving patient quality of life. We believe that various values should be taken into consideration when evaluating drugs.

Presentation 3

New Drugs Bringing Richer Lives to Migraine Patients

Dr. Koichi Hirata, Vice President, Dokkyo Medical University

Rheumatoid arthritis is a common disease among the generation that will lead Japan in the future

Migraine is characterized by pulsating pain on one side of the head, which is well known, but it can also cause nausea, vomiting, sensitivity to light and sound, and, in severe cases, even falling asleep. The prevalence of the disease is reported to be 8.4%, and 8.4 million people in the adult population are said to be affected.

It is particularly common among women in their 30s and 40s, and the percentage of female patients is approximately four times that of male patients. Thus, migraine is a disease that afflicts people in the prime of their working lives, who will be responsible for the future of Japan in terms of paying taxes and raising children ( Fig. 9 ).

Figure 9 Epidemiology of migraine [prevalence by age and sex]

Recently, the pathophysiology of migraine has been elucidated, and the "trigeminovascular theory" is widely accepted. It is believed that some stimulus stimulates the trigeminal nerve, from which neuropeptides, mainly "calcitonin gene-related peptide (CGRP)," are released, causing neurogenic inflammation and ultimately pain, or in the process stimulating the vomiting center and inducing nausea and vomiting.

Patients have a variety of obstacles and problems that are difficult for third parties to see

International data on the burden of disease in daily life for migraine and other neurological disorders indicate that while Alzheimer's disease and stroke are present in older age groups, migraine has a higher burden of disease in very young people, especially women. It also affects daily life, and in some cases, anxiety about the next attack may sacrifice time with family members or keep people away from appointments because of the inability to keep promises ( Figures 10 and 11 ).

Figure 10 Illness burden of migraine and other neurological diseases on daily life

Figure 11 Interference of migraine patients with daily life

Advances in Treatment

Triptans, an acute care drug, have brought much gospel to patients, but they are sometimes ineffective and cannot be administered due to side effects or other reasons, and treatment satisfaction is low. In addition, calcium channel blockers, antiepileptic drugs, antidepressants, and even beta-blockers have been used as prophylactic agents, but their efficacy has been limited. And it is said that patients in their younger years, from junior high and high school students to those in their 20s, become chronic due to overuse and abuse of existing treatments and over-the-counter drugs.

Under such circumstances, the aforementioned trigeminal vascular theory revealed that CGRP is at the core of seizures, and anti-CGRP-related drugs were developed as a mechanism of action to suppress CGRP. Data show that the number of seizure days decreased from 13.8 days per month to 7.6 days after administration ( Fig. 12 ). We believe that patients are greatly helped by the use of anti-CGRP-related drugs because they reduce daily disturbances. In addition, an oral CGRP receptor antagonist is currently in the clinical trial stage.

Yet another new drug is a 5-HT1F receptor agonist that can be used in patients with vascular symptoms, angina pectoris, and cerebral infarction. Triptan could not be used in such patients, but this is expected to be effective in patients with a history of cardiovascular disease and other conditions.

Figure 12 Change in migraine days before and after use of anti-CGRP-related drugs

SUMMARY

Migraine headaches are sometimes very disabling and have been shown to affect productivity. In this context, the use of anti-CGRP-related drugs, a revolutionary new drug, has made it possible to control the onset of migraine headaches. The era of "migraine doesn't kill you, so just stay home and take painkillers and put up with it" has come to an end, and new drugs can clearly improve the quality of life of not only patients but also their families.

Mr. Hirata: Unlike rheumatoid arthritis, migraine patients look exactly the same as healthy people, so there are cases where families cannot understand "Why does it cost so much to treat? and "Why does it cost so much?" In some cases, the family members do not understand.

In your lecture, you mentioned that medicines have various values and cannot be evaluated only in terms of cost-effectiveness. What do you think is the best way to evaluate such a situation?

Mr. Igarashi: For example, in the UK, a simple reading of the guidelines tends to "mislead" people into thinking that only medical and nursing care costs are taken into account. However, in fact, in various areas such as multiple sclerosis, we have seen cases where the impact on the work of patients and their families has also been taken into account in the evaluation.

In fact, the guidelines clearly state that "the impact of this disease or drug on work is significant" should be considered separately. It is difficult to gain understanding by claiming that a hypothetical disease has a significant impact on work. We believe that showing examples such as, "If we only consider medical costs for such a disease, we will clearly lose the essence of the disease," will lead to a change in the way evaluations are made.

-The lecture introduced drugs that lead to productivity loss and QOL improvement for patients, but as a practical matter, even if pharmaceutical companies and researchers develop excellent drugs, the value is not fully evaluated or innovation is not recognized in Japan. What is your opinion on how Japan should value innovation in the future?

Mr. Igarashi: It is good that discussions on value-based pricing have recently become more widespread, but there are two points to consider: First, not all elements of value can be quantified in the first place, and simply adding up the elements that were quantifiable at the time of market launch is not a sufficient evaluation. How to mix quantifiable value, such as the impact on medical costs and productivity loss, with non-quantifiable value, such as unmet needs, is an issue for the future. Pseudo-quantification of qualitative value elements may seem irregular at first glance. However, in the current drug pricing system, qualitative elements such as "novel mechanism of action" and "rarity of the disease" are replaced by quantitative elements such as the addition rate, and examples of pseudo-quantification already exist.

Second, while drugs with high value will be evaluated at a higher level than at present, there will naturally be other drugs that will be evaluated at a lower level than at present, i.e., a pattern where this is not the case. We believe that it will be necessary to discuss whether pharmaceutical companies can tolerate such a situation.

Mr. Tanaka: Developing a single formulation and bringing it to market is expensive for pharmaceutical companies in terms of human resources and costs. Although it may be difficult in light of the current drug price rules, we believe that it would be better to maintain flexibility in the way drug prices are determined, while at the same time taking into account the profits of the company that developed the drug, so that the profits earned can be used to develop the next drug.

Closing Remarks

Today, we introduced pharmaceuticals as one of the solutions based on what kind of treatment is needed, focusing on the lives of patients and their families.

With COVID-19, it has been recognized that with limited medical resources and the recent rapid changes in the international situation, what used to be taken for granted is not actually taken for granted. Under these circumstances, I look forward to further discussions on what is truly important in terms of the value of pharmaceutical products and what we can do to help patients and their families achieve the affluent daily lives they desire.

( Daizo Shimizu, Koji Iida, Ichiro Tamatomi, Masaaki Ozaki, Takuro Matsuda, Industrial Policy Committee, Industrial Development Subcommittee)

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