Opinion A New Look at the "Right" for "Active Pharmaceutical Ingredients Toward the Realization and Maximization of the Value of Pharmaceuticals
Koji Tamura, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Introduction: Five "Rights" for "Active Drug Delivery
Several key phrases are known about initiatives related to medicine and pharmaceuticals. For example, the Japan Agency for Medical Research and Development (AMED) has a phrase "to put research results in the medical field that value the 'three LIFEs' of life, living, and life into practical use and deliver them to patients and their families as soon as possible " 1), while the Pharmaceuticals and Medical Devices Agency (PMDA) has a phrase "Four 'Fs' (Patient First, The Pharmaceuticals and Medical Devices Agency (PMDA) advocates "taking the initiative in addressing the four 'Fs' (Patient First, Access First, Safety First, and Asia First) " 2). The Japan Pharmaceutical Manufacturers Association (JPMA) has stated in its "Industrial Vision 2025" (released in January 2016) that " advanced drug discovery will contribute to 'P4+1' medicine, which will lead the next generation of medicine. P4+1 medicine is a combination of "predictive, personalized, preventive, and participatory medicine" and "progressive," which was introduced in the U.S. about 10 years ago4). We aim to realize innovation in drug discovery that contributes to both P4 medicine and progressive medicine, and to contribute to the next generation of "P4+1 medicine" that integrates the two, and furthermore, to lead the way with advanced drug discovery". The company states that
In contrast to these phrases focusing on drug discovery activities (in a broad sense), there are "5R" = five "Rights" as used in the medical field. Although the order of the "Rs" is not fixed depending on who uses them and the situation, the five "Rs" are generally listed as (1) Right Drug (Medication), (2) Right Patient, (3) Right Dose, (4) Right Route, and (5) Right Time (& Frequency). The five criteria are ( 1) Right Patient, (2) Right Patient, (3) Right Dose, (4) Right Route, and (5) Right Time (& Frequency ).
In the Research Paper No. 73, "A New Look at the Value of Pharmaceuticals," published by the National Institute for Policy Studies (NIPR) in May last year, the author considered three stages in the "value chain" of pharmaceuticals: "creating value (drug discovery)," "cultivating value (drug cultivation)," and "delivering/utilizing value (active drug delivery), The term "active drug delivery" is used to describe the process of properly demonstrating the efficacy and effectiveness of a drug by appropriately delivering the value of the created drug and ensuring that the drug is used appropriately (Figure 1) .6) In order to achieve this "active drug use," it is necessary for pharmaceutical companies and other providers to appropriately deliver to patients the "product (drug)" that is effective and useful for them plus the "(necessary) information," and for users (patients plus caregivers and healthcare professionals as the case may be) to follow the appropriate usage of the product. The user (the patient plus caregivers and healthcare professionals as the case may be) needs to follow the proper usage. Technological advances in medical treatment and diagnosis, as well as the evolution of drug therapies (in the broad sense of the term) using new modalities, have further increased the importance of efforts toward "personalized medicine" and "appropriate medicine. In this article, we will discuss the approaches needed to achieve these goals, organized around the "5Rs," and rethink what is necessary for "active drug delivery" to properly demonstrate the value of medicines7).
2-1. Right Drug (Medication): Creation + Selection + Delivery of appropriate drugs
Although obvious, they are not always realized as a matter of course in practice. In the conventional drug discovery process, phase III clinical trials (validation trials) basically compare the efficacy of a drug in a drug-treated group (= population) and a control group (= also a population) using appropriate evaluation indices, and determine that a drug is "effective" when there is a statistically significant difference. However, this (subject-less) "the drug works" is not the same as "the drug works" for a specific, concrete individual. In other words, the value of a drug to a specific individual differs from the (average) value of a drug to a group of patients, and if the drug actually works for that individual, the result is "valuable"; otherwise, the result is "worthless" (and possibly even harmful). Right Drug (Medication) is therefore required to be "right" for each specific and diverse patient population that exists in the real world (Personalized Medicine). In drug discovery, efforts are being made to create the "Right Drug" based on new technological innovations such as the use of new modalities, and the development and use of companion diagnostics and gene panel tests, which are tools for determining the Right Drug/Right Patient, are also entering the practical stage. Whole genome testing is also expected to be put to practical use in the not-too-distant future (see also 2-2) .8)
2-2. Right Patient: Appropriate patients (target patients) are selected + Patients take appropriate (medication) actions
In 2-1, the delivery of a "right" drug means that the patient is a "right" patient in terms of the drug. The most common method of drug discovery in recent years is to create and develop drug candidates after clearly defining the profile of the drug target (gene, molecule, etc.) that will improve the patient's condition, and in this case, the target patients are profiled in advance. In this case, the "right" patients are often identified from the development stage because the target patients are profiled in advance.
On the other hand, patients are expected to comply with appropriate drug administration based on their understanding of the drug's mechanism of action (pharmacodynamics) and pharmacokinetics, such as absorption, distribution, metabolism, and excretion9) (see the next section for details). (9) (Detailed in the next section.) By fully understanding the meaning of the individual prescription (which is based on standard dosage and administration and adjusted according to the constitution and other profiles of each patient) and complying with it, the value of the drug as an "active drug" will be fully realized. In practice, however, this is easier said than done. In order to increase medication adherence10), it is desirable for patients to be aware that they are actively involved in their own treatment (after understanding the meaning of the prescription). As a practical aid, a system that physically prompts patients to take their medication correctly is likely to prevent them from simply forgetting to take their medication, and smartphone-based medication notification services (applications) are now available.
Of course, drug developers are also devising ways to improve medication adherence. A simple example is an extended-release formulation that reduces the number (frequency) of doses taken. It is also expected to reduce the frequency of side effects by avoiding a rapid increase in the concentration of the active ingredient in the blood.
2-3.Right Dose: Establishment of effective and safe dosage
Information is provided in the package insert, in the "Dosage and Administration" section of the Drug Guide for Patients, and in the "How to Use This Drug" section of the Drug User's Guide. Drugs are often referred to as "double-edged swords" or "drugs are a risk. Drugs are basically ineffective if the dose (strictly speaking, the drug concentration in the affected area or the drug concentration in the blood) is insufficient, and poisonous if it is excessive. Standard doses (normal doses) are established through clinical trials, but since each individual differs in body size, drug metabolism, and other physical characteristics, it is necessary to set appropriate doses (optimal doses) for each individual. In reality, however, this is not sufficient, and the optimal dosage for the patient is adjusted by adjusting the dosage each time while actually continuing the treatment (so-called PDCA cycle). Therefore, it is important to accurately grasp the onset of drug efficacy and safety status during treatment, but information obtained only from a medical interview and laboratory test values once a month, for example, may not be sufficient. In the past, for drugs with a narrow therapeutic efficacy range or drugs with an addiction range and an efficacy range that are close to each other, making it difficult to manage administration methods and doses, therapeutic drug monitoring (Therapeutic Drug Monitoring) 11 has been used to design dosing regimens appropriate for individual patients, and appropriate drug therapy has been implemented. In the future, however, it may become possible to set the optimal dosage by verifying the therapeutic effect through frequent monitoring and recording of various biological indicators (e.g., PHR) using ICT (e.g., biosensors), or even by using AI.
On the other hand, from the drug discovery side, in addition to the development of drugs that are effective at the smallest possible dose and multi-standardization for dose adjustment, it will be beneficial to develop drugs with a wide safety zone (therapeutic index) 12). In addition to the wide safety zone of the drug itself, it may be possible to widen the safety zone (in a broad sense) by formulation innovations. Once an oral or injectable drug has been administered, it is difficult to withdraw the drug, but with a patch (transdermal drug delivery system), it is easy to increase or decrease the dosage or discontinue administration.
Right Route: Appropriate usage and route of drug administration
This information is also provided in the "Dosage and Administration" section of the package insert and the Drug Guide for Patients, and in the "How to Use This Drug" section of the Drug User's Guide. Various efforts are made for each drug to maintain drug concentration in the affected area and drug concentration in the blood in the effective therapeutic range and to properly exert the intended effect of the drug through a proper combination of dosage and administration. Therefore, it is important to take the medication in accordance with the established dosage and administration. In particular, it is strictly forbidden for the user to tamper with a drug that has been devised in the formulation, such as removing the capsule or crushing the extended-release drug, because not only will the intended drug effect not be obtained, but side effects may also occur. In this regard, if the person taking the medication has a good understanding of the meaning of the dosage and administration, inappropriate behavior can be avoided. In addition, it is necessary to obtain a correct understanding of what is obvious to specialists, such as that oral drugs should be taken with water or lukewarm water, and what to do if the person forgets to take the medication, since this is not the case with the general public13).
On the other hand, from the drug discovery side, it is necessary to develop drugs that prevent people from taking them inappropriately. For example, large capsules may be "broken down" because they are difficult to swallow. Since the swallowing function is often impaired in the elderly, it will be essential to develop and provide easy-to-swallow dosage forms, especially for drugs that treat diseases that are common among elderly patients. In addition, injectable drugs may be difficult to use because of the pain they cause when administered. It is necessary to continue to devise formulations that are as easy to swallow as possible so that users can use them naturally and appropriately.
In addition, it may be better to use different expressions for terms such as "between-meal" and "suppository," which may be misleading to the general public.
Right Time (& Frequency): Take medication at the appropriate time and frequency. 3.
The timing and frequency of medication administration is another important element of "dosage. It is important to determine when (timing) and how often to take a drug in order to ensure that the intended effect of the drug is properly exerted and, in the case of drugs that cause side effects, to minimize the impact of the side effects on the quality of life (QOL). As mentioned in section 2-4, it may help to avoid adverse drug reactions if people understand what to do if they forget to take their medications.
If a drug can be provided in a form that allows users to use it without worrying too much about the timing of drug administration, it is expected to reduce human errors related to drug administration, and it can be said to be highly convenient from the viewpoint of safe and reliable drug effects.
3. Additional proposal of "Right Information & Education": For correct drug treatment based on correct understanding, we should also consider "Drugs must be used correctly.
Pharmaceutical companies have contributed to medical care by creating and providing pharmaceuticals with "good products and good service," but as we have said, "Drugs are only medicine when they are used correctly! (14). 14) On the other hand, as we have said, "drugs must be used correctly!" The pharmaceutical industry may have left this "correct use" to physicians, pharmacists, and other medical professionals. Although the Pharmaceutical Affairs Law and other laws and regulations do not allow pharmaceutical companies to proactively provide information directly to patients, there still seems to be room for further innovations for the benefit of patients. In addition, it is said that the provision of quality-assured drug information by public institutions is still low in Japan, and there is a need to develop a system for the provision of correct information15). We expect the mass media to provide correct and easy-to-understand information to the general public based on a certain level of specialized knowledge.
In addition, school education and public awareness activities related to pharmaceuticals would be beneficial in improving basic knowledge about medicine and pharmaceuticals: education on pharmaceuticals has been mandatory in junior high schools since April 2012, and in high schools, more in-depth education on pharmaceuticals has been provided in the 2013 academic year. The Japan Council on the Proper Use of Drugs, the Japan Pharmaceutical Manufacturers Association, and the Japan OTC Drug Association have jointly prepared DVDs to support pharmaceutical education in upper secondary schools, and are distributing them free of charge to approximately 5,000 upper secondary schools nationwide through school pharmacists affiliated with the Japan Pharmaceutical Manufacturers Association16).
The Japan Pharmaceutical Manufacturers Association has also created two types of educational materials on the proper use of drugs, one for elementary school students and the other for junior high, high school students and the general public, based on educational materials provided by the Council for the Proper Use of Drugs, which are used by pharmacists in seminars for students and local residents17).
One example of a pharmaceutical company's efforts is the "Communication Barrier-Free Project (CBF-PJ)" launched in October 2015 by volunteer employees of Shionogi Pharmaceuticals18). Based on the concept of "providing all patients with the information they need for the best medicine," the project is working to eliminate barriers for patients, mainly those with hearing disabilities. This is an activity that goes hand in hand with the concept of "medicine is only medicine when it is used correctly!
4. Conclusion
As mentioned above, efforts on each side to promote the proper use of pharmaceuticals are directly related to improving the value of pharmaceuticals. Most recently, the Pharmaceutical Manufacturers Association of Japan (PMAJ), together with other parties concerned, has been promoting activities based on Patient Centricity and efforts to eliminate the polypharmacy problem19)20). It is hoped that the promotion of patient-centered medical care and appropriate use of medicines through the "5+1Rs" will promote "active drug use.
-
1) Number of reports and countries from which data was obtained
-
2)
-
3)
-
4)"Current Situation and Challenges Surrounding the Pharmaceutical Industry: Delivering Better Medicines to the World," Policy Research Institute Industry Report No. 5 (December 2014)
-
5)The "5Rs" are sometimes referred to as the "6Rs" by adding "RIGHT PURPOSE.
-
6)
-
7)Please note that some of the technical terms (jargon) used in the text may be used outside of strict scientific definitions so that those who are not necessarily familiar with medical and pharmaceutical sciences can easily understand the content.
-
8)
-
9)Article 1-6 of the Pharmaceutical Affairs Law (Role of the Public) states that "The public shall endeavor to use pharmaceutical products, etc. properly and to deepen their knowledge and understanding of their efficacy and safety." This section was amended in 2013. This section was newly added when the law was revised in 2013.
-
10)In contrast to the concept of medication compliance, which refers to the degree to which patients follow the instructions of healthcare providers, this term refers to medication adherence in the sense that patients themselves are actively involved in treatment as part of a partnership in therapy. Adherence differs significantly from compliance in that it is defined by the content of the treatment, factors on the part of the patient, factors on the part of the healthcare provider, and the mutual relationship between the patient and the healthcare provider. Reference: The Pharmaceutical Society of Japan, "Glossary of Pharmaceutical Terms" (in Japanese)
-
11)Appropriate drug therapy can be provided by (1) understanding the pharmacokinetics of drugs, (2) administering appropriate doses of drugs, (3) determining whether multiple drug use is allowed, (4) early detection of addiction and side effects, and (5) confirming noncompliance (not taking drugs as directed). Target drugs include drugs with a narrow therapeutic efficacy range or drugs whose addiction and efficacy ranges are close together and for which administration methods and doses are difficult to control (e.g., the bronchodilator "theophylline").
Reference: The Pharmaceutical Society of Japan, "Glossary of Pharmaceutical Terms" (in Japanese)
Examples of TDM drugs: http://www.pharm.kumamoto-u.ac.jp/Labs/clpharm/database/docs/tdm01_20160902.pdf -
12)In pharmaceutical terminology, TDM is defined as "50% lethal dose (LD50)/50% effective dose (ED50)," but it can generally be thought of as "the range of doses that can be used effectively and safely.
-
13)Although these explanations are included in drug guides for patients and drug bookmarks, it is believed that they are not always fully understood.
-
14)
-
15)
-
16)
-
17)
-
18)
-
19)
-
20)Aiming for Drug Development Utilizing Patients' Voices: Activities Based on Patient Centricity in Pharmaceutical Companies (Pharmacia, Feb. 2020)