Drug development, approval, manufacturing, and post-marketing
- Development of a new drug involves a complicated process that requires a lot of time and enormous amounts of funding. In order to create one drug, you would need to evaluate approximately 700,000 candidates1). Of them, just one reaches the patients. Here, we will share how a new drug begins its journey, from the research and development of candidate compounds, to a product, to the patients, and how we are involved with drugs once the physician prescribes a drug to patients. We will explain what pharmaceutical companies call “the lifecycle of a drug.”
1) from Japan Pharmaceutical Manufacturers Association DATABOOK 2013
The journey of a pharmaceutical product
1. Basic research
- Conduct a research to discover new drug candidate substances and components and create new compounds. Most requires 2 to 3 years. This process also functions as an opportunity to research the yet-to-be-defined mechanisms of diseases, where the basic research conducted may not directly lead to a new drug. Discovering a seed for a new drug is like looking for a piece diamond on the bottom of the deep ocean, where these highly uncertain basic research and drug development research could become the base in identifying several million candidate elements. After this process, a screening method to narrow down potential substances will be developed, and several of the candidate substances move on to the next process.
- There are two types of research, collaborative research and sponsored research, where pharmaceutical companies and others provide funding support.
The research is conducted after an official contract is exchanged with universities and others.- Collaborative research：(Joint research expenses in the JPMA Transparency Guideline)
- Research institutions such as universities and investigators of pharmaceutical companies and others conduct a research cooperatively.
- Sponsored research：(Research commissioning expenses in the JPMA Transparency Guideline)
- Sponsors such as pharmaceutical companies entrust research institutions such as universities to conduct the research, where accomplishments are reported to the sponsors.
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The journey of a pharmaceutical product
2. Development
1) Non-clinical trial
- CMC: Quality
CMC stands for Chemistry, Manufacturing and Control. Design and research for manufacturing procedures, specifications and stability tests are carried out. - A process to investigate the efficacy and safety of candidate drug compounds. An animal testing is conducted for pharmacokinetics, pharmacological and toxicity tests. The next trials are conducted based on data obtained from this first process. This process takes about 3 to 5 years.
- The trial is required to be conducted based on GLP for non-clinical trial regarding safety of pharmaceutical products.
2) Clinical trial
- The clinical trial is conducted by pharmaceutical companies and others based on the Pharmaceutical Affairs Law, in order to have a new drug approved or to apply for a new indication for an existing drug. Other than clinical trials conducted by pharmaceutical companies with an objective of approval application, there are trials called investigator-led clinical trials which are conducted by physicians and medical institutions for the purpose of the approval application.
- The trial process investigates the efficacy and safety of the candidate compound on humans. The clinical trial is conducted mainly in 3 steps, Phase I, Phase II and Phase III. This process takes approximately 3 to 10 years. It is required to conduct the trials based on the GCP.
- Phase I trial (human pharmacology study) :
- Confirms mainly the compound’s safety among healthy people
- Phase II trial (exploratory study) :
- Confirms the drug’s administration method and administration amount among a small number of patients
- Phase III trial (confirmatory trial) :
- Confirms the drug’s efficacy and safety among numerous patients
- CMC: Quality
The journey of a pharmaceutical product
3. NDA and regulatory approval application
- The enormous amount of data gathered on candidate compounds so far is compiled into an approval application document and submitted to the regulatory authority in each country/region. In Japan, it is submitted to the Ministry of Health, Labour and Welfare (MHLW). The Pharmaceuticals and Medical Devices Agency (PMDA) will conduct a strict review from a scientific standpoint, and once the efficacy and safety of the candidate compound is confirmed, it will obtain approval by the MHLW as a new drug to be manufactured and distributed.
- The PMDA website provides a detailed explanation on the complicated and wide-ranging process from application to approval.
The journey of a pharmaceutical product
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4. Production, Quality, Information Provision & Product Distribution
1) Manufacturing of newly approved drugs and the quality control process.
In every process of the drug development, from manufacturing to shipping and transportation after shipments, there are strict standards in place, ranging from those defined by the Pharmaceutical Affairs Law, those that require approval from regulatory agencies, and unique standards set within companies.
- Approval and inspection of manufacturing site: Under the Pharmaceutical Affairs Law, a GMP compatibility investigation is required for a new drug to be approved. This is an investigation that also confirms that the manufacturing site has the building, facility and administrative system to constantly manufacture the product which has been guaranteed its efficacy, safety and homogeneity.
GMP investigation is conducted regularly as well as unscheduled, in addition to the investigation conducted at the time of approval. - The manufacturing process begins from the measuring of raw materials: (Chugai Pharmaceutical “Manufacturing of active pharmaceutical ingredient/solid drug factory”)
- Decision on shipment: Some products, such as vaccines and blood products, require a national test per lot and may take time for it to be shipped out.
National test process for vaccines
2) Product distribution and provision of information
- In order to provide new products to hospitals and pharmacies, marketing personnel of pharmaceutical companies develop a supply and distribution plan and work with both internal and external parties to distribute the product. Further, pharmaceutical companies, through their Medical Representatives (MR), work to provide, gather and communicate information and at times disseminate their pharmaceutical products in order to promote the appropriate use of its products.
Source: MR Education and & Accreditation Center of Japan website - Information is provided via methods such as scientific seminars, where information is not limited just to its own products but also medical and pharmaceutical papers of disease areas related to the product. Pharmaceutical companies hold briefing sessions together with medical academic conferences, medical institutions and physicians to ensure that scientifically-grounded treatments are promoted. It also provides information to support the physicians’ lifelong learning.
- The works of pharmaceutical companies are not limited to distributing products and providing information to healthcare practitioners, but it also provides information on the disease and about treatments. In order to guarantee the credibility and neutrality of the information, physicians specializing in the field provide support in the manner of writing articles, supervising contents, and participating as lecturers at educational seminars and lectures for general citizens.
- Examples of information provision on the disease and treatments
- The JPMA codes and guidelines
- Approval and inspection of manufacturing site: Under the Pharmaceutical Affairs Law, a GMP compatibility investigation is required for a new drug to be approved. This is an investigation that also confirms that the manufacturing site has the building, facility and administrative system to constantly manufacture the product which has been guaranteed its efficacy, safety and homogeneity.
The journey of a pharmaceutical product
5. Post manufacturing and distribution
- Conduct surveys and trials on appropriate use, in order to confirm the new drug’s efficacy and safety in a regular and a daily medical setting that cannot be obtained from a clinical trial conducted for the drug’s approval. For example, through post-manufacturing and distribution clinical trials and post-manufacturing and distribution surveys, collect information on adverse reaction and the drug quality, and communicate assessment and analysis results to medical facilities.
- Making changes to items listed in the application material submitted to obtain marketing approval, requires companies to submit an approval application for partial approval and obtain an approval per the Pharmaceutical Affairs Law.
- The reporting system of adverse reactions and infectious diseases based on the Pharmaceutical Affairs Law, is for pharmaceutical companies and healthcare practitioners such as physicians and pharmacists to report the MHLW. The objective for this is to appropriately collect adverse reaction, infectious diseases and default information of pharmaceutical products and others in approved medical facilities such as hospitals, and promptly conduct safety measures.
- Pharmaceutical companies, in order to promote academic research and provide aid for the research, supports research institutions such as universities, hospitals and medical academic conferences. As an academic research aid, it provides scholarship donations to universities and others. For example, in order to promote case reports that communicate product usage experience by expert physicians for products that have been in the market for 3 to 5 years since post-manufacturing and distribution, pharmaceutical companies will bring together a seminar through donations to the medical academic conferences and co-host seminars with academic conferences. Through such activities, it will promote the products’ safety and appropriate usage post-manufacturing and distribution.
- There are also clinical research and clinical trials that are led by physicians and medical facilities conducted after a product’s post-manufacturing. Some physician-led clinical trials do not have an objective to apply for approval, but rather are conducted by physicians and researchers in order to provide the best treatment to patients and promote evidence-based medicine.
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- The various steps in this process are usually conducted by pharmaceutical companies alone. However, at times accomplishments are made through a cooperative effort with universities and medical institutions. In order for cooperative research with universities and medical institutions to steadily progress, and for new drugs to be created as a result, companies sometimes contribute by providing funding to the research. The types of funding provided are presented in the table below. Also, for certain items an example is illustrated and explained in each process within the “product lifecycle,” and is hyperlinked to the cost items of each member companies’ disclosure target within the JPMA‘s “Transparency guideline for the relationship between corporate activities and medical facilities and others.”
- The progress of each process within the “product lifecycle” is managed by adhering to various laws and self-regulations. We will explain the process of drug development that at times is considered complicated, to the manufacturing and distribution of new drugs, and related laws and regulations to adhere to. The following table shows one part of the product lifecycle chart.
Product lifecycle and requirements overview
Terminology: Product lifecycle and related laws
- PAL：Pharmaceutical Affairs Law
A Law regulating matters related to the manufacturing, distribution, standards and screening, handling and advertising regulation and others for healthcare products, quasi-drugs, cosmetics and medical devices in Japan. (Law No. 145, Aug. 10, 1960). - GLP：Good Laboratory Practice
A standard for conducting non-clinical studies on the safety of drugs. It is a standard regarding animal studies in non-clinical studies, particularly regulated for toxicity studies. - CMC：Chemistry, Manufacturing and Control
Information regarding Chemistry, Manufacturing and Control. It refers to the integrated concept of researches for drug substance process, drug development, and quality assessment, as well as works related to those researches. The pharmaceutical companies’ CMC includes a wide range of work from non-clinical studies, clinical studies to regulatory approval applications. - GCP：Good Clinical Practice
A standards regarding the implementation of clinical trial for pharmaceutical products. - ICH：International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
A project that brings together regulatory authorities in Europe, Japan and the United States. The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration. - GMP：Good Manufacturing Practice
A ministry ordinance related to standards for the manufacturing management and quality management of pharmaceutical products and quasi-drugs. It refers to the standard for the manufacturing management and quality management at manufacturing facilities of pharmaceutical products and others. - PV：Pharmacovigilance
Activities related to the safety monitoring of pharmaceutical products. It refers to the careful monitoring and continuous surveillance of the safety of an approved product during its life on the market. - GQP：Good Quality Practice
A standard on the quality management of pharmaceutical products and others. - GDP：Good Distribution Practice
A standard on pharmaceutical product distribution. - GPSP：Good Post-marketing Study Practice
A standard on the implementation of the pharmaceutical products’ post-marketing surveillance and study. - GVP：Good Vigilance Practice
A standard on the safety management of pharmaceutical products and others after manufacturing and distribution.
Sources:
- e-Gov
- Japan Pharmaceutical Manufacturers Association
- Pharmaceutical and Medical Devices Agency
- EFPIA Glossary
