Business Activities

Ethical Considerations in Research on Human Subjects and Specimens Derived from Humans

Astellas conducts research on human subjects, and obtains and conducts research on specimens derived from humans, after appropriately obtaining the consent of the subjects in accordance with the Declaration of Helsinki* as well as the laws, regulations and guidelines of relevant countries.

In Japan, Astellas provides training for researchers in areas such as bioethics, genomic research and related clinical research based on a strong commitment to respecting the human rights of research subjects and protecting the privacy and confidentiality of their personal information.

The Astellas Research Ethics Committee has been established with external experts participating in the committee to determine the ethical acceptability and scientific propriety of research plans in a fair and impartial manner.

* Declaration of Helsinki: A statement of ethical principles for medical research involving human subjects, addressed to physicians and others who are involved in medical research on human subjects.

Ethical Considerations in Stem Cell Research and Development

Astellas believes that there is a possibility of supplying new stem cell-based treatment methods to address diseases that previously had no known treatment methods. To achieve this, Astellas is advancing research and development activities focused on using stem cells in therapy.

Astellas also recognizes that research into human stem cells could give rise to concerns that warrant close examination. In particular, Astellas is fully aware of the necessity to pay full attention to the social and bioethical issues associated with research using human embryonic stem cells (ES cells).

Based on these principles and awareness, Astellas has established its “Policy on Human Stem Cell Research and Development*,” which sets forth the basic matters it must comply with in the course of conducting human stem cell research and development. Specifically, in all of its research and development activities involving human stem cells, Astellas will comply with the relevant laws, ordinances and regulations of the countries and regions where it undertakes these research and development activities. Moreover, Astellas will set up a committee comprising internal and external experts, from which it will obtain oversight and advice on the ethical aspects and the scientific validity and legitimacy of these research and development activities. All the proposals on research and development programs involving human stem cells will be reviewed and approved by the committee to ensure that these research and development activities are implemented ethically and in line with a legitimate scientific purpose. Furthermore, when establishing and using human ES cells, Astellas will take steps to satisfy the ethical standards established by the world’s major scientific authorities, including the guidelines laid out by the National Academy of Sciences of the United States of America.

* For details, please visit the following website:
https://www.astellas.com/system/files/policy_en.pdf

Ethical Considerations in Animal Testing

Astellas conducts animal testing based on its Policy on Animal Care and Use^*1. We have established the Corporate Institutional Animal Care and Use Committee with external experts participating in the committee, to determine whether to conduct animal testing based on the 4R Principles^*2. All of Astellas’ animal testing facilities have acquired accreditation from AAALAC international^*3.

*1 For details, please visit the following website:
https://www.astellas.com/jp/system/files/policy_on_animal_care_and_use_en.pdf
*2 4R Principles: Developing non-animal testing alternatives and replacing animals of phylogenetically lower species (Replacement); reducing the number of animals involved to the minimum necessary to achieve the scientific purpose(Reduction); avoiding the infliction of distress on animals wherever possible (Refinement); and scientifically and ethically justifying animal use in light of their significance, necessity, predictability and other criteria (Responsibility).
*3 AAALAC International: The Association for Assessment and Accreditation of Laboratory Animal Care International. An international organization that promotes the humane treatment of animals through voluntary accreditation and assessment programs. Studies are undertaken from both scientific and ethical standpoints to verify the quality of animal control and use programs.

Biotechnology and Biohazard Control

Astellas handles genetically modified organisms and performs experiments using materials containing pathogens in compliance with the World Health Organization Laboratory Biosafety Manual^*1, the U.S. Centers for Disease Control (CDC) Biosafety Manual^*2 and the U.S. National Institutes of Health Guidelines^*3, as well as the laws of individual countries.

*1 Laboratory Biosafety Manual 3rd Edition
*2 Biosafety in Microbiological and Biomedical Laboratories 5th Edition
*3 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules

Use of Genetic Resources

Astellas has published its Position on Genetic Resources^*1, and is committed to full compliance with the relevant laws and regulations of countries supplying genetic resources, and to the fair distribution of profits derived from the use of such resources according to the conditions mutually agreed upon with each country. This commitment is based on the concept of genetic resource utilization and the associated distribution of profits set out in the Nagoya Protocol^*2 adopted by the Conference of the Parties to the Convention on Biological Diversity^*3. The impacts of the use of new genetic modification technologies on the environment, biodiversity, and human health are not fully known. Therefore, Astellas will proceed cautiously when using these technologies while remaining mindful of the need to preserve biodiversity and consider ethical issues.

*1 For details, please visit the following website:
https://www.astellas.com/system/files/Position%20Statement_Genetic%20Resources_ver.1.1_EN.pdf
*2 Nagoya Protocol: Protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilization
*3 The Convention on Biological Diversity: International convention on the sustainable use and conservation of biological diversity

Treatment of Intellectual Property

Appropriate protection of intellectual property is critical to addressing unmet medical needs and maintaining a competitive advantage. With this in mind, Astellas has established a Policy on Intellectual Property^*1.

In view of the importance of improving people’s access to health, Astellas participates in the Patent Information Initiative for Medicines (Pat-INFORMED) implemented by the World International Patent Organization (WIPO) to ensure easy access to Astellas’ patent information on medicines by health agencies tasked with the procurement of medicines in various countries.

Moreover, we are committed to not filing or enforcing patents in countries facing significant economic challenges. These select countries are decided by referring to those designated as Least Developed Countries (LDCs) defined by the United Nations or Low Income Countries (LICs) defined by the World Bank^*2.

*1 For details, please visit the following website:
https://www.astellas.com/system/files/property_en.pdf
*2 For details, please visit the following website:
https://www.astellas.com/system/files/ip_en.pdf

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Respect for Human Rights, Protection of the Privacy and Confidentiality of the Personal Information of Clinical Trial Subjects, and Assurance of Reliability in Clinical Trials

Astellas conducts clinical trials to assess the efficacy and safety of new drug candidates in patients under the Declaration of Helsinki, Good Clinical Practice (GCP) and all relevant laws and regulations with full consideration to protecting human rights and the privacy and confidentiality of clinical trial subjects’ personal information. Clinical study protocols developed by Astellas are evaluated and approved for ethical acceptability and scientific validity by internal and external evaluation committees.

In conducting clinical trials, Astellas confirms that clinical trial subjects have provided informed consent, having received a full explanation of the purpose and methods of the trial, its expected benefits and disadvantages, matters related to compensation for health impairment and other details. Moreover, we implement education and training for any employees or staff members involved in clinical trials, and monitor medical institutions that perform clinical trials to ensure full GCP compliance.

In addition, we protect the privacy and confidentiality of the personal information of clinical trial subjects by managing trial data appropriately. Periodic assessments are also made to check that any outsourced clinical trials are conducted in accordance with the same standards.

Disclosure of Information on Clinical Trials and Trial Results

Astellas is committed to increasing transparency and providing disclosure of clinical trial data. Maximizing the value of clinical trial data, and putting it to good use in driving scientific advancement and increasing innovation, requires that the clinical trial data be appropriately accessible to the research community and others who might utilize it. The Policy on Disclosure of Clinical Trial Data^*1 has been published on the Company website to present Astellas’ position on this matter.

Astellas registers clinical trials, posts clinical trial information, and discloses clinical trial results. Astellas provides patient-level data that have been anonymized in accordance with applicable laws and regulations through an external website^*2 to those scientists and healthcare professionals requesting it in the case that review panel consisting of third party experts evaluates and approves the request based on scientific usefulness and scientist eligibility. Healthcare professionals and the public can confirm summaries of clinical trial findings via the website. This website also gives patients access to plain language summaries of study results prepared for non-experts^*3.

*1 For details, please visit the following website:
https://www.astellas.com/system/files/Clinical_Trial_Data_Disclosure_Policy_En_2018_1.pdf
*2 Patient-level data are provided through the following website:
http://www.clinicalstudydatarequest.com
*3 Results of the clinical trials are provided through the following website:
https://www.astellasclinicalstudyresults.com/Welcome.aspx

Expanded Access to Investigational Medicines

Astellas has set forth its approach to supplying investigational medicines to patients for purposes other than clinical studies in its Position on Expanded Access to Investigational Medicines*.

Astellas recognizes that patients with serious or life-threatening diseases may have exhausted all of their available treatment options, may not qualify for a clinical trial and may seek access to investigational medicines. In these cases, in response to a request for investigational medicines from a primary physician, Astellas fairly, impartially and rapidly evaluates whether or not the patient meets the required conditions and commits to establishing an expanded access plan as appropriate. The expanded access program will target countries where the clinical development of an investigational medicine is progressing and the drug is scheduled to obtain approval. Moreover, this procedure will be implemented in accordance with the regulations of the country where expanded access is requested.

* For details, please visit the following website:
https://www.astellas.com/system/files/position_on_expanded_access_e_2017-04-11.pdf

Patient Centricity in Clinical Drug Development

Patient centricity is now a focus for regulatory authorities and the pharmaceutical industry. The patient-centric approach is being discussed at all points in the drug development value chain.

We are pursuing patient centricity in clinical development. To do so, we are trying to incorporate insights from real-world data into the planning of clinical trials by understanding how healthcare is provided to patients. Efforts are being made to include patient input in how to optimally design clinical trials, recruit participants, and identify relevant endpoints that patients care most about. 

For example, we use patient-reported outcomes (PROs) such as questionnaires and patient diaries to monitor and assess patients’ health conditions. We use real-world data for estimation of target populations based on the morbidity rate and ineligible cases in screening, and feasibility of studies in clinical trial facilities. In addition, we established a patient-friendly website to support patient/caregiver-focused recruitment and health literacy recommendations. Especially in the muscle disease field, we are working with patient organizations. Working closely with those organizations, we are striving to reflect valuable insights from patients and caregivers in clinical trial designs. Through these activities, we try to make it easier for patients to participate in clinical trials, as we work to obtain trial results with greater clinical significance.

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Anti-counterfeiting Activities

The infiltration of counterfeit medicines into the legitimate supply chain not only leads to the loss of opportunities for patients to receive effective medical treatment but could also have severe adverse health consequences. This has become a serious problem worldwide.

Astellas has published a clearly defined Counterfeit Medicines Position Statement on our global website.

As a countermeasure, Astellas commissioned an Anti-Counterfeit Committee comprised of leaders from multiple stakeholder functions (quality assurance, supply chain, etc.), and has also established a product security function to oversee daily activities relevant to product-related security risks. These entities monitor the global market for suspicious activities affecting Astellas products, and implement countermeasures targeting not only counterfeit medicines, but also diversion, theft and other illicit activities that potentially affect our products and/or present a potential risk to patients. Astellas systematically introduces anti-counterfeit measures, including, but not limited to, product serialization as stipulated by current regulations and pharmaceutical laws. In addition, Astellas regularly engages in various collaborative activities with other members of the pharmaceutical industry to help prevent the spread of counterfeit medicines. We also proactively endeavor to support and cooperate with national regulatory and judicial authorities to crack down on counterfeit medicines. 

Anti-doping Measures

Doping is an issue closely related to abuse and misuse of medicines in sports. It is a serious priority for the pharmaceutical industry given that it is not only associated with a risk of inducing serious side effects, but it can also become a breeding ground for the unauthorized distribution and counterfeiting of medicines. Astellas is working to identify the compounds under development that have the potential to be used in doping and to prevent the misuse of those compounds.

In October 2016, Astellas made a global agreement with the World Anti-Doping Agency (WADA) to partner on the prevention of misuse and abuse of medicines for doping in sports which aims to contribute to the eradication of doping and improvement of public health.

Doping in sports relies primarily on the misuse and abuse of commercially available medicines, as well as compounds in development that are not as well-known or easily detected. To support WADA in its efforts to address this issue, Astellas identifies compounds solely developed by Astellas or its affiliates with the potential for sport-related doping abuse and cooperates in sharing relevant information to aid WADA in the organization’s development of detection methods for these compounds. Additionally, Astellas cooperates with WADA to minimize the risk of misuse of compounds with doping potential during clinical trials to avoid opportunities for abuse.

Product Recalls

Astellas has a recall system in place that is activated when the safety, efficacy or quality of a product is brought into question. The system ensures relevant information is promptly passed on to medical institutions and other affected parties, and that a recall of the product in question is instigated. Astellas voluntarily initiated 6 product recalls and had 1 authority-initiated recall in fiscal 2018. As of March 2019, there were no reports of any related health impairments received.

History of product recall

FY	The number of recall	Severe (Class I)	Moderate (Class II)	Minor  (Class III)	Non Classified
2014	3	0	1	1	1
2015	3	0	1	1	1
2016	3	0	2	1	0
2017	3	0	2	0	1
2018	7	0	4	2	1*

* Authority-initiated recall

FDA Inspection

Astellas has established its own quality standards in compliance with current Good Manufacturing Practice (cGMP) and applies these standards to Astellas Group manufacturing sites. In fiscal 2018 Astellas had 4 US FDA inspections across the global business, of which Astellas only received a single Form 483. 

*Form 483: An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts.

US FDA inspection history

CY	The number of FDA Inspection	Warning Letter issued	Form 483 issued	Location of Form 483 issued
2014	6	None	1	Takaoka (Japan)
2015	1	None	1	Norman (US)*
2016	5	None	2	Takaoka (Japan), Toyama (Japan)
2017	2	None	0	-
2018	4	None	1	Toyama(Japan)

* The Norman plant in the U.S was transferred to the Avara Norman Pharmaceutical Services, Inc. in August 2016.

Quality Manual

Astellas has set forth the quality assurance function and activities in the Quality Manual. The Quality Manual sits on the apex of the document management system hierarchy. Underneath the Quality Manual, policies, standard operating procedures, and guidelines exist defining quality assurance systems and operational management and procedures for a variety of quality assurance-related activities at the global, regional and national levels. Education and training programs are implemented to promote understanding and awareness of these matters.

These documents are revised periodically and as necessary. We respond swiftly to developments in the external environment, such as regulatory changes and amendments.

Strengthening of Quality Assurance Systems at Affiliates

Astellas has constructed a robust global quality assurance system to ensure the supply of pharmaceuticals of uniformly high quality to patients worldwide.

We are developing quality management systems consistent with our quality assurance policy on a global, company-wide basis. The global quality assurance structure incorporates quality assurance activities of each affiliate. Our sales affiliates globally receive appropriate support in strengthening our quality culture whilst educating our personnel.

Global Quality Assurance Structure (as of July 2019)

Improving the Pharmacovigilance (PV) System

Astellas is continuously improving its pharmacovigilance (PV) system by strengthening collaboration between its PV function and other relevant functions, affiliates and licensing partners. This is to respond to expansion of product strategies and advance the provision of trustworthy product information and proper product use, along with compliance with regulatory requirements.

Astellas has been building a system to collect product safety information from a variety of sources. The Company annually provides product safety awareness training not only to staff closely involved with the PV function but also to all employees and contractors including affiliate staff, to maintain and strengthen swift and appropriate collection of product safety information. For external service providers outsourced by functions other than the PV function, Astellas adds requirements for the collection of product safety information in their contracts as necessary. 

Astellas has been maintaining safety information databases and procedures used globally to respond to environmental change. In fiscal 2018, it completed a major upgrade of its safety information database and procedures to respond to changes in regulatory requirements.

Astellas is exploring utilizing real-world data such as large healthcare databases for evaluation of its product safety to help minimize risk by enhancing collaboration between PV and other functions. Furthermore, Astellas has started exploring and assessing automation technologies and artificial intelligence technologies that can be used for monitoring, processing and reporting of product safety information, and early identification and analysis of safety signals. We plan to use these technologies to strengthen our PV system.

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Stable Supply and Quality Control

Astellas places highest priority on ensuring robust manufacture and stable supply of safe and effective pharmaceuticals to patients. To ensure this, we have established our own standards aligned with Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) as the basis for consistently achieving high levels of quality. We apply these standards to manufacturing facilities and equipment, and to all stages from raw material procurement and storage to production and shipment.

Quality Audits

Astellas has quality systems for auditing both internal sites and external manufacturing and distribution partners. The risk-based auditing approach determines the sites audit frequency and intensity.

Internal audits are conducted on all Astellas organizations that conduct current Good Manufacturing Practice (cGMP) or current Good Distribution Practice (cGDP) activities at all points across the product lifecycle and across the supply chain, in accordance with documented policies and procedures.

Quality audits for external partners are conducted for new or established customers of Astellas. Such audits are performed to evaluate compliance with cGMP and cGDP and applicable regulations at Astellas.

In fiscal 2018, Astellas had a total of 337 audits, including 30 internal audits and 307 quality audits of external partners globally.

Management Structure for Stable Supply

Supply chains are becoming more complicated than ever due to the increase in global products and diversification of modality.

Taking these environmental changes into account, in April 2019 Astellas built a framework to centrally manage demand forecasts, inventory information and supply plans for regions all over the world. This has enabled management of the global supply chain from manufacturing of drug substances through to product supply. 

In addition, the Company is advancing logistics compliance, including for imports and exports, and further strengthening its stable supply management.

Shared Logistics for Stable Supply

Astellas, Takeda Pharmaceutical Company Limited, Teva Takeda Pharma Ltd. and Teva Takeda Yakuhin Ltd. have co-established a shared storage and joint distribution platform in Hokkaido, Japan. The platform aims to ensure a diverse and stable supply of pharmaceuticals with adequate contingency, even in the event of a large-scale natural disaster, as well as enhancing efficiency and quality management of product distribution.

Reductions in costs afforded by sharing logistics with the other companies have enabled us to set up a new logistics base. The joint distribution platform not only prevents a shortage of pharmaceuticals which may impact the health of patients but it also reduces the environmental burden through the reduction of carbon emissions.

The platform was recognized by the Minister of Economy, Trade and Industry in the 2018 Excellent Green Logistics Awards hosted by the Ministry of Economy, Trade and Industry of Japan.

Measures to Prevent Medical Malpractice and to Improve the Distinguishability of Pharmaceuticals

Astellas strives to supply products from the users’ perspective to ensure that healthcare professionals and patients do not mistake one pharmaceutical for another. We are working to prevent medical malpractice in this respect, through measures including printing product names directly on capsules and tablets, as well as printing product names and dosage on packaging sheets (blister sheets) so that the product name and dosage can be easily identified even after the blister sheet is split apart.

To prevent misreading of labeling on blister sheets, Astellas also endeavors to make products easier to identify visually by adopting easily discernible colors and font types for the blister sheets of certain products.

Introducing Universal Design into Product Packaging

We have introduced universal design to certain product packaging. For example, the universal design packaging of Bonoteo 50 mg tablets, which is administered once every 4 weeks, features packaging with good openability. To prevent patients from forgetting to take the drug, there is an area provided on the packaging to write in the day when the drug should be taken. A small label to be used as a calendar is also attached. In addition, the packaging uses a universal design font type for easy reading.

Relationship with Local Communities

To promote sustainable pharmaceutical manufacturing, Astellas arranges opportunities for dialogue with local residents and communities near its manufacturing sites. By proactively disclosing its initiatives, Astellas is working to build good relationships with them.

At the Kerry Plant in Ireland, Astellas has been holding annual events for 15 years with the local community to protect the environment, ensure health and safety, and save energy. Each year, the event themes revolve around environmental protection, health and safety, and energy conservation, and local children draw pictures with the themes. These are made into a calendar which is sold locally, with all proceeds donated to the Irish Kidney Association. Every year, over 1,000 entries are received from 12 schools, and the event is now being developed into a regular community event. Other activities include music events with donations to children's hospitals, cardiopulmonary resuscitation training in the community, and 5km Walk / Run in collaboration with the Pieta House, a non-profit organization which supports patients with mental illness and suicidality. We value our relationship with the local community. We received the SEAI^*1 Award in 2017 and the Green Award^*2 in 2019 as one of Ireland’s leading companies.

*1 SEAI: Sustainable Energy Authority of Ireland is an Irish government-affiliated organization supporting the reduction of CO2 emissions.
*2 Green Award: The leading platform for sustainability intelligence, leadership and innovation in the best green practice in Ireland.

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Ensuring Proper Use

Astellas’ Medical Representatives (MRs) provide information on appropriate usage based on on-label information to healthcare professionals to ensure that Astellas pharmaceutical products are used safely and effectively. In promotion of Astellas products, MRs act with high ethical standards and strictly comply with the applicable laws and regulations, industry codes and company policies including Astellas Group Code of Conduct.
 
Medical Science Liaisons (MSLs) engage with healthcare professionals to exchange scientifically based information to advance their understanding and the safe and effective use of our products in patient care. MSLs also act with high ethical standards and provide reliable, clear, fair, balanced and unbiased medical and scientific information. MSLs refrain from promotion of products, and observe high ethical standards, making compliance their top priority.

Responding to Inquiries

Astellas has a responsibility to provide truthful, balanced and unbiased medical information in response to inquiries regarding our products. By fulfilling this responsibility, Astellas supports the safe and effective use of our products.

In countries throughout the globe, we have Medical Information Call Centers that respond to a variety of inquiries. In our larger call centers, we have systems that allow for 24-hour responses to urgent inquiries, even on business holidays. In fiscal 2018, we responded to approximately 140,000 inquiries.

Astellas makes continuous efforts to improve its medical information services, with the aim of providing accurate, appropriate and consistent information. As part of these efforts, a global medical information system is used where medical responses from group companies around the world are documented. This enables the responses to be communicated to our customers in a simple, swift and accurate manner. At the same time, we can analyze feedback from patients and medical professionals and inform the life cycle management of our products. We look forward to the implementation of a new global medical information system that will set the stage for new and improved services for our customers.

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Sustainable Procurement Initiatives

Astellas considers it important to fulfill its social responsibilities across the entire supply chain. To achieve this goal, Astellas has formulated the Astellas Business Partner Code of Conduct, which requires business partners to implement initiatives in accordance with social responsibilities and sign the Acknowledgement of Astellas Business Partner Code of Conduct.

Risk Assessments of Critical Suppliers

Astellas conducts a global assessment that includes an evaluation of sustainability risk in the selection process for critical suppliers^*, the suppliers that have a particularly significant impact on Astellas’ business continuity. The sustainability risk assessment involves judging a risk level based on a combination of the supplier’s response to a questionnaire, external database information, a basic assessment by in-house experts on risks related to sustainability such as human rights, the environment, occupational health and safety and personal information protection, and, if necessary, the results of a local on-site audit carried out by an Astellas employee. The questionnaire was revised in fiscal 2018 to improve the accuracy of the risk assessment and operations started in Japan, North America and Europe from February 2019.

If Astellas identifies a risk that can be improved during the supplier selection process it encourages the supplier to make the improvement and monitors its initiatives. Astellas does not engage in business if it designates a critical risk it judges will be difficult to improve.

Moreover, business divisions continue monitoring risk status even after business transactions have begun and the supplier’s sustainability risk level is assessed at least once in five years through a questionnaire and on-site audits. If necessary, suppliers can be re-assessed within that five-year period.

* Suppliers judged to have a significant impact on Astellas’ business continuity, including suppliers of raw materials (regardless of whether they are direct or indirect materials), operations outsourcers, pharmaceutical wholesale companies, sales alliance partners and banks. Critical suppliers accounted for approximately 10% of primary suppliers (total for Japan, North America and Europe) in the year ended March 2019.

On-site Audits of Suppliers

In the year ended March 2019, Astellas employees carried out on-site audits and risk assessments related to such matters as wastewater treatment plants, employees’ working environments and initiatives to prevent employees from being exposed to chemical substances. In cases where items were pointed out, Astellas indicated an improvement proposal, requested a plan for corrective measures be drawn up and is currently following up on progress of the improvements based on the corrective measures plan.

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