Zhao Shanshan ,Zhang Boquan ,Wang Hongyun

(1.Department of pharmacy/Drug clinical trial institution office,China Emergency General Hospital,Beijing 100028,China;2.Clinical Pharmacology Research Center,Peking Union Medical College Hospital,Beijing 100032,China)

Abstract Objective To aim at summarizing the role of hospital pharmacists in clinical drug trials in China against the background that hospital pharmacists have already involved in team-based patient care.Methods The roles and responsibilities of Chinese hospital pharmacists were listed and categorized.Results and Conclusion There has been an upsurge in clinical drug trials in China.Hospital pharmacists play increasingly important roles in all aspects of clinical trials,such as stakeholder liaisons,protocol developers,ethics committee members,research team members,study drug managers,and subject intervention agents.Hospital pharmacists are an integral part of a clinical drug trial multidisciplinary team.Their value is reflected in several pharmacist-led or pharmacistparticipating clinical trials as well as the trial project management position within hospitals.Pharmacists should be the designers,researchers,managers and supervisors of clinical drug trials.We expect that all clinical trial projects will include hospital pharmacists in their research teams soon.

Keywords: hospital pharmacist;China;clinical drug trial;good clinical practice (GCP)

1 Background information

With the progress of medical science,the life expectancy of the world’s population has greatly improved.People are paying more attention to their health.Thus,drug demands are more complicated.Over the years,the role of pharmacists has expanded worldwide to suit an ever-changing health system.Internationally,pharmacists are the third largest health care professional group after doctors and nurses,and they are the most accessible to patients.Unfortunately,the responsibilities of hospital pharmacists were confined to procurement and administration of drugs for a long period years ago.Patients do not have much confidence in pharmacists.Pharmacists’ competence and value were not embodied by their work.With advanced technology emancipating hospital pharmacists from tedious dispensing functions,the roles of pharmacists have shifted from being “productbased” and “patient-facing” toward being “servicebased” and “patient-centered”.In 1997,the World Health Organization (WHO) introduced the “sevenstar pharmacist” landmark concept,which means that pharmacists should be caregivers,decisionmakers,communicators,managers,life-long learners,teachers,and leaders[1].The roles of researcher and entrepreneur were included later,leading to the “ninestar pharmacist”[2]and it emphasized the importance of research in pharmacists’ professional practice.In addition,according to the “China Regulations of Pharmacy Affairs for Medical Institutions”[3],hospital pharmacists have to participate in clinical drug trials and drug post-marketing efficacy and safety evaluations.

There has been an upsurge in clinical drug trials in China owing to improvements in the medical infrastructure and government support.As of June 5,2021,the number of phases I to phases Ⅳ clinical drug trials registered on ClinicalTrials.gov was 167 190.China launched 11 258 phases I to phasesⅣ clinical drug trials,accounting for 6.73% of all phases I to phases Ⅳ clinical drug trials registered on this platform.Innovative drugs need to undergo rigorous research before they can appear on the market.In China,clinical drug trials must be performed in hospitals.Clinical drug trials are increasingly emphasized and developed in Chinese hospitals,which provides pharmacists with new challenges and opportunities.By participating in clinical drug trials,pharmacists seek to acquire recognition from the public.Hospital pharmacists take part in several main aspects of clinical drug trials: Liaising between stakeholders,developing protocol,participating in ethics committee decisions,finishing research team tasks,studying drug management,and intervening human subjects.

2 Hospital pharmacists participate in clinical trials

2.1 Liaising between stakeholders

The clinical drug trials involve various organizations and vendors.The stakeholders of the clinical drug trials include but are not limited to subjects,sponsors,investigators,government agencies,contract research organizations (CROs),site management organizations (SMOs),ethics committees,central labs,courier companies,and recruitment companies.Firstly,all parties related to a trial must fully understand their responsibilities.Secondly,they must play their roles and fulfill their duties.Lastly,teamwork is the driving force that keeps trials going.All stakeholders are bound by ethical,scientific and administrative responsibilities.

China’s good clinical practice (GCP) guidelines have some special clauses to ensure the quality of clinical drug trials.They include the followings: (1)Hospital administrators (usually the president) have the responsibilities for contracting with sponsors and supervising the conduct of the trial within the hospital.(2) Only National Medical Products Administration(NMPA) accredited secondary and tertiary hospitals can conduct NMPA-regulated clinical drug trials[4].Accordingly,clinical drug trial investigators must be secondary or tertiary hospital staff in China,and they do not have the power to directly sign an agreement with sponsors.For eligible hospitals,it is necessary to set up a department under the direct leadership of the head of the hospital to deal with clinical drug trialrelated miscellaneous non-research daily routine work.Indeed,hospitals designate a specific office to handle such work,which is called the clinical trial institution office[5].There are more than 1 000 hospitals registered on NMPA website to do NMPA-regulated clinical drug trials,thus there are correspondingly more than 1 000 clinical trial institution offices.The members in this office include directors,secretaries,drug administrators,file clerks,quality assurance and quality control staff etc.This office welcomes all stakeholders to discuss,communicate and exchange ideas.It is generally accepted that pharmacists are the most qualified to be designated for this work due to their unrivaled systematic pharmaceutical education background.In some hospitals,clinical trial institution offices are subordinate to the department of pharmacy.Hence,for pharmacists,the work of this office overlaps with that of the department of pharmacy.

Pharmacists in this office regularly meet with representatives from sponsors,monitors from CROs and coordinators from SMOs,investigators,accountants,ethics committee secretary,and information engineers as well as government officials from the NMPA and National Health Commission (NHC) to establish management system,negotiate agreements,create budgets,coordinate logistics,sign documents,report project progress,conduct statistical analysis and prepare for inspection.As such,pharmacists serve as a “privileged information hub”[6].Pharmacists are not only the liaisons between all the clinical trial stakeholders but the communication bridge between drug development and clinical practice as well.

2.2 Developing protocol

The clinical drug trial protocol specifies the objectives and methodology as well as the design and statistical considerations of a clinical trial.Protocols are usually complex and sophisticated,the preparation and review of protocols are important stages before the trials.An additional challenge in clinical trial planning is the nuanced nature of trials because there are no two studies are alike.This is true for innovative drug studies that are under the control of multiple government regulatory bodies,such as the U.S.Food and Drug Administration (FDA) and China’s NMPA.

High-quality clinical trials come from highquality protocol designs.Sponsors pay much attention to protocol development.After kicking off,sponsors in China usually invite all the principal investigators(PIs),sub-investigators (sub-Is),the head or secretary of the ethics committee[7]or pharmacists in clinical drug trial institution office (as mentioned above) at each site to draft and discuss the research protocol.For example,professor Zhao Xiuli,the director of a clinical drug trial institution office from Beijing Tongren Hospital of Capital Medical University was invited to discuss the trial protocol of a newly developed cough relieving compound drug.

Despite being drug therapists,medical professionals such as doctors or nurses may lack training or basic knowledge in pharmacology,pharmaceutics,and drug administration.It is the pharmacists who can give expert opinions on the pharmaceutical and pharmacological aspects of the drugs under study.This can include reviewing or writing summaries of the general preclinical research situation of the drug studied and of the current global clinical research situation for the trial protocol or investigator brochures (IBs).In addition,choices of control drugs,reference preparation,placebo,implementation of blinding,permitted comedication,and forbidden comedication are also issues that team members turn to pharmacists for advice.A comprehensive and complete drug information section is crucial to ensure that the drug studied is prepared,stored,shipped,dispensed appropriately,and in a way that complies with laws,regulations and guidelines.Pharmacists need to pay special attention to drug management issues such as the source/supplier of the drugs and the drugs’ characteristics,formulation,preparation,stability,compatibility,packaging,labeling,shipping,dispensing,and storage.Besides,incineration should be listed in the trial protocol or the IB[8].

2.3 Participating in ethics committee decisions

Ethics committees are composed of medical professionals,lawyers,patient representatives,etc.They work independently,and their responsibility is to protect the rights and interests and the safety of human subjects involved in a clinical drug trial.This obligation must take precedence over the interests of any researcher or organization.In China,this committee is authorized to approve,suspend or terminate clinical trials that fail to comply with ethical principles or that have been associated with potential serious harm to subjects.

Most secondary and tertiary hospitals have ethics committees,and clinical drug trials are under the supervision of these ethics committees in China.These hospital ethics committees have at least one pharmacist member,who is usually a senior pharmacist,for example,the head of the pharmaceutical department or clinical drug trial institution office[9].At present,multicenter clinical drug trials must be approved by the ethics committee of each site before the study begins (mutual recognition of ethical committee review decision among hospitals is under development in China[10]).

Before approval is granted,pharmacists are ready to evaluate the study’s scientific merit and adherence to the requirements for application for new drug registration and marketing.The validity of the information of drug studied,the feasibility of management,and the dosing strategy are the main concerns in ethics evaluations.Regarding the suitability of the investigators,subject inclusion criteria,subject exclusion criteria,potential risks and benefits,and subject subsidies,these aspects also need attention.If study drug information has not been provided with the protocol,it should be requested from the sponsor to facilitate the evaluation.

After the start-up of a clinical drug trial,the role of the ethics committee is to protect human subjects through continuing review of progress reports,protocol amendments,safety events,protocol deviations (PDs),and protocol violations (PVs)[11].Since the ethics committee has ongoing responsibility throughout a clinical drug trial,pharmacists’ duty on the ethics committee is also continuous and indispensable.

2.4 Finishing research team tasks

Today,pharmacists are widely accepted as PIs by foundations,the pharmaceutical industry,and government regulatory agencies[12-14].Pharmacists have served as PIs either by directing their investigator-initiated trials (IITs) or by working within sponsor-initiated trials (SITs).

The design and implementation of phase I clinical trials involve human tolerance tests,pharmacokinetics,etc.which are not traditional research fields of doctors and nurses.Pharmacists can undertake phase I clinical trials as PIs.Pharmacists are familiar with the principles of pharmacokinetics,such as drug absorption,distribution,metabolism,and excretion,because they have rich biosample analysis laboratory operation experience.In Chinese hospitals,phase I clinical trial units in the clinical trial institutions can be led by pharmacists.

Chinese pharmacists are not authorized by law to prescribe drugs[15],which limits their role in clinical practice,thus also limiting their role in clinical drug trials.While randomized controlled trials (RCTs)remain the gold standard for innovative drug approval,more information is needed on how drugs perform within different physiological groups,including people with different degrees of disease severity and unstudied comorbid conditions,for the use of drugs in the real world.Since a real-world study is observational,it provides pharmacists with a special opportunity to be PIs in these kinds of clinical drug trials.In 2017,pharmacists from Peking University Third Hospital reported a real-world study of salvia miltiorrhiza depside salt injection in Plos One[16].It was the first large-scale,multicenter and prospective international registered clinical drug trial led by pharmacists in China.In addition,a pharmacistled real-world study of Tanreqing injection,another Chinese traditional patent drug,was conducted by the same research team.

Chinese pharmacists can also participate in clinical drug trials as researchers,although they are not PIs or team leaders.For example,in the current COVID-19 pandemic,Chinese pharmacists are using their expertise to actively participate in the exploration of new drugs for COVID-19.COVID-19 has brought pharmacists closer to prove their undeniable value to patient care and that having pharmacists on the front lines save lives.With no approved antiviral drugs for treating COVID-19,pharmacists are actively conducting registered clinical drug trials to explore effective treatment options.Pharmacists from Peking University Third Hospital participated in comparing the efficacy and safety of hydroxychloroquine sulfate and phosphate chloroquine in severe COVID-19 patients (ChiCTR2000029898,registered on Chinese Clinical Trial Registry (www.chictr.org.cn) and established a standardized treatment and optimized dosing scheme for clinical practice[17].

2.5 Management of drug studied

Drugs studied include not only investigational drugs,which are usually innovative drugs,but control drugs,reference preparations,placebos,solvents,remedy medications,basic treatment drugs,etc.Due to safety and accountability concerns,drugs studied are generally stored in a secure and separated area.According to the Chinese GCP,drugs must be managed by authorized specialists[18].

Compared with commercially available products,new clinical drug trials have some unique risks.For example,potential toxicity and drug interactions might not yet have been fully elucidated or entirely defined.Additionally,protocol complexity and the need to maintain blinding in controlled studies may increase risks associated with product appearance,flavor,packaging,labeling,storage,and dispensing.Management of drug studied is a very individualized task,and managing drugs studied and preparing drug prescriptions according to protocols require more time and effort than the dispensing of normal medications.Therefore,proper staffing is a key factor for conducting clinical drug trials successfully.In recent years,all the drugs studied in a hospital have typically been concentrated in a special pharmacy subordinate to the clinical drug trial institution office,and certified pharmacists have gradually replaced nurses in the management of drugs studied[19].

Pharmacists who dispense drugs studied must be familiar with the drug information and design as well as the trial protocol.To ensure that the drug studied is in good condition,pharmacists verify the packaging and labeling,drug analysis report,pharmaceutical form,serial number,lot number,manufacture and expiration dates,storage (temperature,light and humidity),usage and dosage,as well as all dispensing and destruction procedures.Pharmacists dispense only an adequate amount of drugs studied for a visiting period to each subject.Pharmacists should remind subjects of the need to return all unused drugs.To successfully adhere to the protocol,pharmacists know not only how to prepare and dispense the drugs but also how to complete dispensing records and maintain the inventory.The quantity of unused drugs should be recorded on data sheets for future checks and inspection.

2.6 Intervening human subjects

One of the core functions of clinical drug trials,as described and regulated by various agencies,is patient treatment with the drug studied.Pharmacists’daily routine work is carrying out pharmaceutical care to ensure patients’ reasonable and safe medication.In the clinical drug trial process,this responsibility and obligation of pharmacists are still necessary.

Adherence to the research protocol in clinical drug trials is critical to ensure subject safety and maintain the quality and integrity of the data.However,adherence to medication therapies in clinical drug trials is suboptimal.As clinical drug trials become more complex,time,costs and risks are increasing.Nonadherence in clinical trials may lengthen study periods and increase costs,causing misleading,unreliable,conflicting,or invalid results.Managing subject compliance in clinical drug trials has long been recognized as a delicate issue for highquality management.

There are several reasons for nonadherence,such as adverse reactions,dosing frequency,and multiple drug combinations.Intervention means pharmacists correct or intervene to prevent medication errors and PDs.Pharmacists form a pivotal part of a multidisciplinary research team and are immensely valuable in brainstorms.Subjects in clinical drug trials always have many questions and issues that need to be resolved.Pharmacists are health professionals who have rich experience answering drug-related enquiries.Pharmacists’ eloquence,patience and kind smile can make a deep impression on subjects.Pharmacists can identify problems and address multiple types of interventions during clinical drug trials,including those related to medication use,adverse reactions,and other medication-related issues.Medication therapy management (MTM) encompasses a group of services,which optimizes therapeutic outcomes for individual patient.It was recently introduced to Chinese pharmacists from the US[20].Pharmacist-led MTM during clinical drug trials may also improve medication compliance and save money[21].If some of these interventions are not carried out,significant PVs may occur.At present,in China,only pharmacists in a limited number of top-level university-affiliated teaching hospitals or research-oriented hospitals can provide MTM services for patients[22].Therefore,pharmacists in Chinese hospitals are still in the initial stage of exploring the usage of MTM in clinical drug trials.

3 Opportunities and challenges for hospital pharmacists participating in clinical drug trials in China

3.1 Opportunities

Involvement in clinical drug trials has many intangible benefits for pharmacists.The most important advantage is the opportunity to contribute to the advancement of clinical practice through the support of cutting-edge clinical drug trials and to participate in a key step in new drug development.To serve new drug research and development is ultimately to serve patients.The newly recruited pharmacists in modern Chinese hospitals are well educated with a master’s degree or Ph.D.So scientific research is also an important part of their work.The number and impact factor of published papers are important indexes in hospital evaluation systems.Hospital pharmacists are called on to contribute more than ever to scientific publishing.Not surprisingly,exposure to clinical drug trials means more resources and opportunities to publish papers.All these processes involve pharmacists working at various stages of the clinical drug trial.This opportunity means pharmacists can play significant roles in clinical drug trials.

3.2 Challenges

For any of these roles,hospital pharmacists must meet all the qualifications specified by the sponsor,ethics committee,and regulatory authorities.Besides,they must be familiar with GCP,trial protocols,and standard operation procedures (SOPs) to assume responsibility for the proper conduct of the trial.Pharmacists conducting clinical drug trials are required to strengthen the following knowledge and skills: (1)Clinical thinking;(2) Oral and written communication;(3)Interprofessional collaboration and teamwork/leadership;(4) Project management;(5) Information technology;(6) Psychological behavior skills;(7) Ethics,finance and biostatistics knowledge;(8) Clinical drug trialrelated laws,regulations and guidelines.Unfortunately,no systematic training currently exists to prepare pharmacists for participating in clinical drug trials other than on-job training,continuous medical education or academic meetings[23].This is the shortcoming of current pharmacy education in China.

Pharmacists’ major tasks in most Chinese hospitals are still auxiliary because their work is not taken seriously by patients,hospitals,and governments.It is believed that pharmacists make little contribution to hospitals’ wealth and academic reputation,compared with doctors and nurses.Although pharmacists in Chinese hospitals are under the supervision of both the NMPA and NHC,after 21 years of advocacy and preparation,there are still no special laws for pharmacists in China[24].Pharmacists rank after doctors and nurses in Chinese hospitals.What can improve pharmacists’ status is their work performance.With no work evaluation criterion for pharmacists participating in clinical drug trials,pharmacists are still in the exploratory stage and have no thorough or clear understanding of professional planning and career development.Without the consent of government,pharmacists can make little contribution to the clinical drug trials.They have to rely on the support from the government and hospitals.We hope that they can provide more encouragement and support to pharmacists so that pharmacists can give full play to their strengths and devote themselves to clinical drug trials.Hospital pharmacists should seize the opportunity of the formation of clinical drug trial market,and establish their development space and irreplaceable position.

4 Conclusions

Clinical drug trial is an excellent practical setting for hospital pharmacists.An excellent pharmacist is the designer,researcher,manager and supervisor of clinical drug trials.Their core responsibility is to ensure eligible patients’ access to drugs studied and serve as medication experts to all parties involved in these trials.Pharmacists have the responsibility of ensuring that all processes in a clinical drug trial meet the requirements of site,sponsor,professional,legal,and ethics.We expect that one day in the future,all clinical drug trial projects will include pharmacists in research teams,but there is still a long way to go.