Regulatory Express_Q2 2020

1.       FDA Shares Factors to Consider for Decentralized Clinical Trials

(FDA Mar 2020)

FDA：远程临床试验需要考虑的因素

(Mar 2020)

在今年3月的英国GCP研讨会上，来自美国FDA的Cheryl Grandinetti分享了“远程临床试验设计和实施的考虑：监管视角“。鉴于该方法并不适合所有类型的临床试验，Cheryl 提出了需要从试验的疗效终点、受试者安全以及试验用药品的特点考虑采用远程临床试验的可行性，并需要具备相应的流程和技术，支持数据管理、电子数据采集系统、远程访视，同时需要满足相关法规的要求。Cheryl 还介绍了针对远程临床试验，FDA实施检查的要求和方式。请注意，所有这些变化或新的考量，GCP规范下的研究者职责和申办方职责保持不变。

Summary:

At a recent UK good clinical practice symposium, Cheryl Grandinetti of the US FDA presented on Considerations for the Design and Conduct of Decentralized Trials: Regulatory Perspectives.  She outlined various factors that companies should reflect on if they are thinking about conducting a decentralized trial, as this approach is not suited to all types of trials.   Although a fully decentralized approach may be beneficial for some types of trials, most “trials will fit somewhere in the middle of a traditional [randomized control] trial design and a fully decentralized trial,” Grandinetti said.  Below are some Key Factors to Consider:

Efficacy Endpoints:

·       Consider the choice of efficacy endpoints and whether these can be captured remotely. 

o   Objective endpoints such as a serum biomarker or a clinical event like survival or other endpoints that do not require interpretation may be suited for a fully decentralized trial. 

·       Companies should also consider whether the trial endpoints or any other critical assessments that are obtained remotely can be appropriately validated.

Subject Safety:

·       Look at the study population and the disease state. It is important to ensure that the study population is stable enough to participate in a trial with remote components.

·       Sponsors should have protocol-specific safety monitoring and communication escalation plans in place, which should describe the role and use of local health care providers to evaluate adverse events.

·       There should be a plan and procedure for after hour emergencies, including information for study subjects on who to contact to address or treat adverse events.

·       In addition, the trial protocol should describe the electronic informed consent process.

Study Drug:

·       Whether the study drug can be shipped directly to the subject’s home would depend on various practical considerations, such as the trial’s protocol design.

·       If it is a double blinded study, then it is necessary to consider whether the product is already blinded or whether blinding has to be done on site.

·       Consider whether the study drug is a stable, ready-to-use compound versus a product that requires reconstitution and has a short expiry date, and whether the drug can be self-administered by the subject.

·       The drug’s safety profile also plays a key role. If the drug’s safety profile is well-defined, then it is necessary to consider what the expected adverse events are and whether they require close monitoring.

·       There should be systems and procedures in place to ensure a patient’s privacy when the study drug is being shipped to them.

·       The procedures for shipping study drugs directly to the patient should be described in the trial protocol so that the process is clear to everyone involved, including the regulators.

Data Management:

·       The FDA expects issues relating to data collection, handling and management, and the use of electronic systems to be proactively monitored and addressed by sponsors.

·       To ensure data integrity and reliability, you need to have a detailed understanding of the data flow.

·       Companies should have a comprehensive data flow diagram that includes all parties from whom and to whom data are transferred or transmitted, including all third-party vendors contracted for data collection, handling management and/or data processing.  Consider putting this data flow diagram in the protocol or in your data management plan.

Electronic Data Capture Systems:

·       Electronic systems owned by the sponsor should employ necessary data security and integrity controls (eg, access controls, audit trails, encryption and a risk-based approach to validation.)

·       During inspection, FDA will review your use of these electronic systems in the same way as we would in a traditional trial.  They will focus on those systems that capture the primary efficacy endpoint data and any critical or key data in the trial.

·       The FDA encourages the use of centralized monitoring to identify and proactively follow up on missing data, inconsistent data, data outliers and potential protocol deviations that may be indicative of systemic or significant errors.

Telemedicine visits:

·       Sponsor should ensure that internet and wireless technology is available where the trial is being conducted so that study business and assessments can be conducted in accordance with the protocol.

·       Some states in the US have different laws governing telemedicine.

o   For example, they may require that the investigator is licensed to practice medicine in the state where the study subject is located.

o   Some states also require that there is an established doctor-patient relationship for telemedicine treatment and may have different requirements in order to establish such a relationship.

Technical Support And Training:

·       Technical support is critically important for the conduct of a trial and often is the first place where you might identify faults, validation issues or systemic or significant errors.

·       The trial protocol should describe all the training that the study subjects, mobile and local health care providers, clinical investigators and other study personnel will need to use technologies employed in the trial such as electronic systems and telemedicine apps.

Inspections

·       The FDA had not inspected any decentralized trial yet, but they expect that inspection process for decentralized trials would be the same as for traditional trials.

·       The inspections will generally be conducted at the decentralized site, where trial records and source documents are located.

·       The relevant responsible individuals, the investigator and the study personnel should be available on site or by phone to answer any questions that may arise.

·       When necessary, they may also inspect other facilities, local clinics and pharmacies for example, where trial-related activities occurred.

·       The investigator and the sponsor should also save and archive all relevant communications and other records that demonstrate their oversight of the study, including oversight of adverse events, protocol deviations, data collection and handling and the shipment and delivery of study drugs directly to the study patients. This information should be available to the FDA on request during inspection.

Key Takeaways:

·       As interest in conducting remote decentralized clinical trials grows, an FDA representative explains what companies should consider when planning such trials.

·       The responsibilities of the sponsor and the investigator do not change, although some aspects considered “routine” in relation to traditional trials may need extra consideration in the context of decentralized trials.

·       FDA inspections will generally be conducted at the decentralized site, where trial records and source documents are located.

2.       MHRA Blog: GCP Inspections: Expectations and the Dos and Don’ts for Hosting

(MHRA Mar 2020)

MHRA 博客：GCP检查：检查官的期望及接受检查时的“要”和“不要”

(Mar 2020)

MHRA就如何更顺利、有效地接受MHRA GCP检查在其博客上发表了文章：“GCP检查：检查官的期望及接受检查时的“要”和“不要””，对前期如何与检查员沟通、检查现场设施和人员的准备，以及检查过程中的注意事项给出了建议。

Summary:

The MHRA has issued a blog titled: MHRA GCP Inspections: Expectations and the dos and don’ts for hosting.  Inspections can be challenging for all involved and issues have often been encountered during the inspection conduct to do with TMF access and navigation, document request provision and sometimes simply finding the right person to answer a particular question.

The MHRA has identified several dos and don’ts for each of the following topic areas (A few examples are included below.  See the attached article to read all of them):

·       Notification of Inspection

o   DON’T: spend endless hours collating information unless you are sure it is what they want

·       Inspection Dates

o   DON’T: start pestering the Lead Inspector about trial selection.  The Lead Inspector will be working behind the scenes on trial selection and will notify you in due course and usually in advance of the inspection.

·       Inspection Plan

o   DON’T: allocate only senior management to the interviews who are not involved in the day to day processes and therefore are not familiar with the detail of the procedures and associated documentation.

·       Office Based Inspection (OBI)– The MHRA is increasing using OBI for large organizations in advance of going on site.

o   DO: ensure there is a Host available via telephone and email to manage any further requests and queries during the day.

·       Inspection Facilities on site

o   DO: ensure the inspection room is set up in advance, including the set-up of the computers and screens.

·       Electronic System Access

o   DO: anything you can to aid electronic system access, links on desktop, short crib sheet, ensure lock-out times are reasonable, minimize need for numerous passwords where possible etc.

·       Opening Meeting

o   DO: prepare and provide an introduction to the organization, please keep it brief and pertinent to clinical trials

·       Document Requests

o   DON’T: provide redacted, shortened, incomplete responses. This could also be seen as impeding the inspection.  Work transparently with the inspectors to ensure what is provided is provided as expected the first-time round.

·       Interviews

o   DO: ensure those that are selected for interview can cover the full end to end processes being inspected and can demonstrate evidence of compliance within documentation available on the selected trials.

·       Closing Meeting

o   DO: ensure you are clear on what the findings are and ask questions if you are unsure.

·       Report, Responses and Inspection Closure

o   DO: ensure CAPA provided is proportionate, measurable, timely, fixes the root cause and is followed-up through implementation with effectiveness checks.

Key Takeaways:

·       The Inspection Host can be key to a smooth inspection, the host needs to be sufficiently senior, needs to have a thorough understanding of the organization and the processes and should be an excellent organizer and communicator.

·       A good relationship built on professional respect between the Host/s and Lead Inspector makes the Inspection process much more pleasant for all involved even if the inspection outcome involves significant findings.

·       Communication is key not just with the Lead Inspector, please copy in the full inspection team on any emails. This enables the full team to keep up to date with the inspection and if the Lead Inspector is not available one of the Assisting Inspectors can help with any urgent queries.

3.       EMA Updates Questions and Answers on Good Clinical Practice (GCP) about Electronic Systems and Vendor Contracts

（EMA Apr 2020）

EMA GCP Q&A 有关电子系统和供应商合同问题的更新

（Apr 2020）

在今年4月更新的“EMA检查：GCP Q&A”的文件中，更新了问题8“在与临床试验相关的电子系统供应商签署合同时，需要意识到哪些陷阱？”和问题9“对于供应商已验证的电子系统，申办方在使用之前至少确认哪些方面？检查时需要提供哪些文件？”。

基于检查时发现的常见问题，对于问题8给出的建议是：需要在合同中明确描述所有与临床试验相关的系统的确认和验证有关的任务，包括哪一方持有证明哪些活动的文件，以及就由谁负责进行确认和验证达成一致，并要求供应商及时与申办者沟通任何潜在的严重违规事件和安全漏洞，约定在某些情况下供应商需要接受特定的稽查或检查。

针对问题9，建议申办者应在合同中明确，可随时查阅供应商的系统验证相关文件，并确认供应商在检查时可提供上述文件。在供应商不提供系统验证相关文件的情况下，，申办者必须根据其自身和供应商的系统要求规范，对系统进行确认。

Summary:

The EMA has published a revised document: EMA Inspections: Questions and Answers on Good Clinical Practice (GCP). 

This document provides a list of questions and answers on the following GCP topics:

·       Investigational medicinal products (IMPs) in bioavailability and bioequivalence trials

·       GCP matters (Revised to amend Questions 8 & 9)

·       Expectations of European Union (EU) competent authorities on the use of electronic trial master files

·       Records of study subject data relating to clinical trials

Question 8: What are the pitfalls to be aware of regarding contractual arrangements with vendors for electronic systems in connection with clinical trials?

Rev. April 2020

Qualification and validation particulars

On the basis of recent GCP inspection findings, inspectors would like to reiterate that sponsors should contractually ensure:

·       That all tasks relating to a clinical trial and/or tasks relating to the qualification and validation of a system are clearly described, including which party holds documentation for which activities.

·       That sponsor pre-qualification audits or other on-site pre-qualification activities and later audits of the IT vendor can take place. It should also be ensured that these audits and/or other on-site pre-qualification activities are performed with a sufficient amount of time and that sufficiently in-depth review of the vendor qualification documentation is performed in order to establish the qualification and validation status of a system.

·       That GCP inspections can take place at the vendor in case the vendor is performing services for the sponsor, when the sponsor has relied fully or partly on the vendor to perform the qualification activities and when it was established during the inspection of the sponsor that part of the documentation can only be verified by inspection of the vendor.

·       That any qualification documentation prepared by the vendor in relation to the system should be available for inspection.

·       That the sponsor has access to the vendor’s system requirement specifications, if the sponsor chose to perform all qualification activities themselves and/or if the vendor does not agree to undertake qualification activities for the sponsor. In case the sponsor retains the full duty/function for the qualification and validation of the software, the sponsor should possess all the necessary information and documentation upfront to be able to carry out this task.

·       That the vendor should escalate any potential serious breaches to the sponsor in a timely manner, including security breaches that they become aware of (e.g. by notification from other sponsors using the same system), if they could have any impact on the data integrity, reliability and robustness and on the safety and rights of the trial subjects

Question 9: What is the level of validation/qualification needed to be performed by a sponsor when using an electronic system previously qualified by a provider? What documentation is required to be available for inspections?

Rev. April 2020

What should a sponsor do if the sponsor intends to submit an MAA without being able to provide documentation of qualification activities for clinical trial computerized data collection tools/software and access for inspectors is not ensured contractually? 

In case a sponsor has relied fully or partly on vendor qualification efforts and documentation for any system function, the sponsor should make sure that such documentation is readily available for inspection if requested. Failure to provide access to the documentation is likely to result in critical findings that will impact the acceptability of the clinical trial data.

A sponsor should amend any contract with vendors to ensure availability of qualification documentation. If a vendor is not willing to amend the contract, the sponsor is responsible to demonstrate that the system concerned is in a validated and qualified state. In case a sponsor cannot rely on a vendor to provide documentation, the sponsor has to requalify the system on the basis of their own and of the vendor’s system requirement specifications. In case the trial is ongoing, this should be done without delay; if the trial is completed, this should be undertaken prior to the submission of the MAA. A documented risk assessment is required to assess integrity risks to data captured and held by a computer system that was not in a confirmed qualified/validated state following the retrospective qualification/validation activity. Depending on the outcome of the requalification, the sponsor may need to change to a new vendor/system. The required migration of previously captured clinical trial data should be validated. Findings that are the responsibility of the sponsor are still likely to be issued for the lack of documentation and inadequate vendor assessment prior to trial initiation

Key Takeaways:

·       This document updated questions 8 and 9 under GCP matters with further guidance on computerized systems and vendor contracts.

·       The update is based on the recent: Notice to Sponsors on Validation and Qualification of Computerized Systems Used in Clinical Trials, 07-Apr-2020

4.       MHRA Post Blog on Patient Support Programs and AE Reporting

(MHRA 7 May 2020)

MRHA关于患者援助项目和AE报告的博客文章

(7 May 2020)

根据药物警戒相关法规（GVP Module VI (Rev 2), section VI.C.2.2.11），患者援助项目（PSP）被定义为“上市许可持有人接收并收集其药品使用信息的一个有组织的项目”，包括上市后患者支持和疾病管理计划、患者和医务人员的调查等。MRHA于今年5月发布博客文章，对如何规范收集PSP中的安全性报告给出分类建议，并指出实践中应采取的相应措施（如合同条款、培训、定期核对、稽查等）和常见缺陷。

Summary:

The MHRA has posted a blog on Patient Support Programs, where they explain the expectations for the collection of safety data from these programs.  There is a risk that safety reports received spontaneously via a program not based on organized data collection may not be correctly reported as adverse drug reactions.  The following definition of a PSP is included in GVP Module VI (Rev 2), section VI.C.2.2.11:

·       “A patient support program is an organized system where a marketing authorization holder receives and collects information relating to the use of its medicinal products.”

Examples are:

·       Post-authorization patient support and disease management programs,

·       Surveys of patients and healthcare professionals

·       Information gathering on patient compliance, or compensation/re-imbursement schemes

Categorizing safety data collection from PSPs for compliant safety reporting.  Programs termed as ‘PSPs’ could be categorized as follows:

In practice ‘appropriate measures’ to ensure AE reporting often includes:

·       Contractual language with third parties regarding collection and forwarding of safety information.

·       Training of company staff and third parties on pharmacovigilance concepts and use of data collection tools.

·       Reconciliation of safety data (periodically or at the end of the program).

·       Quality assurance activities, including audit and source data verification.

Key Takeaways:

·       In practice, some of the programs that are internally termed ‘PSPs’ by an MAH might not actually meet the definition above.

·       The structure of these programs should be evaluated on an individual basis to determine if there is any organized data collection or if information is being solicited from patients or healthcare professionals.

·       MAHs should have a system in place to collect safety data and ensure that data from each PSP is handled consistently.

·       The extent of the measures implemented to collect safety data should be proportionate to the likelihood that the program will generate safety data.

Reference:

1-1: UK good clinical practice symposium

(https://mhragcp.co.uk/home)

1-2: US FDA Outlines Wishlist For Decentralized Clinical Trials (https://pink.pharmaintelligence.informa.com/PS141843/US-FDA-Outlines-Wishlist-For-Decentralized-Clinical-Trials)

2-1: MHRA GCP Inspections: Expectations and the dos and don’ts for hosting.  (https://mhrainspectorate.blog.gov.uk/2020/03/10/gcp-inspections-expectations-and-the-dos-and-donts-for-hosting/)

3-1: EMA Inspections: Questions and Answers on Good Clinical Practice (GCP) (https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-clinical-practice/qa-good-clinical-practice-gcp)

3-2: EMA Issues Notice to Sponsors on Validation and Qualification of Computerized Systems used in Clinical Trials

(https://pink.pharmaintelligence.informa.com/-/media/supporting-documents/pink-sheet/2020/04/ct-system-validation.pdf)

4: Patient Support Programs

(https://mhrainspectorate.blog.gov.uk/2020/05/07/patient-support-programmes/)