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Layperson Summaries of Clinical Trials:

An Implementation GuideTable of ContentsBackground..........................................................................................................................................................3

Introduction.........................................................................................................................................................3

Purpose, Assumptions, and Considerations........................................................................................................3

Scope of this Implementation Guide...................................................................................................................4

Out of Scope.....................................................................................................................................................5

Sponsor Policies and Planning Considerations....................................................................................................5

Impact on A Sponsor’s Transparency Policy.....................................................................................................6

Protocol and Informed Consent Form (ICF)......................................................................................................7

Investigator Involvement..................................................................................................................................7

IRB/REC Impact.................................................................................................................................................7

Budget Considerations......................................................................................................................................8

Writing Layperson Summaries.............................................................................................................................8

Reporting Results............................................................................................................................................10

Reporting Safety.............................................................................................................................................10

Use of Visuals and Non-written Material........................................................................................................10

Translations.....................................................................................................................................................11

Distribution Options..........................................................................................................................................11

Additional Considerations for Site-Based Distribution...................................................................................15

Investigator Role.............................................................................................................................................15

Additional Considerations for Web-based Distribution..................................................................................16

Conclusion..........................................................................................................................................................17

References..........................................................................................................................................................18

Version 1 1 Draft 20Jan17© 2016 TransCelerate BioPharma Inc. All rights reserved.

Appendix 1: Sample Process Flow.....................................................................................................................20

Appendix 2: Implementation Toolkit................................................................................................................21

Appendix 3: Comparison of Guidance Documents...........................................................................................22

Appendix 4: Communication Tools....................................................................................................................23

Participant-Centric Communication Tools......................................................................................................23

Internal Communication Tools........................................................................................................................23

External Communication Strategy..................................................................................................................25

Note: Nothing in this paper should be construed as legal advice, nor does anything in this paper imply or warrant that use of this approach complies with applicable laws or regulations. Users implement the approach outlined in this paper at their own risk and bear the sole responsibility for ensuring their compliance with applicable laws and regulations in their respective jurisdictions


BackgroundTransCelerate BioPharma Inc. is a non-profit organization of biopharmaceutical companies focused on advancing innovation in research and development (R&D), identifying and solving common R&D challenges, thus increasing the quality of clinical studies and delivering high-quality medicines to patients. TransCelerate has undertaken a commitment to enhance public health and medical and scientific knowledge and streamline regulatory compliance by facilitating the sharing and transparency of clinical trial information.

IntroductionIn the spirit of data transparency, returning aggregate trial results to study participants, both healthy volunteers and patients, in the form of a layperson summary is recognized as an important emerging practice by both industry and non-industry sponsors, by regulators and health authorities as well as by researchers and participants themselves. The European Union Clinical Trial Regulation (EU CTR) No 536/20141 has added impetus and urgency to the development of layperson summaries.

This implementation guide was developed to facilitate sponsor’s efforts to implement the obligations of the EU CTR. This guide also discusses practical considerations should sponsors choose to go beyond the regulatory requirements. Such a program may be broader geographically and more comprehensive in considering various distribution options for returning study results to participants. How sponsors develop their own processes for layperson summaries is solely up to each sponsor and without constraints based on the substance of this guide.

As layperson summaries are not currently required by the FDA, the timing of when to distribute layperson summaries outside the EU is a consideration to be addressed during the development of the sponsor’s overall strategy.

Related regulatory requirements on a local or regional level should be consulted for applicability though regulations pertaining to layperson summaries per se do not exist outside the EU.

It is TransCelerate’s hope that by sharing this guidance regarding the development of layperson summaries, we will ultimately enhance transparency and the study participants’ experience in clinical trials and thereby strengthen trust in the drug development process.

Purpose, Assumptions, and ConsiderationsThis guide is intended to present pharmaceutical industry sponsors with practical options and considerations when developing and delivering aggregate result summaries to study participants and general public. Existing guidances propose that result summaries be written in lay language (also known as plain language) so that results can be more understandable to a general audience. We refer to these documents as layperson summaries, terminology consistent with the EU CTR.

A number of assumptions have been made while preparing this implementation guide.


Concepts, applicable studies, and technical guidance provided in existing publications, such as those prepared by Multi-Regional Clinical Trials (MRCT), European Federation of Pharmaceutical Industries and Associations (EFPIA), and Health Research Authorities (HRA), and EU regulatory requirements have been considered to ensure adherence when planning the writing and distribution of layperson summaries.

A layperson summary of clinical trial results should be an easily understandable, non-promotional, high-level summary of overall study results from the clinical study report (CSR) to ensure the most pertinent information is provided to study participants and the public.

Individual sponsors can exercise flexibility in implementation based on their respective corporate needs and/or preferences.

Returning layperson summaries will require industry sponsors to establish new standard operating procedures (SOPs) for their respective organizations.

Further considerations were made when writing this document including:

The EU CTR was adopted and entered into force in 2014. It will become applicable 6 months after the European Commission publishes confirmation that the full functionality of the EU portal and database has been confirmed by an independent audit. This provides sponsors the opportunity to develop and test pilot programs and internal policies and procedures before the EU CTR becomes applicable (expected by October 2018).

This guide encompasses elements of planning, writing, and distributing layperson summaries as well as suggested educational guidance.

Sponsors have to develop policies and procedures that ensure implementation will meet regulatory requirements, and align with corporate values and strategic priorities while also necessarily considering budgetary implications.

It would make sense for companies to develop plans regarding the review and approval process including suggestions for internal stakeholder review as well as the potential for external review. (High-level communication strategies are addressed along with tools for internal use and use at the study site.)

It is important to understand how to assess study participants’ overall understanding, including translated versions, and how to best establish communication as to whether or not they wish to receive a summary of clinical trial results.

Various potential options are presented for distributing layperson summaries, including possible advantages and disadvantages of each.

Scope of this Implementation GuideWhile results of clinical trials have been published in scientific/medical journals and scientific summaries are already posted to global websites such as clinicaltrials.gov2 and EU Clinical Trials Register3, little has been done to provide aggregate results in a manner that can be easily understood by the general public or study participants. Thus, the layperson summary is a new type of regulatory document that sponsors will have to learn how to generate. The information contained within layperson summaries needs to align, to the extent


appropriate, with other well-established forms of clinical trial documentation (registry entries and clinical study reports).

EU CTR No 536/20141 requires layperson summaries to be made publicly available for all interventional [including low-interventional according to Article 2(2)(3)] clinical trials in healthy volunteers and patients, Phase 1 to Phase 4, conducted in at least one site in the EU. The regulation requires release of layperson summaries 12 months after the end of the trial (Last Subject Last Visit [LSLV] for adult studies) in the EU unless this is later for scientifically justified reasons detailed in the protocol. Sponsors may defer the publication of Phase 1 clinical trial results summaries and layperson summaries for up to 18 additional months or until the time of the marketing application, whichever is earlier.a

The requirement for layperson summaries also applies to pediatric trials regulated under the Pediatric Regulation No 1901/20064 ; however, the timing for pediatric layperson summaries has not yet been made clear5 the 6-month results reporting requirements and timeline for pediatric studies under the Pediatric Regulation may or may not supersede the 12-month timeframe permitted by the EU CTR. Clarification is expected once the final status of the draft EU Commission Consultation Document -Summary of clinical Trial Results for Laypersons has been determined.

The rules of EU CTR 536/2014 will apply to newly authorized trials under the Regulation or trials authorized under Directive 2001/20/EC6 but still ongoing for 3 years after EU CTR 536/2014 comes into effect according to Article 98 Transitional Provision and Article 99 Entry into Force.

The Regulation shall apply 6 months after the publication of a notice from the EU Commission stating its satisfaction with the functional specifications of the EU Portal and database. This is anticipated to be late 2018.

Layperson summaries are not required at this time for studies investigating devices or diagnostic products.

Out of ScopeThe following topics are out of scope of this document:

The return of individual patient data; Information on various computer programs or IT capabilities to meet EU portal requirements; Guidance related specifically to health literacy and numeracy best practices.

Sponsor Policies and Planning Considerations Before layperson summaries can be fully implemented, sponsors will need to develop a strategy which aligns with the regulatory mandate and potentially extends beyond these requirements to build on the sponsor’s ethical principles related to human subject research. For example, sponsors may want to think more broadly about trust, transparency, and partnering with patients in the process of drug development.

aFor phase 1, bioequivalence and bioavailability trials and biosimilarity trials, “sponsor may opt to defer the publication of the summary of results and layperson summary in all or in part up to a maximum of 18 months after the due date (usually 12 months after the end of the trial unless Article 37[4] applies).The summary of results and layperson summary may be deferred in total, a potential maximum of 30 months after the end of the trial or until the time of MA if the time is earlier.”


There are a number of administrative and regulatory challenges to be considered when implementing the development of layperson summaries. As they are a new type of regulatory document with a target audience that is distinct from that of other regulatory documents, a sponsor will need to develop a new SOP(s).

It may be helpful for a company to consider these factors when developing a standard internal approach to drafting layperson summaries:

Focusing on enhancing trial participants’ experience in clinical trials, Increasing participants’ understanding of the clinical trial process and outcomes, Recognizing and appreciating participants’ contributions while maintaining participants’ privacy.

Once a remit is established, specific decisions relating to a sponsor’s internal process may become more apparent as they align to its overall strategy.

A sponsor will then need to develop a standard approach (or process) to implementing layperson summaries. Key initial considerations include:

Scope: details of expanded process. For example, some sponsors may choose to provide layperson summaries for studies outside the EU.

Budget: costs associated with writing, reviewing, translating, distributing, and investigator and participant out-of-pocket expenses as a practical matter would likely need to be taken into consideration (refer to Budget Consideration section).

Timelines: The timing of layperson summary development and dissemination needs to align with the EU CTR requirement (12 months from study end in the EU unless this is later for scientifically justified reasons detailed in the protocol).

Regulatory standards: It may be critical to define terms in accordance with EU CTR such as end of study and adverse reactions in the context of layperson summaries (refer to section on Protocol and Informed Consent Form [ICF ] and Reporting Safety ).

Once these key considerations and a path forward are well-defined, the process activities and role accountabilities will need to be established and embedded into the sponsor’s clinical trial process. A sample process diagram is available in Appendix 1: Sample Process Flow.

A new SOP may mirror existing internal procedures such as those for the clinical study report. It may be helpful to use a single new SOP that incorporates all elements discussed in this guide related to writing, reviewing, translating, and distributing lay language summaries. In addition, existing procedures that are impacted by layperson summaries may require modification. A review of all SOPs that span the clinical trial process may be needed to determine the impact of layperson summaries and the modifications required.

Impact on A Sponsor’s Transparency Policy While industry sponsors will need to follow the regulatory mandate set forth in EU CTR 536/2014 to provide layperson summaries to study participants and the public, a sponsor should also consider developing a policy and overall strategy for returning results that encompasses the entire research enterprise within the sponsor’s organization. The regulation is limited to trials that include sites within the EU. When going beyond the legal requirement, a sponsor would likely find it efficient to develop a consistent global policy.


Although each sponsor will need to adhere to regulatory requirements, a sponsor may also wish to consider whether and how to implement expanded processes; for example, some sponsors may choose to provide layperson summaries:

for studies not conducted in the EU - additional summaries could include all clinical trials or a subset of trials (e.g. trials in patients only)

by posting on a public website or even in a more direct, more personal way if the logistics can be worked out.

Protocol and Informed Consent Form (ICF) A sponsor should consider what information to include in the protocol and ICF about layperson summaries. In the absence of a protocol-defined end-of-study date, the EU CTR would require a layperson summary to be submitted one year after the end of the clinical trial (LSLV) in all member states concerned. However, this can be changed since the EU CTR provides, “at a later point in time as defined in the protocol”. It is important that the protocols define “end-of-study” for any global study that include sites both inside and outside the EU, along with scientific reasons to justify the alternative definition. For example, when the clinical trial is still ongoing in other countries outside of the EU, data from that part of the study are not yet available and thus statistical analysis for the entire study cannot be completed. If the study data cannot be analyzed until all global sites have reached LSLV, this could justify re-defining end-of-study for the purposes of the layperson summary.

Beyond the inclusion of an end-of-study definition, other explicit plans around the layperson summary are not recommended for inclusion in the protocol. For example, a detailed description of the distribution methods may be regarded as research procedures and require IRB/REC review and, if these distribution methods change, it may put the protocol at risk for an amendment. Other study documents that are provided to participants, (e.g., informed consent form [ICF], Welcome Letter, and Thank You Letter [TYL]) should align with the participants’ expectations and with the sponsor’s plans for the layperson summary.

Informed consent forms could include a statement making participants aware that they will be offered a summary of study results once the study has completed and results are analyzed. Depending on how a sponsor has chosen to distribute layperson summaries, study participants might be asked to select an opt-in/opt-out option in the ICF or end of study information sheet.

Investigator InvolvementSome sponsors may choose a distribution method that will depend upon the continued involvement of investigators (as discussed in Distribution Options). If this is the case, a good time to solicit feedback from the investigator is during the feasibility phase of the study. This will allow the sponsor to discuss mutual expectations with the investigator, consider delivery options when drafting investigator contracts, and build the associated costs into the site contract and budget.

IRB/REC ImpactTransCelerate presents what it believes are the prevailing views of IRBs/RECs in the United States, Canada, and United Kingdom based upon a focus-group discussion with IRB/REC representatives and consultation


with Harvard MRCT.7 Stakeholders including regulators, industry, and study participants generally seem to agree on the importance of providing high-level result summaries in plain language to make study results more accessible to a broad audience. To this end, we encourage IRBs/RECs to recognize the need for a harmonized and consistent approach so layperson summaries can be distributed in a timely fashion across jurisdictions.

IRBs/RECs are established to protect the rights, safety, and well-being of patients involved in a clinical trial throughout conduct of the trial. Once a study is completed, there are no longer human subjects to protect and the jurisdiction of the committee ends. Layperson summaries will normally be produced after a study ends and therefore, review by IRB/REC would not be needed.b

In alignment with postings and publications, such as scientific result summaries posted to ClinicialTrials.gov and/or EU Clinical Trials Register and publications in journals, layperson summaries posted to a publically available registry would not need IRB/REC review.

Moreover, a reference in an informed consent form that participants will be offered the opportunity to receive a layperson summaries after the study is complete and results are analyzed does not warrant IRB/REC review of the layperson summary once it is developed. The Health Research Authority (HRA) guidance on information for participants at the end of a study 8 encourages the provision of layperson summaries, along with notice in the informed consent that summaries will be offered. The HRA guidance also states that the mere fact that plans are not stated upfront in the informed consent does not mean that the HRA would require a review at the later time of lay summary distribution.

Stakeholders have raised concern that IRBs/RECs may begin asking to review layperson summaries or templates. If so, edits and changes that may then be suggested or even required may become a challenge for the sponsor to offer a uniform and timely summary that is consistent across geographic areas.

Budget Considerations Budget will need to be set aside for any or all of the following:

Writing the layperson summary, either by in-house staff or outsourced to vendors. Translating the layperson summary, either by in-house staff or outsourced to vendors. Stakeholder alignment and participant feedback on the layperson summaries. Investigator expectations and contractual issues – where they are directly involved in discussing study

results with the study participants, including costs and timing associated with the educational guidance on conveying trial results to participants in plain, non-promotional language.

Layperson summary distribution costs where applicable. Out-of-pocket expenses possibly incurred by study participants returning to site to receive layperson

summary (participants may have to pay for an office visit that is not part of the study and not covered by insurance, travel expenses, etc.).

b A layperson summary conveying an intermediate analysis to study participants (e.g. not merely posting to a register) while the study is on-going would likely be under the purview of the ethic committee


Writing Layperson Summaries Annex V of the EU CTR lists 10 elements that should be included in the layperson summary of any clinical trial that is conducted in at least one EU member state. While the regulation itself contains very few instructions, this year the EC has released for public consultation the “recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use” 9 which provides recommendations and templates for the production of layperson summaries .

In addition, other publically available resources for writing layperson summaries include:

Multi-Regional Clinical Trials (MRCT) – Return of Results Guidance Document and Toolkit;7

Reflection Paper – EFPIA Guiding Principles on Layperson Summary;10

European Patient Forum – guidance which provides a good indication of what study participants would like to see in layperson summaries;11

TransCelerate Biopharma Inc. – Recommendations For Drafting Non-promotional Plain Language Summaries of Clinical Trial Results;12

A high-level comparison of the content of the layperson summaries from two guides, MRCT and the draft

(published for formal commenting) EU Guidelines on the Summary of Clinical Trial Results for Laypersons5, as

well as the EFPIA Reflection paper is given in Appendix 3.

TransCelerate believes the following are important considerations for layperson summaries as sponsors develop their respective policies (see Sponsor Policies and Planning Considerations):

The information contained within layperson summaries will also be publicly available in the form of a scientific summary, publication in a peer-reviewed journal, or patient leaflet. Additionally, detailed result summaries will be accessible globally in public registries such as clinicaltrial.gov and EU Clinical Trials Register and the EU Database when it is completed. It is important to recognize that layperson summaries are a subset of this more detailed information and links should be provided to these resources as appropriate.

Given the need to provide information to the general public and to study participants in lay or plain language, the overall length of the document ideally would be kept short and concise.

Sponsors may also wish to develop templates of required information that should be included in layperson summaries to help standardize and facilitate production of the summaries as much as possible within an organization.

Layperson summaries describe the results of one trial; product-level documents such as patient information leaflets (PIL) describe results across multiple trials. Sponsors may wish to explain within the content of the layperson summary that the different documents may therefore contain different information and potentially different data.

The requirement for reports on adverse “reactions” in layperson summaries according to the EU CTR will mean that sponsors may wish to explain how this is different from adverse event reporting in the scientific summary.

The current draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons5 expects that layperson summaries be made available in the local language of each of the EU countries where the trial took place. The draft EU Guidelines suggests that layperson summaries be provided in English regardless of whether an English-speaking country has participated. This provision is likely be included in the final guidance,


Sponsors should also be mindful of the need to account for cultural and regional differences (there may be some countries where the portal cannot be accessed or summaries cannot be sent). Sponsors should consider the pros/cons of central vs local-level autonomy (e.g., Japan can own this process for their sites).

Reporting ResultsFor results reporting, TransCelerate considers it is best for all stakeholders, including the participant, if a layperson summary reports the results of the primary endpoint(s) in a short, high-level, balanced, and factual document in alignment with the EU CTR Annex V requirement to provide “overall results of the clinical trial”. TransCelerate considers that layperson summaries should describe the results of primary endpoints as the general approach to preparing layperson summaries for several reasons:

Primary endpoints will address the main purpose of the study. Studies are statistically powered to show differences in primary endpoints. Some secondary endpoints or exploratory endpoints may lack statistical power and validation

which could lead to misinterpretation and confusion by the public and give more weight to a result than appropriate.

Without clear guidance regarding which secondary endpoints should be included, sponsors may be exposing themselves to a risk of “cherry-picking” and thus being accused of inappropriate promotion.

Layperson summaries will be posted for a general audience; what may be of interest or relevant to some people may not be of interest to others. Choosing key endpoints is subjective and could be confusing or misleading to participants.

Layperson summaries should refer readers to further information (including the full list and results of secondary endpoints). 2,3

There may in some circumstances be a need to report safety information that impacts the primary endpoint (e.g. vaccine studies).

In addition, the draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons suggests that “where examined in a trial as a part of the original statistical analysis plan, differences between subgroups may be described.” TransCelerate considers that, as the layperson summary is a summary of data from one clinical trial with limited numbers of study participants, especially if a Phase 1 and 2 trial, presenting subgroup analyses may not be appropriate in all or most circumstances.

Reporting SafetyThe EU CTR uses the definition of “adverse reaction” in Directive 2001/83/EC as “a response to a medicinal product which is noxious and unintended”. This implies a causal relationship between the event and the investigational medicinal product. Multiple studies are often needed to elucidate a causal relationship. In an individual clinical trial, the investigator will usually give an opinion on causality, but the sponsor’s assessment of causality may subsequently differ (e.g., when more extensive clinical trial or pharmacovigilance data are available).

Reporting adverse events that the investigator determines to be related to study treatment as an “adverse reaction” in layperson summaries is proposed as this provides an objective determination of causality upon completion of an individual study. Text could be included in the layperson summary to explain the


differences between adverse events and adverse drug reactions. Describing and reporting “drug-related adverse events” may be the best alternative to indicate a possible causal relationship in an objective manner.

Use of Visuals and Non-written Material At the time of writing this document, the draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons on the use of visuals in layperson summaries suggests avoiding figures that present more than one message. TransCelerate suggests, when determining whether to use visual aids, consideration should be given to whether the intended message conveyed by using figures is unambiguous and how that aid may reduce the need for lengthy text. Visuals that are overly complicated and difficult to interpret should be avoided.

Sponsors may wish to explore additional formats such as infographics and videos suitable for the communication channel selected.

Translations The draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons 5 expects layperson summaries in the local language where the study was conducted within the EU, which may be interpreted as the “official” language(s) or the languages used in ICFs. Creating a master version in English, however, may facilitate a sponsor’s ability to ensure that all translations express the same concepts, by comparing the translation back to the English version. An English version is expected to be uploaded to the EU database according to the most recent draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons. Sponsors should anticipate that for translations some deviations will have to be accepted as many medical concepts are culturally formed. A balance will be needed for harmonization of information across summaries in multiple countries while managing cultural needs and sensitivities.

There are numerous methods and considerations for creating and managing translations:

A sponsor may choose to provide local language translations centrally without involvement of a local function once layperson summaries are posted on the EMA website and the sponsor website. This approach has a low complexity and facilitates alignment of the various translations.

A sponsor may provide translations to be checked/reviewed by its local country representatives. The review should assess whether the translated summary has not lost its intent. However, if a sponsor determines such checks are necessary or desirable, adequate educational guidance of their local staff should be considered.

A sponsor should have non-promotional guidelines in place and ensure layperson summaries in all languages remain non-promotional.

Other methods include forward-back translation and forward-back-forward translation, either method may be used depending on availability of local staff. Such methods may increase cost and possibly time needed for the provision of the layperson summaries.

Distribution OptionsIn addition to developing a process to write layperson summaries, industry sponsors also need to determine their overall strategy on how to distribute them. Per the EU CTR, for all studies conducted in an EU member state, sponsors will be required to post a layperson summary to the EU database once the portal becomes


available late 2018. However, even within the draft EU Guidelines on the Summary of Clinical Trial Results for Laypersons, it is stated that the summary for lay persons in the EU database should not be regarded as the only way of communicating with trial participants3. Furthermore, if layperson summaries are prepared for studies that were not conducted in the EU, these studies will not be posted to the EU database; therefore, a different distribution method will be needed.

Additional distribution options include:

“Web-based” provision of the summary electronically on a sponsor-supported site. “Site-based” provision of the summary to study sites or a third-party for distribution to study participants.

Some of the possible advantages and disadvantages to each of these methods are detailed in the following table. Additional potential complexities are also described below. These factors should be considered as an individual sponsor selects the most appropriate method for its organization. In some cases, multiple methods of distribution may work best.


Method of Distribution Advantages DisadvantagesEU portal:A permanent option once launched and summaries are posted.

1. Will be required for all trials subject to the EU CTR.

2. Study participants and the general public will always be able to access the layperson summary through the EU portal once it is available.

1. Implementation delays since the availability is not expected until late 2018.

2. Sponsors will need to provide notice of availability of results to participants.

3. Portal not owned by sponsor and therefore difficult to export metrics. Only studies conducted in the EU will be posted to the portal.

4. Posting does not necessarily meet participant expectation for a more interactive dissemination and could increase the risk for misinterpretation without additional opportunity to ask questions and get clarifications.

5. Will not be an option for posting studies out of scope of EU CTR.

Web-based distribution of layperson summaries:Options include sponsor-supported site, academic-sponsored site, non-profit organizations, multi-sponsor platform, vendor platform, etc.

For sponsor website, the landing page must be free from commercial bias, i.e., study participants/public should be able to directly navigate to the information without proceeding through promotional webpages on a commercial website.

1. Utilizing or building a sponsor website or registry may carry initial expenditure, but maintenance costs are lower.

2. Summaries could be made available to public as well as study participants.

3. A third-party-hosted portal may allow for interactive elements such as submission of questions from participants.

4. Metrics could be easily collected related to website access (e.g., number of people viewing).

5. Does not need an explicit opt-in or opt-out option in the ICF, since it is participant’s choice to access site.

6. Posting to a website would not require IRB/REC review or approval.

7. Participants may be provided information during the study regarding how and when to access the website.

8. Benefit of a multi-sponsor platform is having a single place for participants to access.

1. This mode of dissemination is not required by regulation and will carry additional costs and resource requirements.

2. There could be a risk for misinterpretation of the layperson summaries if the participant receives the information without explanation. The risk of misinterpretation is likely to be reduced when a statement in the layperson summary is included to discourage any therapeutic changes before consulting a physician/healthcare professional.

3. May create a gap in being able to reach special participant populations such as:

illiterate participants and participants with very low literacy; participants without internet access; blind participants.

For these populations, sponsors may wish to use an alternative method of sharing the study results.

Note: #2 and #3 also apply to EU portal.


Method of Distribution Advantages Disadvantages

Interactive, site-based distribution of layperson summaries: Options include asking study site to distribute via meeting with principal investigator, email with attachment, hard copy mail, or engaging a third-party to manage layperson summary distribution with careful consideration of privacy concerns.

1. Provides the option of an interactive experience for the participant where questions can be addressed, lessening the risk for misinterpretation.

2. Considered more personal and more valued by the participant (trusted source).

3. Addresses some of the concerns for special participant populations

1. This mode of dissemination is not required by regulation and will carry additional costs and resource requirements.

2. The logistical (e.g., cost and distribution) challenges of printing paper summaries could be considerable and a constant cost (no economies of scale over time).

3. Will require sites or third-party vendors to manage and retain participant contact information for future contact.

4. Sites need to track opt-in/opt-out responses. Creates a compliance issue with a potential risk of deviations

5. Direct mailing of a layperson summary to a study participant would need to be done in a manner that minimizes the risk of breaching privacy of study participation (e.g., name on mailing in some situations could be problematic). This needs to be considered particularly in trials for indications that have the potential to result in social discrimination such as dementia or alcohol abuse.

6. Investigators need to be trained on the content of the layperson summary and how to answer participant questions. Need for educational guidance; time, cost, and effort could be substantial.

7. Due to lag time between end of study and completion of layperson summary, investigator may no longer be at the site and/or site may no longer be active.

8. Participant may have to pay for a follow-up appointment with investigator.

9. Not available to general public.


Additional Considerations for Site-Based DistributionUsing a more interactive method of distribution of layperson summaries is more participant-centric and allows for an opportunity to address participant questions. However, as sponsors are typically not in direct contact with study participants, this distribution method could place additional burdens on investigators and sites. Investigators and study site staff will need to be trained on how layperson summaries are to be handled. They will need to maintain contact information and opt-in/opt-out preferences and schedule follow-up visits that may take place years after the study is over at their site.

Interactive forms of distribution are also a potential avenue for new safety information that will need to be processed by the investigator (i.e., participants coming back and reporting side effects) which may entail time and cost at the investigational site.

Maintaining participant contact information

In order for sites to distribute layperson summaries, they (or third-party vendors) will have to manage and retain participant contact information as well as develop a process for managing address changes. Sites or third-party vendors will need to comply with local data protection regulations when retaining contact information details of study participants. While this contact information is essential if the layperson summary is distributed by the site, safeguards are needed to ensure that participant confidentiality is not breached.

Opt-in/Opt-out considerations

As the participant will be contacted by the study site again, permission to do so may need to be obtained during the study. One approach may be to give all participants who have consented the choice to opt-in/opt-out of receiving a layperson summary.

For certain specific trials, (e.g., in oncology), participants may be provided the opportunity to designate a third party (e.g., a family member) to receive the layperson summary on their behalf. This choice could be documented in the ICF. However, the tracking of participant choices poses logistical challenges and may create a compliance issue (i.e., the need to verify whether all those who wanted to receive the layperson summary have actually received it).

The investigational sites should exercise due diligence in their attempts to contact the recipients (e.g., tried to deliver the layperson summary 3 times via various ways/channels). Further attempts at contact may be perceived as a nuisance and thus a reasonable effort should suffice.

If a participant has withdrawn his/her consent, sponsors may no longer ask whether he/she may be contacted nor may sponsors send him/her any information. It might be helpful to ask participants at the time of withdrawal whether they wish to receive the layperson summary (similar to asking about biomaterials); otherwise, a summary of the study should not be sent to those participants.

Investigator RoleA sponsor may decide to involve the investigators in the distribution of the layperson summaries or to assist in answering questions from participants once they receive the layperson summary. The sponsor and investigational site would have to negotiate the terms upon which the investigator would provide these services, which may complicate the contractual arrangement and the terms of dealings between them.


Should investigators have a role in distribution, appropriate educational guidance for investigator and site staff (i.e., sub-investigator, study nurse, etc.) may include:

1. Increasing awareness about the importance of the layperson summary as part of the overall participant experience.

2. Gain buy-in around the value of this summary and how to best share with participants

3. Providing guidance on how to discuss the results of the study with the participants and how to answer study participants’ questions in a non-promotional manner, including the following (See Appendix 2: Toolkit, Participant Frequently Asked Questions):

The results relate to the overall population included in the study and not the individual study participant;

The summary represents a single study and does not represent full knowledge of the investigational product;

The application of the results to the individual participant should be discussed with the treating physician/healthcare provider (if not the investigators themselves);

Contact information, if further information is sought (e.g., other non-commercial publications or the link to the scientific summary if requested) and/or sponsor’s contact phone number and email address;

Guidance on non-promotional communication in the context of plain language summaries.

Timing of such guidance would need to be considered at the study planning stage. Ideally, such guidance could be performed in alignment with the completion of the layperson summary. In regions where no regulation currently exists for the public disclosure of layperson summaries, a similar distribution method and timeframe could be considered for return of layperson summaries to ensure all study participants are treated/informed equally, allowing a sponsor to implement consistent global procedures and application of global metrics across its organization.

A sponsor could consider developing an educational slide set on appropriate language for the investigators (see example in Appendix 2: Toolkit). This may be presented at study closeout meeting(s), or at the time the results are shared, or both.

Additional Considerations for Web-based Distribution Posting to a registry or database enables a sponsor to communicate results to the general public as well as to study participants. If a sponsor chooses to distribute the layperson summary through these outlets, instructions for accessing the web portal should be included in the informed consent and may be provided to the participants together with the Thank You Letter or another end-of-study document. Some sponsors may request that the investigator print instructions for accessing the portal and distribute them to the participants.

On a portal, opt-in/opt-out preferences are simplified. The participant would opt in when they access the site. Depending on how the portal is designed, participants might be able to register themselves or delegate a family member to register on their behalf. This may be beneficial particularly in pediatric situations as well as in those cases where study participants may not survive until the end of the study.7


ConclusionProviding clinical trial results via layperson summaries to participants, along with transparency, can show recognition and appreciation for their participation, which can increase their confidence and strengthen their trust in the drug development process.

TransCelerate has published other documents on assisting sponsors in the process of implementing layperson summaries and on protecting study participant privacy:

Recommendations for Drafting Non-Promotional Lay Summaries of Clinical Trial Results12: The recommendations are intended to provide general principles to help sponsors prepare layperson summaries in a manner that reduces the risk that they could be perceived as promotional, which could raise regulatory concerns.

Protection of Personal Data in Clinical Documents – A Model Approach13 Data De-identification and Anonymization of Individual Patient Data in Clinical Studies – A Model

Approach13

The guidance provided intends to help sponsors meet the requirements of the EU CTR and explore considerations beyond the regulation that may arise in developing a comprehensive program to deliver results to the general public and possibly return results to study participants more directly.

TransCelerate presents the guidance in this document as optional and as best practice. It is up to each sponsor to determine what is best for its own organization.


References

1. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC. Available athttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf. Published 16 April 2014. Accessed 5 August 2016.

2. Clinical Trials registry and results posting database. Available at https://clinicaltrials.gov . Accessed September 2016.

3. European Clinical Trials Database (EudraCT) V10. Available at https://eudract.ema.europa.eu/index.html. Accessed August 10, 2016. Accessed September 2016.

4. REGULATION (EC) No 1901/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Available athttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. Published 12 December 2006. Accessed 5 June 2016.

5. Draft published for formal commenting: Consultation document Summary of Clinical Trial Results for Laypersons Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. Available at http://ec.europa.eu/health/files/clinicaltrials/2016_06_pc_guidelines/gl_3_consult.pdf. Published June 2016. Accessed 30 June 2016.

6. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the Approximation of the Laws, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use. Available athttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF. Published 3 April 2001. Accessed September 2016.

7. MRCT Return of Results Guidance Document. Available athttp://mrctcenter.org/wp-content/uploads/2016/07/2016-07-13-MRCT-Return-of-Results-Guidance-Document-Version-2.1.pdf. Published 13 July 2016. Accessed 8 August 2016.

8. Health Research Authority: Information for participants at the end of a study: Guidance for Researchers/Sponsors/ Chief Investigators/Principal Investigators. Available athttp://www.hra.nhs.uk/documents/2015/08/hra-guidance-end-study-pis-v4-1_20-august-2015.pdf. Published 20 August 2015. Accessed 5 August 2016.

9. Risk proportionate approaches in clinical trials. Recommendations of the expert group on clinical trials for the implementation of 13 Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. Available athttp://ec.europa.eu/health/files/clinicaltrials/2016_06_pc_guidel i nes/gl_4_consult.pdf . Published June 2016. Accessed 5 August 2016.

10. MRCT Return of Results Toolkit. Available at http://mrctcenter.org/wp-content/uploads/2016/07/2016-07-13-MRCT-Return-of-Results-Toolkit-Version-2.2.pdf . Published 13 July 2016. Access September 2016.

11. EFPIA Reflection Paper – Guiding Principles on the Content of the layperson Summary. Available at http://www.efpia.eu/uploads/EFPIA_Reflection_Paper_-


http://www.efpia.eu/uploads/EFPIA_Reflection_Paper_-_Guiding_Principles_on_The_Content_of_the_Layperson_Summary_Sep_2015_FINAL_clean.pdf

http://mrctcenter.org/wp-content/uploads/2016/07/2016-07-13-MRCT-Return-of-Results-Toolkit-Version-2.2.pdf

http://mrctcenter.org/wp-content/uploads/2016/07/2016-07-13-MRCT-Return-of-Results-Toolkit-Version-2.2.pdf

http://ec.europa.eu/health/files/clinicaltrials/2016_06_pc_guidelines/gl_4_consult.pdf

http://www.hra.nhs.uk/documents/2015/08/hra-guidance-end-study-pis-v4-1_20-august-2015.pdf

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF

http://ec.europa.eu/health/files/clinicaltrials/2016_06_pc_guidelines/gl_3_consult.pdf

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf

https://eudract.ema.europa.eu/index.html

https://clinicaltrials.gov/

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

_Guiding_Principles_on_The_Content_of_the_Layperson_Summary_Sep_2015_FINAL_clean.pdf. Published September 2015. Accessed September 2016.

12. European Patients’ Forum (EPF) position: Clinical trial results – communication of the lay summary. Available athttp://www.eu-patient.eu/globalassets/policy/clinicaltrials/epf-lay-summary-position-final_external.pdf . Published 2 March 2015. Accessed September 2016.

13. TransCelerate Recommendations for Drafting Non-Promotional Lay Summaries of Clinical Trial Results. Available at http://www.transceleratebiopharmainc.com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1.pdf . Accessed September 2016.

14. TransCelerate Biopharma Inc. Clinical Data Transparency initiatives. http://www.transceleratebiopharmainc.com/assets/clinical-data-transparency/ . Accessed November 8, 2016


http://www.transceleratebiopharmainc.com/assets/clinical-data-transparency/

http://www.transceleratebiopharmainc.com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1.pdf

http://www.transceleratebiopharmainc.com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1.pdf

http://www.eu-patient.eu/globalassets/policy/clinicaltrials/epf-lay-summary-position-final_external.pdf

http://www.efpia.eu/uploads/EFPIA_Reflection_Paper_-_Guiding_Principles_on_The_Content_of_the_Layperson_Summary_Sep_2015_FINAL_clean.pdf

Appendix 1: Sample Process Flow


Appendix 2: Implementation Toolkit

Tool # Tool Name1 Investigator Educational Materials Regarding Layperson Summary 2 Sample Thank You Letter3 Study Participant - Frequently Asked Questions4 Introductory Letter to Investigative Sites5 Roadshow Slide Set


Appendix 3: Comparison of Guidance Documents

Issues / Challenges

MRCT Return of Results Guidance Document

DRAFT EU Commission Consultation Document (Summary of Clinical Trial Results for Laypersons)

EFPIA Reflection Paper Laypersons Summary

Scope Considers broader delivery of layperson summaries than the EU (e.g., US/FDA perspective, dissemination more directly back to participants).

Guideline applies only to layperson summaries included in EU database.

Short summary EFPIA position on lay summaries

Depth and breadth of content

Comprehensive document covering process and logistics, content of layperson summaries and special considerations (e.g., trials that close early, vulnerable populations, return of results in the event of participant death).

Concise document including annexes (templates and neutral language guidance) focussing mainly on writing for a lay audience including health literacy, lay or plain language presentation.

Straightforward, brief outline for sponsors to create layperson summaries, encourages considerations from other participant-based perspectives.

Template and content

Separate toolkit (MRCT Return of Results Toolkit) including templates and examples, examples of neutral language, research ethics committee checklist.

Guidance document including a layperson summary template with example of lay language, and neutral language guidance.

Simple outline of the 10 required elements with brief descriptors, no template, no sample language provided.


Appendix 4: Communication ToolsParticipant-Centric Communication ToolsOnce layperson summaries become available, sponsors should consider the best and most appropriate methods to inform study participants and the public about the availability of the summarized study results.

Sponsors are limited in their ability to communicate directly with study participants. Conversely, investigators communicate regularly with study participants before, during, or after clinical trials. Therefore, adding a section describing the approach and means of accessing layperson summaries into the site specific communication plan could be an efficient way to help sites communicate details about the layperson summary to participants.

Posting of layperson summaries on a web site will require sponsors to define a method of making the public and study participants aware that the layperson summary has become available. TransCelerate solicited participant opinions on this aspect of sponsor/participant communications and received guidance and feedback provided in the Appendix 2: Toolkit.

Some sponsors use a Thank you Letter (TYL) at the close of a trial to thank participants for taking part in the study and provide information on how, when, and where the results and/or layperson summaries will be made available to participants. Such details will vary by sponsor.

As participant-centric communication tools and methods evolve to include direct text messaging and use of social media platforms, sponsors should remain flexible to adapt emerging best practices with respect to providing layperson summaries to study participants as well as the larger continuous participant contact framework.

Internal Communication ToolsSponsors may develop a communication and change management approach using a formal communications plan. The communication plan could describe the objectives, audience, method, and timing of communication including how change impacts stakeholders and how to measure the impact of returning layperson summaries. The best time to develop the communication plan is in conjunction with the development of the process of returning layperson summaries. (See Appendix 2: Toolkit, Roadshow Slide Set to facilitate internal communications)

Below are key elements to consider in a communications plan:

Objectives:

Communicate the rationale, purpose, and goals of returning layperson summaries; Identify internal stakeholders involved in the return of layperson summaries; Provide appropriate educational guidance and messaging to enable successful endorsement and

deployment of the return of layperson summaries; Customize messaging based on stakeholder roles and responsibilities (i.e., RACI table below).

Goals:


Enhance understanding and support for the adoption of the return of layperson summaries; Adapt messaging to organizational needs and align the return of layperson summaries with overall

sponsor goals, mission, and vision.

Key Message:

Include description, purpose, and impact of returning layperson summaries.

Audience:

Identify the people and/or roles that may be involved in or impacted by the return of layperson summaries. The following is a suggested list of generic sponsor groups and their potential accountability as it relates to implementation of the return of layperson summaries:

RACI (Responsible, Accountable, Consulted, and Informed)

Key Stakeholders Responsible Accountable Consulted InformedClinical operations central team

X

Medical Writing X X Safety X Statistics X Data Management XRegulatory X Legal X CRO partners or other vendors involved in the process

X

Life Cycle Teams XMedical Information XAdvocacy Relations X

Communication channels: Share information about the return of layperson summaries through the specific sponsor’s media. A list of suggested media may include sponsor intranet, internal social media sites, meetings, forums, town halls, emails, posters, presentations, internal process systems, and champion network channels.

Below is a generic tool to help you with planning delivery channels and timing:


Prompt for Communication Timing

Message Content Channel Author Delivery Date

Status Feedback

Before launching the return of layperson summaries – post implementation

• Slide set overview

• Process map• Supplemental

material• Guides and

templates

Email Smith, Ann

Sept 20XX Completed Knowledge check score – 90%

Feedback measures and success criteria: Implement validation checks to ensure the return of layperson summaries adoption and messaging understandability. Some ideas to measure success may include:

Knowledge checks to determine if messages resonated with intended audience; Feedback forms to evaluate engagement, buy-in and support from key stakeholders; Surveys to determine whether selected channels reached targeted audience; Internal audits to inspect adoption of the return of layperson summaries.

External Communication StrategyThis section is intended to point out some considerations relating to a sponsor’s communication with external stakeholders regarding the actions and activities they are undertaking with regard to the availability of layperson summaries.

With study participants:

A sponsor may want to include language in the ICF letting study participants know they will be offered a layperson summary of the trial results after it is completed and the analysis is performed which may occur years later.

A sponsor may want to share a note of appreciation and thanks with a participant at his or her last visit. This note may be distributed by investigators on behalf of the sponsor and may also provide information concerning when and where to expect the layperson summary as well as instructions should he or she have any follow up questions. If a last visit note is to be provided, this visit may be an opportune time for study participants to “opt- out” of receiving the summary depending on the method of delivery selected.

What is TransCelerate doing? o Appendix 2 provides a sample “Thank you” note that a sponsor may use to express its

appreciation for a participant’s study involvement at his or her last visit. Participants may opt-in or opt-out of receiving the layperson summary and may be notified how and when to expect the summary should they wish to receive one.

With patient advocacy organizations and patient groups:

A sponsor may wish to engage patients and/or patient advocacy groups for input and collaboration during the development of layperson summaries or potentially to provide feedback on templates or drafts after they are written.


A sponsor may want to inform patients and/or patient advocacy groups about the availability of layperson summaries, and where and when they can be accessed. A sponsor may also wish to set expectations among these stakeholders about the limitations the sponsor has on the content and distribution methods (e.g., as a highly regulated industry, sponsors are not to compare investigational drugs to the standard of care as this may be considered promotional).

A sponsor may wish to provide a mechanism for patients and/or patient advocacy groups to provide feedback (e.g., via an email link on a sponsor web site) allowing the sponsor to assess the feedback and determine if a modification in approach may be beneficial.

What is TransCelerate doing? o TransCelerate has provided frequently asked questions in Appendix 2: Toolkit after engaging with

patients and/or patient advocacy groups to gain insights on various approaches to content and distribution.

With investigators:

The information communicated to investigators and study sites will be dependent on how a sponsor will distribute the layperson summaries and what it will ask of the investigator. A sponsor may wish to communicate with investigators particularly for distribution models where investigators will be involved in delivering results back to study participants whether in-person, electronically, or through postal service. Any such arrangements should be discussed with sites early in the feasibility stage or at site initiation.

Educational or communication materials may include a general overview of layperson summaries and the importance of presenting information in a factual and non-promotional manner to educate investigators and site personnel.

What is TransCelerate doing? o TransCelerate has provided in Appendix 2: Toolkit, a sample investigator letter which may be

used by sponsors as the basis for a communication with investigator’s and site personnel the plans to provide layperson summaries.

o TransCelerate has also provided in Appendix 2: Toolkit, a sample investigator educational deck on how to communicate results in a fair, balanced, and non-promotional way, the main elements of the layperson summary, and the importance of sharing study results with study participants, and an example of how to communicate and illustrate the anticipated role the investigator may play in this process.

With the general public:

A sponsor may want to develop an external communication plan to inform the public on its plan with regard to layperson summaries. The timing, scope, availability of translations, method(s) of distribution may be of interest to various entities and individuals.

A sponsor may wish to include a formal statement on their public facing web sites with key messages as a part of an overall communication plan.

What is TransCelerate doing? o By way of this Implementation Guide, TransCelerate is raising awareness/educational campaign

for the general public about the steps industry will need to take and may take to develop the appropriate content and method for distribution, given the EU CTR. For example, one key message in this awareness campaign is that this will be an evolving process, and feedback on this approach is welcome.
