Public Access to Clinical Documents the new Transparency Policies in Europe

Public Access to Clinical Documents the new Transparency Policies in Europe Thomas M Schindler, PhD Medical Writing Europe This material is protected by copyright. All rights reserved. Thomas M Schindler

Disclaimer, Thanks, and Abbreviations The views and opinions expressed in the following PowerPoint slides are mine and should not be attributed to Boehringer- Ingelheim Pharma or AMWA. Special thanks to my colleagues Dr Wendelgard Pisternick-Ruf and Dr Kirsten Herbach. EMA European Medicines Agency MAA Marketing Authorization Application CSR Clinical Study Report 2

Why is this interesting for you (ie someone outside EU)? Requirements for submission documents are globally standardised (ICH M4E). Companies submit marketing applications (EU) and NDAs (US) at the same time using similar or even identical sets of documents. Most important trials are conducted globally, with study sites in EU and US. There is a high likelihood that clinical documents written in the US will become public via the EU transparency channels. 3

Channels of Disclosing Clinical Trial Results Transparency Posting of summary results on Clinicaltrials.gov* EuDRA CT Posting of CSR synopses on sponsor websites Access to / release of clinical documents by EMA policies 43 and 70 Provision of study results in lay language (EU-regulation) Sharing of raw data *New rules 21 Sept 2016! 0043 = reactive, upon request to EMA 0070 = proactive, public release after decision 4

The 2 EMA policies for the provision of sponsor clinical documents Reactive Policy 0043 on Access to Documents Is currently effective Specific documents are provided by EMA to individuals upon request EMA and sponsors have some experience EMA is restrictive regarding protection of personal and commercially confidential information Proactive Policy 0070 on Publication of Clinical Data Go-live in October 2016 All clinical documents that are part of a submission dossier will be published on EMA website EMA and sponsors have very little experience EMA is restrictive regarding protection of personal and commercially confidential information 5

EMA policy on access to documents (related to medicinal products for human veterinary use) Policy 0043

EMA Policy 0043 reactive provision of documents Policy published: 1 December 2010 EMA Access to Documents Service (ATD): established 2013 Guide on access to unpublished documents: published 2014 Process: EMA (Web Form) Requester Sponsor EMA Redacted document 7

Access to documents Who can request a document? Anybody can request a document via EMA web form. What type of clinical documents can be requested? Any clinical documents held by EMA can be requested. How will you receive the document? The document will be sent via a secure electronic system (EudraLink). The e-mail will mention an expiry date; you have 50 days to download. Will I receive unchanged documents, ie as the EMA has seen them? No, sponsors are entitled to redact the documents to remove commercially confidential information (CCI) and protected personal data (PPD). However, EMA has a very strict policy and has to agree to all redactions. Source: EMA/304162/2014 Guide on access to unpublished documents, published 26 August 2014 8

Definition of PPD and CCI Protected personal data (PPD): Personal data shall mean any information relating to an identified or identifiable natural person ('data subject'); an identifiable person is one who can be identified, directly or indirectly, in particular by reference to an identification number or to one or more factors specific to his physical, physiological, mental, economic, cultural or social identity. Purpose: to prevent re-identification of patients and sponsor personnel Commercially confidential information (CCI): CCI shall mean any information contained in the clinical reports submitted to EMA by the applicant/mah which is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant/mah. Purpose: to protect intellectual property of the sponsor Source: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use EMA/90915/2016 9

Request form for documents under EMA policy 0043 Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/landing/ask_ema_landing_page.jsp&mid=wc0b01ac05806499f0 10

EMA experiences with policy 0043: Number of requests Initial requests and appeals received Nov 2010 to Oct 2015 Initial Appeal Source: Anne-Sophie Henry-Eude: Data Sharing and Disclosure: Operational Aspects of EMA Policies, 2015 11

EMA experiences with policy 0043: Access granted Closed requests: Access granted/refused Nov 2010 to Oct 2015 Refused Granted Source: Anne-Sophie Henry-Eude: Data Sharing and Disclosure: Operational Aspects of EMA Policies, 2015 12

EMA experiences with policy 0043: Who is requesting documents? Source: Anne-Sophie Henry-Eude: Data Sharing and Disclosure: Operational Aspects of EMA Policies, 2015 13

EMA experiences with policy 0043: What type of documents are requested? Source: Anne-Sophie Henry-Eude: Data Sharing and Disclosure: Operational Aspects of EMA Policies, 2015 14

EMA experiences with policy 0043: Extent of agreement on redaction 2014 and 2015 54% 30% Redaction rejected Redaction agreed 70% 46% Source: Anne-Sophie Henry-Eude: Data Sharing and Disclosure: Operational Aspects of EMA Policies, 2015 15

EMA Policy on publication of clinical data for medicinal products for human use Policy 0070

EMA Policy 0070 Policy published 2 Oct 2014, effective since 1 Jan 2015 Q&A document: published on 2 Oct 2014, revised on 8 Jun 2015 External guidance on the implementation, published 2 March 2016 Scope: Any marketing authorization application (MAA) submitted via the centralized procedure from 1 Jan 2015 onwards Post-authorization procedures for existing centrally authorized medicinal products (extension of indication and line extension applications) submitted from 1 Jul 2015 onwards 1 st phase: only clinical reports, published on EMA website 2 nd phase (planned): individual patient data http://www.ema.europa.eu/docs/en_gb/document_library/report/2014/10/wc500174378.pdf http://www.ema.europa.eu/docs/en_gb/document_library/other/2014/10/wc500174796.pdf http://www.ema.europa.eu/docs/en_gb/document_library/regulatory_and_procedural_guideline/2016/03/wc500202621.pdf 17

Clinical reports to be published by EMA EMA will make the following clinical reports accessible on website: Module 2.5: Clinical Overview Module 2.7 2.7.1 Summary of Biopharmaceutical Studies 2.7.2 Summary of Clinical Pharmacology Studies 2.7.3 Summary of Clinical Efficacy 2.7.4 Summary of Clinical Safety Module 5: all Clinical Study Reports, including appendices: 16.1.1 Protocol and protocol amendments 16.1.2 Sample case report form and 16.1.9 Documentation of statistical methods Sponsors need to redact protected personal data (PPD) and commercially confidential information (CCI). 18

Process for EMA policy 70 EMA sends notification to submit redaction proposal document Sponsor reviews documents for PPD and CCI Sponsor prepares redaction proposal and 1 Justification Table per document (for CCI) and Anonymisation Report (for PPD) per dossier, sends to EMA EMA agrees with redaction proposal EMA disagrees with redaction proposal EMA releases documents Negotiation with sponsor Agreement Disagreement Court 19

EMA Policy 0070 Protection of the following information is allowed/required: Commercially confidential information (CCI) Any information that is not in the public domain and where disclosure may undermine the legitimate economic interest of the applicant/mah 1 Justification Table per clinical report with CCI Personal data of trial participants, investigators, staff: Any information relating to an identified or identifiable natural person ('data subject ) 1 Anonymisation Report per dossier (is also made public) that describes the approach to protect personal data in all clinical reports of a submission 20

What is personal data? Personal data shall mean any information relating to an identified or identifiable natural person ('data subject'); an identifiable person is one who can be identified, directly or indirectly, in particular by reference to an identification number or to one or more factors specific to his physical, physiological, mental, economic, cultural or social identity. Applies to: Patients, study participants Sponsor personnel (study administrators) Investigators, committee members, vendors, consultants Based on US census data: 87% of people are likely identified with three pieces of information: 5-digit zip code, date of birth, gender; 53% are identifiable with place, gender, date of birth L. Sweeney, Simple Demographics Often Identify People Uniquely. Carnegie Mellon University, DataPrivacy Working Paper 3. Pittsburgh 2000. 21

Personal information of patients What could lead to re-identification? Direct identifiers: Names, initials, patient numbers Indirect (quasi) identifiers: Demographic information such as gender, race/ethnicity, height, weight, BMI, socio-economic information Dates: birth date, age, date of death, serious adverse events, adverse events, medical history, current medical diagnosis Where in the report? Demographics, disposition, mini-narratives in safety section, full patient narratives, in-text listings / tables, CIOMS-forms, information on small subgroups, etc Options: Remove/mask the information Generalise the information 22

Redaction of personal data Example: Patient numbers in an in-text narrative Step 1: Identify personal information Step 2: Mark information for proposed redaction (red rectangles): Step 3: Carry out redaction (black bars): 23

Patient level information in in-text tables <=25 treated patients/single-centre trials Redacted Rectangle document indicates text that needs to be redacted

Balance between data protection and data utility If too much detail is redacted, the data are not longer informative and their medical usefulness is compromised.

Anonymisation going beyond redaction Anonymisation is the process of turning data into a form that does not identify individuals and where identification is not likely to take place. It allows for a much wider use of the information. If the following 3 criteria are met, anonymisation is considered robust against identification: Individuals cannot be singled out. Records relating to an individual cannot be linked. Information cannot be inferred concerning an individual. If not all 3 criteria can be met, the risk of re-identification of an individual should be assessed qualitatively or quantitatively after anonymisation techniques have been applied. 26

Anonymisation report 1 Anonymisation Report needed per dossier, it describes: Methodology of anonymisation Measurements and management of the re-identification risk EMA reviews Anonymisation Report and provides comments 27

Examples for CCI that can be redacted Exploratory study objectives and information on planned clinical studies that could provide clues on Rationale for new hypothesis (eg, extension of indication) Potential future uses (eg, subgroups) Regulatory advice from outside the EU that could include agreements on study design Detailed information on stereochemistry issues, quantitative composition, and company assays or analytical methods Information that drives the sample size calculation, such as estimates of endpoints variability Details in Annex 3 of EMA Policy 0070 28

Template for Justification Table For each CCI within a clinical report, a justification needs to be provided in a Justification Table" (1 table per clinical report) Completed by Applicant Completed by EMA http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000555.jsp&mid=wc0b01ac0580999a9d 29

EMA reasons for rejecting CCI proposals EMA will reject a justification if the agencies determines that: Information already available in the public domain or publicly available Common knowledge Disclosure due to public interest Insufficient justification Irrelevant justification Details in Chapter 4, Section 3.2 of Guidance on EMA Policy 0070 30

Lay summaries

Shaping lay summaries Lay summaries are required by law. Regulation 536/2014 EU BI transparency initiative; BI EU clinical trial regulation working group (work stream #2) Patient organisations (EPF, Patvocates, ) PO BI LAY Language Content Numeracy Graphics Weblinks SUMMARY MRCT HRA Multi-Regional Clinical Trials centre at Harvard; cross-functional working group developed guidance and toolkit for lay summaries Health Research Authority taskforce in UK; worked on EU guideline on lay summaries European Federation of Pharmaceutical Industries and Associations; trade association representing pharmaceutical industry in Europe (equivalent to PhRMA in the USA) EFPIA Trans- Celerate Non-profit organisation; Returning results work stream develops non-promotional language recommendations and implementation guide for industry

Pharma-political context of transparency 2014: EFPIA/PhRMA on Principles for responsible clinical trial data sharing: our commitment to patients and researchers 2015: EU regulation 536/2014 mandates a summary of results for every trial 2015: MRCT (Multi-Regional Clinical Trials) starts to develop a guidance on Return of results, latest update version 2.2 in Sept 2016 2015: EFPIA Reflection Paper: Guiding Principles on Layperson Summary 2016: HRA (Health Research Association) in UK develops a guidance on EU guidelines on summaries of clinical trial results for laypersons 2016: TransCelerate Recommendations for drafting non-promotional lay summaries of clinical trial results, Implementation Guide available Dec 2016 2016: Summary of Clinical Trial Results for Laypersons Recommendations of the expert group on clinical trials for the implementation of Regulation = Consultation Document

(39) The sponsor should submit a summary of the results of the clinical trial together with a summary that is understandable to a layperson, and the clinical study report, where applicable, within the defined timelines. (67) The EU database should be publicly accessible and data should be presented in an easily searchable format, with related data and documents linked together by the EU trial number and with hyperlinks, for example linking together the summary, the layperson's summary, the protocol and the clinical study report of one clinical trial, as well as linking to data from other clinical trials which used the same investigational medicinal product. 37 Irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial in all Member States concerned, the sponsor shall submit to the EU database a summary of the results of the clinical trial. The content of that summary is set out in Annex IV. It shall be accompanied by a summary written in a manner that is understandable to laypersons. The content of that summary is set out in Annex V.

Annex V of the EU-regulation - Content of lay summaries 1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other identifiers); 2. Name and contact details of the sponsor; 3. General information about the clinical trial (including where and when the trial was conducted, the main objectives of the trial and an explanation of the reasons for conducting it); 4. Population of subjects (including information on the number of subjects included in the trial in the Member State concerned, in the Union and in third countries; age group breakdown and gender breakdown; inclusion and exclusion criteria); 5. Investigational medicinal products used; 6. Description of adverse reactions and their frequency; 7. Overall results of the clinical trial; 8. Comments on the outcome of the clinical trial; 9. Indication if follow up clinical trials are foreseen; 10. Indication where additional information could be found.

EU-regulation For which clinical trials? Lay summaries are needed for trials of all clinical phases I IV including studies in healthy volunteers EU-regulation uses a very wide definition of clinical studies: any study involving any measure beyond the normal clinical practice Timing: Scientific and lay summary need to be available 12 months after end of the study (defined as last visit last patient for primary endpoint assessment) for studies in adult patients. For studies in that have their primary endpoint before the overall end of the trial (according to the study protocol), results of the interim analysis need to be posted within 12 months For studies in children: 6 months after study end. Availability of EU-portal: Autumn 2018

Absence of guidance in EU-regulation EU regulation contains no guidance on: Format: text only, text plus tables, graphics, synopsis-like, font-size Length: what is a reasonable length Structure: structured headings with subheadings if needed, safety and efficacy separated Target reading level: Flesch-Kincaid reading level, reading ease scale Language: English or in other European languages? Need for a disclaimer: preventing readers from over-interpretation of single study results Many issues with the items provided in Annex 5, for details see: Brauburger K, Sroka-Saidi K, Schindler TM: New European Clinical Trial Regulation: The requirement for lay summaries and its impact on medical communicators AMWA Journal / V30 N2 / 2015, 60-64

Summary of the EMA Consultation Document Consultation Document contains recommendations and templates Lay Summary (LS) are meant for the general public (layout, style, level of detail) LS should be short, factual, non-promotional, follow health-literacy writing principles and numeracy principles Simple everyday language, free from jargon, technical terms, medical concepts need to be explained Should be written to a low literacy and low numeracy level (12-14 years) Use headings, leave white space, limited use of graphics, don t overwhelm the reader with information, big picture before detail, use bullet points LS should be in English and in all languages where the trial took place Limited use of imaginary and graphics, 1 message per graph LS should provide info on primary endpoints, patient-relevant secondary endpoints, key patient reported outcomes High-level statement summarizing results, important limitations of study

EMA Consultation document: Specific recommendations on LS content Title: have a simplified, lay title in addition to the scientific title Objectives of the trial: purpose, choice of comparator, critical changes during the study, premature stop y/n, explain scientific concepts simply Population of subjects: in each member state, in EU, outside of EU, age group and gender break down Inclusion and exclusion criteria: only most important ones, including references to diagnosis, indication and disease stage, must avoid identification of subjects Investigational medicinal products: INN to be used, randomisation and blinding should be described (list of product names at the end) Adverse reactions (=related to treatment), most serious first, others listed by frequency, number and percentages, serious adverse reactions and deaths, adverse reactions leading to withdrawal, clinical lab only if useful, MedDRA terms to be translated (PT and LLT as lay description) Comments on the outcome: high-level statement, emphasis on that this is just a single study not all the available evidence.

Transparency: latest developments in the US 16 Sept 2016: NIH Final rule on trial reporting on Clinicaltrials.gov Applies to all interventional studies, phase II-IV with at least 1 investigational site in the US, conducted under an IND (investigational new drug application) or an IDE (investigational device exemption) Requires trial registration no later than 21 days after enrolling the first participant descriptive information, recruitment information, location and contact information, and administrative information. Results need to be provided for trials of approved and un-approved investigational products! Results need to be posted 1 year after primary completion, can be delayed by a maximum of 2 years for unapproved products

Content of the results that need to be made available Results information consist of tables of information summarizing: Participant flow information, Demographics and baseline characteristics Primary and secondary outcomes, including results of any scientifically appropriate statistical tests, and Adverse events: i. 1 table that summarizes all serious adverse events ii. 1 table that summarizes other adverse events that exceed a frequency of 5 percent in any arm. iii. The Final Rule adds a 1 table for summarizing all-cause mortality, with the number and frequency of deaths due to any cause by arm. All results information is aggregated, summary level data, not data for the individual subjects who participated in the clinical trial. The Final Rule also adds a requirement to submit the clinical trial protocol and statistical analysis plan at the time of results information submission. Personally identifiable information and trade secret and/or confidential commercial information may be redacted from the protocol

Thank you! Questions?