The EMA Clinical Data Website – a Conceptual Exploratory Approach to Benchmark Clinical Development Indicators in Marketing Authorizations

Lehmann S1, Allard R2, Boehler YB1 1 TH Koeln – University of Applied Sciences, Faculty of Applied Natural Sciences, Leverkusen, Germany 2 Grünenthal GmbH, Aachen, Germany

ObjectivesThe European Medicines Agency (EMA) policy on clinical data publication entered into force on 1 January 2015. Data have been regularly uploaded and are accessible to the public on the EMA Website. For the fi rst time Clinical Study Reports (CSR) of the full Clinical Development have been made available. The aim of this study was to give an overview on the number and types of trials published and to analyze Clinical Development Pathways (CDPs).

MethodsAll available initial marketing applications on the EMA Clinical Data Website up to 1 April 2018 were analyzed. Data extraction was time-consuming and took place from 2 March to 31 May 2018. The methodology followed to access and navigate the EMA Clinical Data Website is described in detail by Billiones and Schneider7. A total of 3974 documents on the EMA Clinical Data Website were manually revie-wed by application category and analyzed iteratively as outlined using a Deming cycle approach8. For the data extraction and preparation of fi rst analysis a work fl ow was established to guarantee that all dossiers were treated equally. This work fl ow can be broken down into 5 individual steps, refer to Figure 2. The correspon-ding European Public Assessment Report (EPAR) was also consulted as a Quality Control (QC) step. Dates to permit the construction of GANTT charts were ob-tained from the available protocols and the dates on the CSR on the EMA Clinical Data Website. GANTT charts were generated in SAS® version 9.4 using a script de-veloped by the Programming Department in Data Sciences at Grünenthal GmbH.

Conclusions– As shown for lesinurad the availability of CSRs and appendices, e. g. protocol,

permit an insight into the strategic decision making process of CDPs. – Phase I studies constituted 57% of the studies available, a considerable amount.

This is the fi rst time that such analyses could be performed as complete CDPs were previously not available.

– Generally Phase III studies started in the latter half of the clinical developments. It appears, based on the limited number of CDPs available for analysis, that a CDP was planned according to the therapeutic indication and the physicoche-mical properties of the compound under development.

– The EMA Clinical Data Website provides a wealth of information that can be used to educate on clinical as well as project management aspects of clinical development. The more data is shared the more reliable the benchmarking of CDP timelines. This can be used to better plan for future clinical developments.

– Process design analyses can be performed if the study reports do not have re-dacted dates.

– The redaction of information in documents posted follows the EMA guidances, however, they do not automatically permit a consistent analysis across all clini-cal developments. As the protection of information appeared to be adapted ba-sed on the patient population investigated it would not be advisable to expect that all sponsors make all timeline dates public.

From 86 dossiers published, 55 Initial Marketing Authorizations (IMA) were availa-ble from 37 applicants for 48 indications by ATC classifi cation, refer to Figure 3. The 55 IMA were categorized into 17 generic, 3 biosimilar, 10 orphan and 25 other applications, by the EMA. In total 610 study reports were available, 349 phase I, 80 phase II, 124 phase III, 15 phase IV and 42 clinical studies without a designated phase, refer to Figure 4. Not all studies for a CDP were made available, e.g. fi xed-dose combination IMAs did not necessarily contain all studies from the individual substance development pathways. Phase I reports contributed to more than half of the studies made available, Figure 4, whilst together phase II and III study re-ports were found to constitute 33% of the documents available. The median time from First Subject-In (FSI) in the fi rst phase I to the FSI in phase II was found to be 24 months (Interquartile range [IQR]: 9, 38) for 19 IMA. The median time from FSI in the fi rst phase I to the FSI in phase III was found to be 55 months (IQR: 30, 62), refer to Figure 5 and Table 1.Time data available was used for project management analysis shown in Table 1 and then prepared in GANTT charts for the simple visualization of the CDP process, refer to Figure 6. A more detailed breakdown for the lesinurad CDP is shown in Fi-gure 6. From the 22 CDPs listed in Table 1 there were 28 unique active ingredients available from 17 applicants for 22 therapeutic areas. Multiple myeloma, Hepatitis C and HIV had more than one CDP available for timeline analysis. Table 1 shows that for lesinurad time to phase II and phase III were 8.2 and 40.2 months, respec-tively. In the lesinurad GANTT analysis, fi gure 7, the fi rst study in the CDP was to obtain safety and pharmacokinetic (PK) data. Twenty seven phase I studies were planned after the fi rst phase II study was initiated. A phase IV study to ascertain the safety of allopurinol at medically appropriate doses over a period of six months was initiated prior to initiation of phase III studies. Seven phase I studies were plan-ned after the last phase III study had been initiated. The last study to be initiated in the lesinurad CDP determined the bioequivalence of lesinurad formulations from two diff erent manufacturing sites.Figure 7 shows a slightly more detailed operational breakdown of the lesinurad CDP, based on dates of fi rst subject-in from the dates available. In the lesinurad CDP the Renal Impairment (RI), Mass Balance (MB) and TQT (Thorough QT/QTc) studies were initated after the fi rst phase II study had started recruitment. The He-patic Impairment (HI) study was initiated after the last phase III study had been initiated. A total time of 2325 days could be tracked from the available document dates for the lesinurad CDP.

Results

1. European Medicines Agency. Questions and answers on the European Medicines Agency policy on publication of clinicaldata for medicinal products for human use, <http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/10/WC500174378.pdf> (accessed on August 08, 2018).

2. European Medicines Agency. European Medicines Agency policy on publication of clinical data for medicinal products for human use, <http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/WC500174796. pdf> (accessed on April 08, 2018)

3. European Medicines Agency. External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use: Version 1.1, <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/12/WC500218567.pdf> (accessed on August 08, 2018).

4. European Medicines Agency. External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use: Version 1.3, <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/09/WC500235371.pdf> (accessed on May 01, 2018).

5. European Medicines Agency. External guidance on the implementation of the European Medicines Agency policy Euro pean Medicines Agency. External guidance on the implementation of the European Medicines Agency policy on the publi-cation of clinical data for medicinal products for human use: Version 1.2, <http://www.ema.europa.eu/docs/en_GB/docu-ment_library/Regulatory_and_procedural_guideline/2017/04/WC500225880.pdf> (accessed on August 08, 2018).

6. The European Parliament and the Council of the European Union. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medi-cinal products for human and veterinary use and establishing a European Medicines Agency, <http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0001:0033:en:PDF> (accessed on April 08, 2018).

7. Billiones R, Schneider A. Navigating the EMA clinical data website. Medical Writing 27(2), 19–21 (2018).8. Maylor H. Project Management. 2nd ed. London: Financial Times Pitman Publishing; 1999, p 6-7.

References

Background EMA Policy 0070– is a European initiative for the disclosure of clinical reports with the objective

to increase transparency. The development of Policy 0070 started in year 2012.1

– was adopted on 2 October 2014 with entry into force on 1 January 2015.1,2 – initiated the fi rst dossier upload on the EMA clinical data website on

20 October 2016. Detailed guidance on the implementation of Policy 0070 can be found in three external guidance documents with the fi rst published on 19 Dec 2016, the second on 12 Apr 2017 and the third on 22 Sep 2017.3,4,5 The history and development of Policy 0070 is illustrated in Figure 1.

– was issued based on Article 80 of Regulation (EC) No 726/2004, which requires the Agency to “ensure an appropriate level of transparency”6 and “to ensure the availability to the public of regulatory, scientifi c or technical information con-cerning the authorization or supervision of medicinal products which is not of a confi dential nature”.6

– does not repeal Regulation (EC) No 1049/2001 (of the European Parliament and of the Council of 30 May 2001 regarding public access to European Parliament, Council and Commission documents) and Policy 0043 (European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use).2

Figure 1: Overview on EMA Policy 0070 development

10 April 2012

22 September 2017

1 January 2013

1 January 2014

1 January 2015

1 January 2016

1 January 2017

10 April 2012PUBLICATION “OPEN CLINICAL TRIAL DATA FOR ALL? A VIEW FROM REGULATORS”

22 November 2012EMA WORKSHOP ON CLINICAL-TRIAL DATA AND TRANSPARENCY

1 January 2013 - 30 April 2013EMA MET WITH ADVISORY GROUPS

30 April 2013FINAL ADVICE RECEIVED

24 June 2013DRAFT POLICY 0070 RELEASED FOR PUBLIC CONSULTATION

12 June 2014MANAGEMENT BOARD MEETING: DISCUSSION OF PROPOSED AMENDMENTS

AND PLANNING OF FINALIZATION AND ADOPTION OF POLICY 00702 October 2014

ADOPTION OF POLICY 00701 January 2015

ENTRY INTO FORCE OF POLICY 0070

20 October 2016FIRST DOSSIERS ON THE EMA CLINICAL DATA WEBSITE

19 December 2016GUIDANCE ON IMPLEMENTATION OF POLICY 0070 - VERSION 1.1

12 April 2017GUIDANCE ON IMPLEMENTATION OF POLICY 0070 - VERSION 1.2

22 September 2017GUIDANCE ON IMPLEMENTATION OF POLICY 0070 - VERSION 1.3

Figure 2: Work fl ow for data extraction and preparation of fi rst analyses

Download of policy 0070 dossier

Creation of a “Breakdown for analysis“ and

extraction of data of interest

Analysis of anonymization report

Module 5 breakdown

Download of EPAR

ICH E8 characterization

Find study numbers in relevant chapters

Check wheter all studies listed in the

EPAR were identified

Figure 2: Work fl ow for data extraction and preparation of fi rst analyses

Figure 3: Data availability within 55 IMAs – The breakdown of data available for analysis within the 55 IMA on 1 April 2018. There were 13 IMAs with no CSRs, 4 IMAs with no phase I studies, 8 IMAs with dates redacted and 6 IMAs with only phase I studies. For analysis a core and a non-core analysis set was defi ned. The core analysis set comprised 15 IMA dossiers for detailed analy-sis, including the lesinurad clinical development pathway. The non-core analysis included IMAs where analysis were possible but limited.

349; 57%

80; 13%

124; 20%

15; 3%

42; 7%

Number of studies , percentage breakdown by phase

Phase I Phase II Phase III Phase IV Without designated phase

Figure 4: Breakdown by phase of development of the 610 studies in the 55 IMAs

Presented at the ISPOR 21st Annual European Congress November 13th, 2018, Barcelona, Spain

Table 1: Timeline analyses of phase II and III clinical studies by International Nonproprietary Name

Active Substance Therapeutic areaTime from first subject in FIM/FIH study to first patient-in in phase II

[months]

Time from first subject in FIM/FIH study to first patient-

in in phase III [months]

Empagliflozin / linagliptin Diabetes Mellitus, Type 2 27.3 64.5Rociletinib Carcinoma, Non-Small-Cell Lung 15.3 N/ALenvatinib Carcinoma, Renal Cell 39.7 72.3Eluxadoline Diarrhea - Irritable Bowel Syndrome 34.4 59.4

Drisapersen Duchenne muscular dystrophy 1.7 4.7

Sofosbuvir / velpatasvir Hepatitis C, Chronic 9.6 32.6Emtricitabine / rilpivirine / tenofovir alafenamide HIV Infections 81.1 52.9

Elbasvir / grazoprevir Hepatitis C, Chronic 24.0 59.3Ixekizumab Psoriasis 33.9 60.5

Ceftazidime / avibactam

Gram-Negative Bacterial Infections Pneumonia, Bacterial & Soft Tissue Infections Urinary Tract Infections

23.7 64.1

Pancreas powder Exocrine Pancreatic Insufficiency 4.1 N/A

Pandemic influenza vaccine H5N1 (live attenuated, nasal) Influenza, Human 0.9 2.0

Daclizumab Multiple Sclerosis 1.9 61.8Trifluridine / tipiracil Colorectal Neoplasms 80.8 157.5

InfliximabArthritis, Psoriatic & Rheumatoid Colitis, Ulcerative / Crohn Disease Psoriasis / Spondylitis, Ankylosing

N/A 1.0

Osimertinib Carcinoma, Non-Small-Cell Lung 13.7 N/AAlbutrepenonacog alfa Hemophilia B N/A 26.9Emtricitabine / tenofovir alafenamide HIV Infections 81.1 52.9

Elotuzumab Multiple Myeloma 62.0 54.4

Idarucizumab Hemorrhage N/A 20.3Carfilzomib Multiple Myeloma 23.0 57.9Lesinurad Hyperuricemia 8.2 40.2

Figure 6: Lesinurad CDP – GANTT chart showing the complete lifecycle of each of the clinical studies in relationship to each other. Earliest timepoint, the date of the fi rst version of the pro-tocol available in the EMA clinical data website; and last timepoint, date of CSR. The various phases have been color coded to show the distribution of phase I studies in the CDP.

Faculty of Applied Natural Sciences

TechnologyArts SciencesTH Köln

Figure 7: Process design showing the inclusion of specifi c phase I studies in the lesinurad CDPAs visible in the GANTT chart, the CDP started and ended with a phase I study. Studies in RI, MB and TQT were conducted before phase III was initiated. A study in HI had FSI after FSI in the fi rst phase III study.

Figure 5: Box plot of time data for the CDPs (N=19) with data available (median times in months are shown)

AbbreviationsATC: Anatomical Therapeutic Chemical; CDP: Clinical Development Pathway; CSR: Clinical Study Report; EC: European Com-mission; EMA: European Medicines Agency; EPAR: European Public Assessment Report; FIH: First In Human; FIM: First In Man; FSI: First Subject In; HI: Hepatic Impairment; IMA: Initial Marketing Authorization; IQR: Interquartile Range; LSO: Last Subject Out; MB: Mass Balance; PK: Pharmacokinetic; QC: Quality Control; RI: Renal Impairment; TQT: Thorough QT/QTc