A holistic Next Generation RIM design model champions major synergies compared to the traditional table-oriented. Once in the system, all entities can be versioned and life cycled, allowing full record track. Master data can be used as meta data in multiple modules of an integral application. Such product information, centric-approach allows a seamless transition to a higher granularity and consistency of information, from planning and tracking, towards IDMP, including Master Data Management, content creation and maintenance automations. Precondition for such holistic approach is a combination of Product Master Data and Regulatory Intelligence capabilities, building the foundation for automation of all regulatory processes including configurable interactions with other systems, allowing efficient and right-first-time data management to the utmost possible extent. As there is a direct correlation between realized value, compliance and complexity, reduction of complexity translates into the reduction of TCO’s driven by magnitude wide reduction of hidden costs, which are rarely measured. Under hidden costs, we understand: - Not realized productivity due to complexity of systems, processes, organizations and products - Challenges in reflecting global versus local requirements - Missed process performance improvement, due to complex interfaces - Quantification of compliance risks - Backlog of projects (IT and business) Complexity is the main exponential cost driver in R&D IT and it is the major compliance risk. Reduction of complexity contributes to higher compliance and reduces costs. Integral approach can change the paradigm of compliance being cost of doing business and create value from compliance. Elements of compliance value: - Consistency between data and content - Process automation - Faster product to market - Lower product maintenance effort - R&D IT can focus on innovation versus on supporting legacy

Turn Compliance into Value – Decrease Complexity, Increase Compliance and Reduce Total Costs of Ownership

Objective:

Goal of the poster presentation is to show how different adaptive features can be combined in one overall adaptive trial design, allowing sponsors to explore various options and still provide confirmatory evidence to assist regulatory decision making.

Method: 

After a Phase I study with promising results, an adaptive trial for Phase IIB is planned; it includes dose selection, sample size re-assessment, and a potential enrichment. Type-1-error control is achieved by splitting the significance level, p-value adjustment, and closed testing principle. 

Results: 

The trial is planned as a randomized, double-blind, placebo-controlled, 3 parallel arms adjuvant trial to assess the efficacy of two doses of 2-hydroxyoleic acid (2-OHOA) versus placebo in patients with newly diagnosed GBM IDH wildtype.  In all arms patients will receive the Standard of Care and will be randomized to receive either placebo, low-dose or high-dose 2-OHOA.

The primary endpoints of the study are progression free survival (PFS) and overall survival (OS) as assessed after observing at least 150 PFS events and 133 OS events, respectively. It is expected that the analysis for PFS can be performed about 2 years earlier than the analysis for OS.

One formal interim analysis will be performed by an independent statistical group and reviewed by an independent Data Monitoring Committee (iDMC) when 75 PFS events are observed. After reviewing the interim results, the DMC will make recommendations regarding: the dose to take forward to the second part and the continuation of the trial overall. 

At interim analysis, if a molecular signature permits to identify a subpopulation of patients who respond better to the treatment, and this subpopulation needs enrichment the signature will become part of the inclusion criteria fora third cohort in the second stage of the trial, and the treatment effect will be estimated in the corresponding subgroup in the second and third cohort (Freidlin and Simon, 2005).  

Further, the sample size and events will be re-estimated for the selected dose to ensure that the power is well maintained given the estimated treatment effect at the interim analysis using the promising zone design (Mehta and Pocock, 2011).  

The poster will give details on all steps and how they are combined for evidence generation and what is done to protect type-1-error and the scientific integrity of the trial.

Conclusion : 
The adaptive trial design and statistical simulations are novel approaches to provide solutions to complex clinical development questions/scenarios and are presented to further scientific understanding in the clinical trials community.

The overall drug development plan and specifically the study design for Phase IIB presented in the poster recognizes that the European Commission has awarded a Horizon 2020 project grant to support the execution of this particular study in a stipulated timeframe and according to mutually-agreed specific conditions an

Adaptive trial design with dose-selection and enrichment for assessing 2-OHOA for treatment of glioblastoma

Objective: To present information gathered over the years 2017-2019 from current and potential customers including large innovative pharmaceutical companies, orphan drug, and generics companies, on their views of outsourcing pharmacovigilance functions, in particular the EU QPPV role, and the impact of Brexit.

Method: Following decisions on outsourcing pharmacovigilance functions including the EU QPPV role, a questionnaire is sent to companies and/or a personal conversation is scheduled to understand the companies’ reasons why and how the decisions were made. Response rates and answers are analyzed and compared.

Results: The results are currently preliminary and will be finalized by the time of creation of the poster and presentation at the DIA Europe meeting in February 2019. 26 companies in different stages of marketing different medicinal products that were in touch with Syneos Health due to their interest in outsourcing post-marketing pharmacovigilance functions in the EU/EEA, including the EU QPPV role, were asked to provide feedback on their decision what and how to outsource. While the analysis of response rate and answers is still ongoing, the following areas of interest were already identified: all companies considered Brexit an issue for pharmacovigilance outsourcing and wanted to ensure that any future EU QPPV, be it outsourced or in-house, would be based in an EU country outside the UK. Besides this, main issues that companies considered when deciding on outsourcing pharmacovigilance functions were pricing and technological setup. Specifically, the feedback received shows pricing being a higher concern than quality, i.e. companies asked far more questions and spent more time analyzing the budget than the time spent analyzing the service providers’ experience, processes, and track record. A difference here appears to be in the size of the companies: while smaller companies in the process of launching their first product and with no previous experience with pharmacovigilance inspections were primarily concerned about cost, larger companies with products on the market and experience with inspections were more interested in quality and experience of the provider. Finally, the digital setup of the service provider was a primary consideration, with companies being interested in service providers capable of providing cloud-based safety databases as compared to traditional license and local server database models.

Conclusion: While further conclusions may be reached once data analysis is complete, it seems clear from the preliminary results that virtually no company currently outsourcing pharmacovigilance functions is expecting the possibility of an EU QPPV to be able to remain in the UK after Brexit to become a reality. No matter the legal landscape after Brexit, this mindset is certainly having a significant impact on the EU QPPV function as a whole, considering that the majority of EU QPPVs pre-Brexit were based in the UK. The prelimina

Considerations for outsourcing EU QPPV services taking into account the impact of Brexit

Objective:

To assess the opportunities, challenges, and current applications of real-world data and artificial intelligence in the regulatory approval and post-marketing process.

Method:

A literature review was conducted from September to December 2018 using publications from the Duke Margolis Center for Health Policy, regulator and industry communications such as from the FDA and EMA, stakeholder reports including those from the DIA, and media releases such as Pink Sheet. 

Results:

As traditional clinical trials continue to be inefficient, pharmaceutical companies look to utilize internally stockpiled data and real-world data (RWD) gathered externally from sources such as electronic health records (EHR), insurance claims, and patient registries.  Artificial intelligence (AI) such as predictive modeling and machine learning provides stakeholders the opportunity to more efficiently screen for and develop successful drug candidates. For this reason pharmaceutical companies have partnered with and acquired biotech companies specializing in AI. The impact of RWD and AI use is already quite evident. For example, Vertex Pharmaceuticals received a label expansion in May 2017 from the FDA for its cystic fibrosis product supported by post-marketing registry data and in vitro mechanism of action information. Additionally, the FDA Sentinel Initiative conducted an interventional clinical trial (IMPACT-Afib) to evaluate the effect of education on oral anticoagulant prescribing habits in patients with atrial fibrillation. Roche also recently utilized Flatiron Health’s RWD database to generate control arms including data on medication use, uptake, and outcomes following standard of care across the globe in order to receive faster market access for its non-small cell lung cancer product in over 20 countries.  Furthermore, the Observational Health Data Sciences and Informatics program accesses over 50 international databases and applies a common data model to integrate these data. In addition, Japan has two big data projects enabling the systematic use of EHR and the combination of health records from 23 hospitals to benefit regulatory decision making. Current limitations to RWD in the regulatory process include the proprietary nature of large datasets as well as p-hacking, which affects how data are analyzed and interpreted. Additionally, claims and health records are not always linked and may not capture the full scope of patient treatment.

Conclusion:

As increased interest and utilization of RWD and AI continues, more guidance and support will be required from regulators.  The latest Prescription Drug User Fee Act, PDUFA VI, directs the FDA to assess the use of real-world evidence for regulatory considerations, and the agency is working towards a draft guidance for drug development targeting the end of fiscal year 2021. The Heads of Medicines Agencies/European Medicines Agency Joint Big Data Task Force also plans to make recommendations for using RWD in

An Assessment of Real-World Data, Artificial Intelligence, and their Use in Drug Development

The possibility of harmonization/convergence in the OTC  drug regulations in Asia-Pacific is discussed.

There have been found a number of yet-to-harmonized elements in the regulations, i.e. categorization of OTC drugs, data requirements for marketing authorization application and regulatory review process, monographs ad approval standards, Rx to OTC switch, etc.

Currently the related industry and the regulators in the region separately organize the conferences to deal with the issue. The industry founded the Asia Asia-Pacific Self-Medication Industry (APSMI) in 2010. The following 7 industry associations participate in the organization, namely China (CNMA), Taiwan (TPMMA), Korea (KPBMA), Indonesia (G.P. Farmasi), Japan (JFSMI), Philippines (CHAP), Thailand (TSMIA), as well as several corporate members. The principal aim of the APSMI is to contribute to enhancing the OTC industries and to promoting responsible Self-Medication in Asia-Pacific　

The regulators, on the other hand, established Self-medication Collaborative ASIAN Regulator Expert Roundtable (Self-CARER ), a Platform for regulators to optimize OTC regulation in Asia-Pacific in 2014. In its Taipei meeting in 2018, the regulatory authorities from 10 countries participated, i.e. from Chinese Taipei, India, Indonesia, Japan, Malaysia, Myanmar, New Zealand, Singapore, Thailand, Vietnam.

Strengthening collaboration between the two bodies is highly expected.

Convergence in OTC drug regulations

Objective: 
The objective of this discussion is to highlight the challenges that may arise with improving compliance at a senior level and the methods for improving organizational effectiveness and promoting pharmacovigilance excellence within biopharma when the role of the EU QPPV is outsourced to vendor.

Method: 
We provided initial pharmacovigilance training to key Marketing Authorization Holder (MAH) staff on the role of EU QPPV and basic PV training. Over a 6-month period, we monitored the effectiveness of the training by measuring the deviations that occurred following the training on the role of the EU QPPV and basic PV training. 

Results: 
Training was provided to MAH senior management with the aim of enhancing the pharmacovigilance system, enhancing QPPV oversight, and promoting compliance in the organization. The training focused on areas of the legislative requirements, responsibilities of the MAH in relation to EU QPPV, responsibilities of EU QPPV, the requirements of adding new partners to the PV system, how to report safety information to the pharmacovigilance department. A key element of the training was making the MAH aware of their responsibilities towards the EU QPPV and ensuring that the MAH was aware that any business changes can have the potential to affect the PV system.  Training was received well and over the course of 8 weeks, outsourced EU QPPV started to see improvements. Improvements noted included more involvement in the QMS, improved MAH reporting compliance of ADRs and notification of changes that had the potential to change the PV system for the MAH. However, after 4 months, the EU QPPV started to experience situations where there was a failure of the MAH to facilitate QPPV pharmacovigilance system oversight with the QPPV being omitted from critical processes that would have an impact on the pharmacovigilance system i.e. product acquisitions/ product divestments

Conclusion: 
Based on the case study, results demonstrate the EU QPPV and the MAH Senior Management need to work in partnership to ensure that the PV system & QMS are robust to ensure that Patient Safety is protected. Challenges noted for the EU QPPV from the case study are mainly around contracts between third party vendor and MAH with the level of work required vs what is required per EU legislation, input into QMS and the level of detail required for PV at the MAH and having the oversight of the MAH.  In order, to mitigate the results presented in this case study and to enhance working relations between the EU QPPV and MAH Senior Management annual refresher training on the MAH responsibilities to the EU QPPV and the responsibilities of the EU QPPV are added to the MAH Senior Management training plan. Furthermore, the MAH responsibilities to the EU QPPV could be described within Senior Management Job Descriptions to achieve harmonization.

Considerations for promoting pharmacovigilance excellence within biopharma

Objective: 
To discuss the opportunities and purposes of ClinLine – the new integrated infomedia platform for all parties involved in clinical trials, which could facilitate clinical trial search, site selection, patient recruitment, and improve transparency of clinical trial process in Russia.
Abstract Text:
The database for clinical trials, investigators and clinical sites was developed based on official MoH registers. The cross-searching functionality was implemented. The platform allows creating personal accounts/profiles for patients and investigators and facilitates prescreening and communication.
Results:
The platform was launched in July 2018. The functionality includes cross-searching of clinical trials, sites and investigators, registration and creating profiles of patients/healthy volunteers and investigators, authorization of investigators with access to patient registry, application/invitation to a clinical trial, chat between patients/healthy volunteers and investigators, rating of patients/healthy volunteers and investigators. The database is up-to-date and synchronized daily; it contains 6,040 trials including 2,604 ongoing studies, 3,859 investigators, and 1,434 accredited clinical sites. Top 10 indications for clinical trials in Russia include lung cancer, breast cancer, bronchial asthma, diabetes mellitus, rheumatoid arthritis, ulcerative colitis, infections (prophylaxis), lymphoma, multiple sclerosis, and flu. 137 investigators, 87 patients and 61 healthy volunteers registered within the first three months. The monthly web-site activity was approximately 13,000 page views with 5,000 individual visitors including over 20% visitors aged 45 year and older (6.0±0.3 minutes per visit). The platform was presented at several industry conferences and received positive feedback from representatives of clinical trial community. Further steps will include promotion among patient communities including internet and conferences, involvement of more investigators and development of functionality for Sponsors/CRO (i.e. site selection, analytics, etc.).
Conclusion:
Having a common platform for clinical trial participants will encourage more patients in drug development process, allow better access to clinical trials, streamline communication between patients and investigators, and provide the society with more transparency and understanding of drug research. Feasibility and pre-screening capabilities will improve the site selection process and minimize enrollment timelines. The platform also aims to attract more Sponsors to the Russian clinical trial market.

ClinLine.ru – the first Russian clinical trial platform for Patients, Investigators, Sponsors and CRO

The objective was to systematically review and conduct a meta-analysis of the spontaneous remission percentage in the placebo arm in order to get a better estimation of the needed patients for future clinical trials of biotherapies for systemic erythematosus and nephritis lupus.	Among 180 studies screened, 36 studies were included in the meta-analysis. 16 studies are from phase II, 15 from phase III and 5 of them are also post hoc studies. Most of the studies were evaluated belimumab (anti-BAFF mAb), abatacept (CTLA4-Ig), rituximab (anti-CD20 mAb) and tabalumab (anti-BAFF mAb). Only belimumab met his primary objective and obtained the marketing authorisation in Europe, United States and Canada. Final results will be available at the beginning of 2019. The expected results would show that the spontaneous remission percentage in the controlled arm of selected trials is higher than expected at the start of the studies. The meta-analysis would allow to a better estimation of the effect size and could increase the strength of future trials The needed number of subjects will be consequently more precise for future studies and could lead to more successful trials. Furthermore, it will will play a key role in estimating trial cost.

Meta-analysis of spontaneous remission percentage in placebo arm of biologic agents in randomized controlled trials for lupus

•There is no question that the medical device and pharmaceutical industries are embarking on a technological journey focused on the utilization of digital health technology.
•This journey is the convergence of several regulated industries coupled with information technology which has created novel approaches to the future of healthcare and medicine. We can see first hand that our dependency on technology provides the ideal conduit for further utilization of our smartphones, tablets, and personal computers.
•This utilization of our daily technology has created a digital healthcare sector which is often thought of as products utilizing telemedicine, smart products, disease management, therapy reminders, and support message to advance diagnosis and treatment.

Opportunities and Challenges for Digital Health Solutions

Chances for reducing Rodent Carcinogenicity Testing of Human Pharmaceuticals

Objective: The objective is to find the factors which influence parents’ consent, reasons leading to an early termination of clinical trials on neonates and infants and solutions which could improve the inclusion rates of this population in clinical trials by analyzing the scientific literature.

Methods: Analysis of articles on database (PubMed) in order to find, with specifics keywords (neonates, clinical trial, informed consent, etc.), relevant articles particularly in the pediatric clinical trials.
Results: A meta-analysis of 30 studies and 42 articles were collected and enabled us to answer to the question of this research. First of all, most of the articles raised the fact that parents have to make a decision within a tight time frame. Thus, the time limit to consent can impact the amount and the quality of the information given by the physicians. That is why physicians have to determine the right moment they have to give all the information to the parents. And, this moment has a real impact on the parents’ decision. Some studies show also the fact that conversations about consent to research should be performed by health professionals with previous clinical experience (usually neonatal nurses, nurse-
practitioners, respiratory therapists, or neonatologists). They must be sensitive to the current stress and vulnerability of the parents. Indeed, most of the time, parents are under stress, anxiety or pain. Those feelings can easily affect the understanding and the capacity of the parents to consent. For making the right decision they have not to feel informeless. Moreover, a European Delphi survey carried out on parent representatives and clinicians suggest that informed consents could be optimized thanks to the quality of the information given to the parents. This survey revealed the fact that parent representatives prefer to be informed about the study by the physician in charge of their child. Another study enabled to raise the determinants of parental authorization for involvement of
neonates and infants in clinical trials, which are principally the risks and benefits assessments, the illness severity of their child, their sociodemographic characteristics, the professional who gives the information on the research, and the advice given by the physicians which extremely matter for the parents. 

Conclusion: Our analysis generates a listing of many studies concerning obstacles in the informed consent process when it is come to neonates. It collects several parameters of different studies: number of subjects, medical field of the clinical trials, etc. It will play a key role in helping to improve the informed consent process in the pediatric clinical trials.

Systematic review of bibliography about barriers and difficulties in informed consent process in pediatric clinical trials.

Objective: The aim of this meta-epidemiologic (ME) pilot study is to give an overview of single-arm studies (SaS) provided as ultimate proof of treatment efficacy for authority approval, to highlight weakness and potential sources of biases of this type of clinical trials (CT).

Method:  SaS of antineoplastic agents were selected in Medline database with a combination of MeSH terms. The design was reviewed and potential approval checked. Descriptive statistics will be used to identify the key features of the methodology of these studies.

Results: A total of 2451 articles have been found with the combination of MeSH terms on Medline. Concerning the pilot study, on the 12 articles we identified that external comparisons were informal in 25% of studies, 33% were done with an historical control and 33% with a prefixed norme. A confirmatory study (to confirm results of phase II) was done in only 36% of studies and was inconclusive in 25% of studies.

Conclusion: SaS design raises many questions, such designs are source of biases specific to descriptive studies: confounding factors and methods used for external comparisons which that do not  allow the same level of evidence as a RCT. These elements call into question the internal validity of SaS and the clinical relevance of their results. In addition, there is a need of evidence-based guidelines, or scientific recommendations for the use of this study design. The ICH E10 guidelines describe the use of external control design as “ restricted to situations in which the effect of treatment is dramatic and the usual course of the disease highly predictable”. This definition question the threshold of “dramatic”. It seems clear that the simplistic design of SaS can not replace RCT to assess the benefit of a treatment, because of its many limitations making it very difficult to interpret the results

Could we do without RCTs? The emergence of single-arm studies as a basis for approval, a meta epidemiologic study

"Earlier than expected: FDA early approvals and an analysis of their frequency, importance and targeted products"

FDA’s PDUFA (Prescription Drug User Fee Act) sets precise goals regarding the duration of review of NDAs and BLAs, but in some cases, for example in diseases with higher unmet needs, FDA can offer a quicker assessment, with an Early Action in advance of the PDUFA action date.
This research assesses the frequency and importance of such early approvals, with comparisons based on various criterias such as the type of medicines (BLA, New Molecular Entity (NME) NDA and non-NME NDA), if the application received Priority Review or not, the therapeutic area, or the Orphan Designation status. This study highlights the number of drugs that were granted an Early Action in each category, as well as the average difference between the PDUFA target approval date and the actual one.
This study was performed on 433 NDAs/BLAs approvals granted by FDA between January 2015 and June 2018.

When submitting a NDA/BLA, having a precise estimation of the assessment duration is extremely valuable for decision-making, , regulatory and business strategy. This research aims to provide insight to help Pharmaceuticals Industry make a more precise estimate of review expectations, and better understand the key influencing parameters.
Furthermore, by highlighting the type of application that were granted early approvals, this study also highlights FDA's current priorities.

Early Actions granted by FDA: a review of the frequency and importance of NDA/BLA approvals in advance of DUFA action date

Objective 
The objective of this project is to review the possibilities and means available in the field of data sharing in paediatric clinical research and to suggest the involvement of young persons to improve information and results dissemination.
Methods 
We conducted a literature review on pubmed without time consideration based on the defined eligibility criteria and the keywords, Pediatric and Data sharing or Information dissemination and Clinical trial, mentioned in the abstract and the title. We will continue with expert young persons involvement.
Results 
On Pubmed, we found 902 articles using the pre-established search strategy. Given the eligibility criteria, 21 relevant articles were selected.
Based on our previous experience, we know that contrary to many studies and efforts that have been made to improve the quality of patients’ health care provision to young patients and their families’ satisfaction, unfortunately, the matter of the information dissemination to these children according to their health conditions and considering the sensitivity of their low age, has been minimal.
We expect that the results of the review will show relevant information about the means used to disseminate the results at the end of a clinical research in children. To evaluate the relevance of the dissemination ways, we will consider concepts such as minimizing harm to children by disseminating information, protecting the privacy of their information, making it possible for children to directly ask questions from their physician and consult with them.
As an effective way of disseminating information in paediatric clinical studies, the participation and accompaniment of experienced and expert young persons in this regard willbe studied. We expect valuable results such as i) friendly and effective communication with young patients and families ii) information dissemination in a friendly atmosphere appropriate to patients’ conditions and iii)boosting hope and efforts to recover, building up self-confidence and self-esteem in young patients as well as children who participated in this pathway.
Conclusion
Our first results indicate that there is a shortage of studies on the information dissemination in paediatric clinical trials and there are many challenges that should be addressed. Our completed review will provide information on needs and expectations, particularly from patients and their families in terms of results information. Providing direction and moving towards effective results in this regard requires the agreement and the creation of new insights and standards that will surely take into account the children’s conditions. The involvement of young persons advisory groups in the information dissemination at the clinical level is a practical and effective strategy that should be designed as much as possible to empower them, and benefit ultimately from its advantages.

Means to improve information dissemination in paediatric clinical trials: involving young persons to improve dissemination

[Objective]
PMDA conducted a surveillance to understand the status of utilization of RMP in medical practice of which preparation and implementation by MAH are conditions for granting marketing authorization of a drug from October 2014 in Japan and to consider our approach for promoting further utilization.
[Method]
The surveillance was conducted from January 9, 2018 to February 16, 2018 and targeted 10% of hospitals and 5% of health insurance pharmacies across the country. The questionnaire was mailed out to the targeted facilities. Responses were submitted either through online or by post. 
[Results]
　Answers were obtained from 373 hospitals (44.2%) and 1,647 pharmacies (56.3%). The percentages of hospitals stating that they understand the contents of RMP was 48.2%, an increase from the previous surveillance conducted in FY 2014 targeted hospitals. The percentage of pharmacies stating that they understand the contents of RMP was 17.4%, no marked difference was noted in comparison with previous surveillance conducted in FY 2015 targeted pharmacies. When asked the reasons for not utilizing RMP, the number of the facilities stating that ‘no opportunities to use’ is the most, followed by ‘do not know how to utilize’ in both hospitals and pharmacies. Furthermore, of the facilities that they stated that they understand the contents of RMP, the percentages of utilization of RMP of hospitals and pharmacies were 50.6% and 39.4% respectively, an increase from the previous surveillance conducted in FY 2014 and FY 2015 respectively. In addition, of facilities that they stated that they understand the contents of RMP, the percentage of the facilities that they utilize materials distributed based on RMP as activities for safety measures taken to minimize the risk (risk minimization activities) when providing medication guidance to patients or providing materials to other healthcare professionals was less than 20% which revealed that these materials are not fully utilized in medical practice.
[Conclusion]
Preparing and implementing RMP are conditions for granting marketing authorization of a drug. RMP outlines important potential risks and important missing information revealed on the process of approval review and it is important for pharmacists to overview the contents and provide risk information and cooperate to collect missing information for the purpose of risk minimization. Furthermore, materials distributed as additional activities in addition to routine activities are information required to be provided to healthcare professionals and patients as post-marketing safety measures considering the individual properties and pharmacists are asked to utilize these materials. Thus, utilizing RMP is essential to minimize risk of the pharmaceutical product and PMDA has been making effort to promote utilization of RMP by such as publication on PMDA website, however, result from the surveillance revealed that RMP is not utilized well in medical practice. It is co

Current status of utilization of Risk Management Plan in medical practice in Japan and PMDA’s approach to further utilization

Objectives: 
Patient engagement (PE) in medicines R&D needs a cultural change supported by measures that can demonstrate the ‘return on engagement’ of patients; we reviewed the literature on the evaluation of PE to inform a draft framework for evaluating patient engagement at 3 points in medicines development.
Methods: 
We did a literature review, using search terms including ‘Patient, Public, Engagement, Involvement, Framework, Impact, Indicator, Measure, Outcome’. Data describing outcomes and impacts of patient engagement and any monitoring or evaluation criteria were extracted and thematically analysed.
Results: 
1305 records were retrieved; from these 91 publications were included for data extraction after exclusion of duplicates and screening for relevance by two researchers. A few documents describe metrics in terms of numerical output but most used qualitative methods to evaluate PE practices and describe outcomes in subjective terms. Some publications use mixed methods.
The literature demonstrates valuable insights into PE processes outcomes and impacts, but few describe the relationship between input, output, outcomes and impact.  Most studies focus on the benefits of PE on research; the value across all stakeholder groups is missing. In addition, limited attention is given to the context and mechanisms that influence outcomes and impact. 
We present a summary of the benefits, costs and challenges and some indicators for measurement extracted from the literature we reviewed.
Conclusion: 
To embed PE in the development of medicines at the key decision making points of priority setting, clinical trial design and HTA approval, better measurement and articulation of the benefits to the output of the research and development process are needed.  
This study has mapped the outcomes and impact of PE in medicines development. On the basis of this review PARADIGM is developing and testing an evaluation framework that describes the relationship between input, outcomes, impact and value in relation to the context and mechanisms of PE for all stakeholders in medicines development.

Monitoring and Evaluating Patient Engagement in Medicines Development:  How literature informed a draft evaluation framework.

Internal Safety Advisory Groups (ISAG): A Win-Win for Effective Decision-Making in Biopharmaceutical Companies

Objective:  Our goal is to develop a natural language processing (NLP) algorithm to detect adverse drug events from hospital discharge summaries. Method: An NLP algorithm was developed using customised dictionaries of drugs, adverse event (AE) terms, and rules based on trigger phrases, negations, fuzzy logic and word distances. Results: A customised annotation tool facilitated expert review of discharge summaries from a tertiary hospital in Singapore in 2011.  A total of 33 trial sets with 50 to 100 records per set were evaluated (1,620 discharge summaries).  Pharmacovigilance experts reviewed the NLP results using a customised entity recognition, relationship detection and annotation tool named REAP (REadpeer for Active Pharmacovigilance).  After every 6 trial sets, drug and AE dictionaries were updated, and rules were modified to improve the performance of REAP.  Excellent performance was achieved for drug and AE entity recognition with over 92% precision and recall.  On the final 6 sets of discharge summaries (600 records), REAP achieved 75% precision and 59% recall for identification of valid drug-AE relations.  Conclusions: Adverse drug reactions are a significant contributor to health care costs and utilization. REAP is not restricted to particular drugs, drug classes or specific medical specialties, which is an important attribute for a national regulatory authority to carry out comprehensive safety monitoring of drug products. Drug and AE dictionaries may be updated periodically to ensure that the tool remains relevant for performing surveillance activities. The development of REAP, and the ease of reviewing and correcting the results of the algorithm as part of an iterative machine learning process, is an important step towards use of hospital discharge summaries for an active pharmacovigilance programme.

Text Mining Discharge Summaries of Hospital Electronic Medical Records to Detect Adverse Drug Reactions

Objective: 
Marketing Authorization should be granted based on clinical criteria. Surrogate criteria whose validity is often questioned is still used to speed up clinical development. We assessed the implementation and results of a grading approach to test substitution criteria validity.
Methods: 
The validity of Primary Criteria considered as Surrogate Endpoints in 21 clinical trials was checked using 3 methods. These criteria were used in various therapeutics areas. Finally, their level were compared with the Biomarker-Surrogacy Evaluation Schema (BSES3).
Results: 
Surrogates must fulfil several criteria, called Prentice criteria: correlation, capture and prediction. To test them, several methods are available: meta-regression of clinical outcome alteration as a function of surrogate outcome alteration due to treatment on summarized data. It allows to calculate R-squared value (coefficient of determination), Surrogacy Threshold Effect (STE) and Surrogacy Threshold Effect Proportion (STEP). STE is defined as the minimum treatment effect on the surrogate necessary to predict a non-zero effect on the true endpoint. STEP is the absolute value of the STE defined as 1- (STE/(x-axis values)). The other method used is regression on individual data which models clinical criterion alteration as a function of treatment exposure and of surrogate criterion alteration. It allows to calculate the proportion of treatment effect (PTE). This PTE value should tend to 1 to validate a surrogacy criterion. Our literature search found articles which we organised according to statistical methods used to test the surrogate criteria validity. We then analysed the conclusions of these studies separately depending on whether or not surrogate criteria tested were validated. Among 15 criteria, 11 (73%) were validated in accordance with statistical tests employed BUT none of these articles tested the three Prentice criteria together. Criteria tested using the STE/STEP approach or both STE and meta-regression (R²) were always validated. The Biomarker-Surrogacy Evaluation Schema (BSES) was applied to score the surrogate criteria assessed. Only 7 criteria (47%) were possible to classify according to this schema, due to lack of information, since STEP and R² are both needed to define this score.
Conclusion: 
Surrogate criteria must satisfy the three Prentice criteria (capture, correlation and prediction) which is the reference method recommended by the French Haute Autorité de Santé. Surrogate criteria are usually considered validated, even if not all the three criteria be verified. Among all therapeutic areas we explored, oncology studies are the most frequent and use meta-regression (STE, R²) to evaluate criteria and thus make it possible to score them with the BSES. Indeed, two variables can be correlated without having any causality link.  Furthermore, the statistical methods described present limits. When meta-regression is used, attention must be paid to linearity. A good 

Surrogacy : myth or reality ? A review of its testing methods and their applications

Objective	To describe the quality of published pharmacogenetic associations in randomized trials and assess the need for complementary specific reporting guidelines.
Abstract Text	We focused our research on Randomized, Controlled, Pharmacogenetics Clinical Studies, reporting a clinical phenotype outcome in Human. We used PubMed as database over the last three years. References were screened based on Title/Abstract, then on the full text.
Results	From October 2015 to October 2018, 330 publications were found through the research equation on PubMed, covering several medical areas. 289 of them were screened after removing duplicates. We respectively excluded 203 and 86 articles by the sorting on title/Abstract and on full text according to our PICOT criteria. 41 publications are currently being analysed in this Systematic Review. Extracted data include: analysis of the study design, genotyping methods, statistical results, presence or absence of a spin of conclusion, and several items of the STrengthening the REporting of Genetic Association studies (STREGA) guidelines.
Conclusion	These last few years, research in personalized medicine increases as the cost of genotyping decreases. Hence, the following of reporting guidelines may enhance the quality and the harmonization of published studies. Our Scientific Review will enable to determine the reliability of published pharmacogenetic associations in trials and thus to establish an overview of the transparency, the completeness and the homogeneity of the publications. The final results will be available by this end of the year.

QUALITY ASSESSMENT OF PUBLISHED PHARMACOGENETIC ASSOCIATION IN RANDOMIZED CLINICAL TRIALS, A SYSTEMATIC REVIEW

How common are claims on the association between the onset of autism and drug exposure: a systematic review

REGULATORY CHALLENGES AND SUCCESS MODELS FOR REGISTRATION OF GENERIC PHARMACEUTICAL PRODUCTS IN VARIOUS GLOBAL MARKETS

Objectives: The aim of our study was to understand the current status and trends of the Breakthrough Designation (BTD), PRIME and SAKIGAKE expedited review programs regarding number of reviews, most benefited therapy areas, drugs reviewed, profile of applicants and time to regulatory approval.
Methods: We reviewed published literature, news articles, press releases and data published by the Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) released since the launch of the expedited review programs until the end of 2018.
Results: As of 16th January 2019, we identified 326 expedited review designations across the three regulatory agencies (FDA=78% EMA=15%, MHLW=7%). The acceptance rate appears to be higher with the FDA (35%) than with the EMA (22%) and the PMDA (14%, data from 2015). The FDA has been granting a steadily increasing number of BTDs since the start of the program, in 2012. The MHLW more than tripled its granted designations in 2018 compared to 2017 (11 vs 3), while the EMA might granted less PRIME designations in 2018 than 2017 (19 vs 14). Regarding the most benefited therapy areas, oncology and rare non-cancer diseases make up two thirds of the designations. Oncology designations make up nearly half of the BTDs, but less than a third of PRIME and SAKIGAKE designations. In opposite, rare non-cancer indications make up a higher share of PRIME (31%) and SAKIGAKE (25%) than BTDs (12%). Interestingly, despite the overall low number of designations granted compared to the FDA, the EMA granted a substantial share of the designations in haematology/haemostasis (68%), while the PMDA granted more than half of the designations in Cardiovascular disease (57%). Regarding drugs that received expedited review designations, only two drugs have received BTD, PRIME and SAKIGAKE designations, but none have received regulatory approval yet (one has been submitted for regulatory submission in the three geographies). Only 9% of the drugs were granted an expedited review by at least two agencies. 38% of the expedited review designations are held by small and medium-sized enterprises (SMEs), but one third of all designations appear to be currently held by less than 5% of pharmaceutical companies/groups. 108 designations have already led to regulatory approvals, mostly by the FDA and with median of 6.1 months from filing to approval.
Conclusions: SMEs developing drugs for oncology and rare diseases could consider applying for expedited review programs, as these comprise most of the designations granted to date. The PRIME and SAKIGAKE programs appear to encompass a broader range of therapy areas, while the BTD program has been considerably focused in oncology. Few drugs obtain expedited review designation by more than one agency, which might be explained in part by the SME nature of nearly half the companies applying for the designations. Nonetheless, these data highlight the impor

An overview of the current status and trends in the Breakthrough Designation, PRIME and SAKIGAKE expedited review programs

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