Drug Review Process Research Articles

A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document

Regulatory agencies consistently deal with extensive document reviews, ranging from product submissions to both internal and external communications. Large Language Models (LLMs) like ChatGPT can be invaluable tools for these tasks, however present several challenges, particularly the proprietary information, combining customized function with specific review needs, and transparency and explainability of the model's output. Hence, a localized and customized solution is imperative.To tackle these challenges, we formulated a framework named askFDALabel on FDA drug labeling documents that is a crucial resource in the FDA drug review process. AskFDALabel operates within a secure IT environment and comprises two key modules: a semantic search and a Q&A/text-generation module. The Module S built on word embeddings to enable comprehensive semantic queries within labeling documents. The Module T utilizes a tuned LLM to generate responses based on references from Module S. As the result, our framework enabled small LLMs to perform comparably to ChatGPT with as a computationally inexpensive solution for regulatory application.To conclude, through AskFDALabel, we have showcased a pathway that harnesses LLMs to support agency operations within a secure environment, offering tailored functions for the needs of regulatory research.

Drug review process advancement and required manufacturer and contract research oraganization responses.

The United States Senate passed the "FDA Modernization Act 2.0." on September 29, 2022. Although the effectiveness of this Bill, which aims to eliminate the mandatory use of laboratory animals in new drug development, is limited, it represents a significant trend that will change the shape of drug applications in the United States and other countries. However, pharmaceutical companies have not taken major steps towards the complete elimination of animal testing from the standpoint of product safety, where they prioritize patient safety. Nonetheless, society is becoming increasingly opposed to animal testing, and efforts will be made to use fewer animals and conduct fewer animal tests as a natural and reasonable response. These changes eventually alter the shape of new drug applications. Based on the assumption that fewer animal tests will be conducted or fewer animals will be used in testing, this study explored bioinformatics and new technologies as alternatives to compensate for reduced information and provide a picture of how future new drug applications may look. The authors also discuss the directions that pharmaceutical companies and nonclinical contract research organizations should adopt to promote the replacement, reduction, and refinement of animals used in research, teaching, testing, and exhibitions.

Benchmarking Drug Regulatory Systems for Capacity Building: An Integrative Review of Tools, Practice, and Recommendations.

Benchmarking has been increasingly used on drug regulatory systems to achieve sustainable pharmaceutical system strengthening. This study aimed to identify the scope, tools and benefits of benchmarking regulatory capacities and the most recent development in such phenomenon. Method: This study employed an integrative and critical review of the literature and documents on benchmarking drug regulatory capacities identified from 6 databases and 5 websites of related organizations and government agencies in compliance with the Preferred Reporting Items for Systematic Review (PRISMA) guidelines. Forty-three studies and 6 documents about regulatory benchmarking published between 2005 and 2022 were included in this review. Five benchmarking assessment tools or programmes recommended or adopted by international organizations or government agencies had been identified, which collectively covered 12 major regulatory functions (4 at system level and 8 at operational level) involving 9 indicator categories and 382 sub-indicators. Benchmarking drug regulatory systems was reportedly employed at national, regional and international levels for either internal assessment (mostly on regulatory system establishment, drug review process and post marketing surveillance) or external evaluation (mostly on regulatory standards, drug review process and pharmacovigilance systems) to assess current status, monitor performance, determine major challenges and inform actions for capacity building. Priority of actions in areas such as regulatory process, resources allocation, cooperation and communication, and stakeholder engagement have been suggested for strengthening drug regulatory systems. Nevertheless, the evidence about benchmarking in optimizing regulatory capacities remained underreported. This integrative review depicted a framework for decision-makers about why and how benchmarking drug regulatory systems should be undertaken. For effective benchmarking, well-informed decisions about the goals, the scope, the choice of reference points and benchmarking tools are essential to guide the implementation strategies. Further studies about the positive effects of regulatory benchmarking are warranted to engage continuous commitment to the practice.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Expedited Drug Review Processes for Approval in the United States and European Union with an Illustration

Expedited approval processes push new drugs to the market faster than ever. Regulatory Authorities of the United States (US) and European Union (EU) are using different approval pathways to cut down the time it takes to conduct a clinical review. Conventional drug discovery is a costly and time-consuming process. A study found that pharmaceutical industries spend an average of $3 billion in R&D activities, and more than 10 years are required to develop and market one new drug. Patients can hardly wait 10 years for a lifesaving drug. For this reason, in the field of new drug discovery, Regulatory authorities and pharmaceutical companies are pursuing a strategy that expedites the approval of certain drugs that treat severe conditions and address unmet medical needs. Expedited approval processes could attract attention as a solution to dramatically reduce the time and cost required for the new drug discovery. In this article, it is presented with different expedited approval processes in the US and EU with an illustration of these speedy approval processes by taking Crizotinib drug for a better understanding.

The Importance of Electronic Health Record Access For Accurately Completing Drug Regimen Reviews.

OBJECTIVE: To challenge the standard of practice by evaluating the identification of medication discrepancies found depending on type of access to an electronic health record (EHR). In other words, is there a difference in the number of discrepancies between a pharmacist with only access to the postacute long-term care (PALTC) EHR (ie, single-access pharmacist [SAP]) compared with a pharmacist with access to both the PALTC and hospital EHRs (ie, dual-access pharmacist DAP) In October 2018, the Improving Medicare PostAcute Care Transformation (IMPACT) Act mandated admission drug review (DRR) upon admission to a postacute, long-term care (PALTC) facility.<br/> SUMMARY:This was a prospective study investigating the occurrence of medication therapy problems (MTP) identified by two different DRR processes; SAP versus DAP. Data were collected in a community hospital and a stand-alone PALTC facility. It was found that the DAP identified more safety-related medication needs and medication omissions than an SAP. There was a significant association between the type of access and whether a MTP (ie, yes or no) was discovered, the type of medication-related need, and MTP category.<br/> CONCLUSION: These results strongly suggest that current standard of practice should change to require access to both hospital and PALTC EHR systems for a pharmacist completing the medication reconciliation. Until the gap in EHR interoperability is closed, the potential breakdown in communication associated with SAP places patients transitioning from hospital to PALTC facilities at increased risk for medication problems and accompanying adverse medication events.

The Importance of Electronic Health Record Access For Accurately Completing Drug Regimen Reviews

OBJECTIVE: To challenge the standard of practice by evaluating the identification of medication discrepancies found depending on type of access to an electronic health record (EHR). In other words, is there a difference in the number of discrepancies between a pharmacist with only access to the postacute long-term care (PALTC) EHR (ie, single-access pharmacist [SAP]) compared with a pharmacist with access to both the PALTC and hospital EHRs (ie, dual-access pharmacist DAP) In October 2018, the Improving Medicare PostAcute Care Transformation (IMPACT) Act mandated admission drug review (DRR) upon admission to a postacute, long-term care (PALTC) facility.&lt;br/&gt; SUMMARY:This was a prospective study investigating the occurrence of medication therapy problems (MTP) identified by two different DRR processes; SAP versus DAP. Data were collected in a community hospital and a stand-alone PALTC facility. It was found that the DAP identified more safety-related medication needs and medication omissions than an SAP. There was a significant association between the type of access and whether a MTP (ie, yes or no) was discovered, the type of medication-related need, and MTP category.&lt;br/&gt; CONCLUSION: These results strongly suggest that current standard of practice should change to require access to both hospital and PALTC EHR systems for a pharmacist completing the medication reconciliation. Until the gap in EHR interoperability is closed, the potential breakdown in communication associated with SAP places patients transitioning from hospital to PALTC facilities at increased risk for medication problems and accompanying adverse medication events.

Time to Revisit a Voluntary FDA Comparative Effectiveness Pathway.

Given the renewed policy focus on drug pricing and pharmaceutical innovation, this article examines the historical backdrop of efforts to integrate comparative effectiveness research into the FDA drug review process. Noting previous policy efforts over a decade ago, we characterize industry challenges and suggesta path forward.

New Drugs Regulatory Program Modernization: Vision, Strategic Objectives, and Impact.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration’s Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

FDA’s Benefit–Risk Framework for Human Drugs and Biologics: Role in Benefit–Risk Assessment and Analysis of Use for Drug Approvals

Structured, descriptive approaches are utilized by drug regulatory agencies to support and communicate approval decisions about human drugs and biologics. The US Food and Drug Administration (FDA) uses the Benefit-Risk Framework (BRF), which has been integrated into its drug review process. This paper reviews how FDA review teams have used the BRF to communicate approval decisions. This paper (1) uses content analysis to systematically review the decision factors communicated by FDA review teams in all BRFs associated with novel drugs approved by FDA in 2017-2018 and (2) presents a case study about how the BRF was used for three drugs approved for HIV-1 in 2018-2019. The content analysis found most BRFs for novel drug approvals communicate what we call an "urgent" context and complicating decision factors around benefit and/or risk; the HIV-1 case study highlights the flexibility of the structured BRF tool. FDA's BRF provides a flexible mechanism for communicating important decision factors, allowing it to support the diversity of drug approval decisions made by FDA.

DIVA: Exploration and Validation of Hypothesized Drug‐Drug Interactions

AbstractAdverse reactions caused by drug‐drug interactions are a major public health concern. Currently, adverse reaction signals are detected through a tedious manual process in which drug safety analysts review a large number of reports collected through post‐marketing drug surveillance. While computational techniques in support of this signal analysis are necessary, alone they are not sufficient. In particular, when machine learning techniques are applied to extract candidate signals from reports, the resulting set is (1) too large in size, i.e., exponential to the number of unique drugs and reactions in reports, (2) disconnected from the underlying reports that serve as evidence and context, and (3) ultimately requires human intervention to be validated in the domain context as a true signal warranting action. In this work, we address these challenges though a visual analytics system, DIVA, designed to align with the drug safety analysis workflow by supporting the detection, screening, and verification of candidate drug interaction signals. DTVA's abstractions and encodings are informed by formative interviews with drug safety analysts. DIVA's coordinated visualizations realize a proposed novel augmented interaction data model (AIM) which links signals generated by machine learning techniques with domain‐specific metadata critical for signal analysis. DIVA's alignment with the drug review process allows an analyst to interactively screen for important signals, triage signals for in‐depth investigation, and validate signals by reviewing the underlying reports that serve as evidence. The evaluation of DIVA encompasses case‐studies and interviews by drug analysts at the US Food and Drug Administration ‐ both of which confirm that DIVA indeed is effective in supporting analysts in the critical task of exploring and verifying dangerous drug‐drug interactions.

The frequency and availability of population-specific patient reported outcome measures and minimal clinically important differences among approved drugs in Canada

BackgroundPatient reported outcome measures (PROMs) and minimal clinically important differences (MCIDs) are included in Canada’s Common Drug Review (CDR) process to approve new drugs. Often, the measures report on the health-related quality of life (HRQoL), but can also describe the symptoms, efficacy and harms important to patients. They can be generic or population/condition specific, validated or not. We examined the frequency, availability and accessibility of validated, specific PROMs and MCIDs reported in the CDR reports.MethodsWe searched the Canadian Agency for Drugs and Technologies in Health (CADTH) on-line database for completed Common Drug Review, Clinical Review Reports (CDR-CRR) between November 2013 and February 2017. Two independent reviewers examined the reports and references for PROMs and MCIDs. Both reviewers separately categorized the PROMs and MICDs according to purpose, validation, availability and funding received. Discrepancies were rectified by consensus with a third investigator.ResultsOne-hundred and five unique PROMs were extracted from 39 CDR-CRR, 57% with a HRQoL component. 91/105 (87%) referenced a validation study and 62/105 (59%) referenced a validation study in the study population of interest. Fifty-seven MCID references were extracted from 39 CDR-CRR. 34/57 (60%) were specific to the study population of interest, and 36% had a HRQoL component. 50% of PROM and 53% of MCID references were publicly available.ConclusionsPROMs and MCIDs referenced in CDR-CRR show similar trends. The majority are validated, but not necessarily in the study population of interest. Continued critical examination is required to evaluate new drugs specific to the population of interest.

A descriptive analysis of clinician input and feedback into the CADTH pan-Canadian Oncology Drug Review process.

42 Background: In Canada, through the pan-Canadian Oncology Drug Review (pCODR) process, CADTH conducts evaluations of clinical, economic, and patient evidence on cancer drugs to provide public reimbursement recommendations. The pCODR Expert Review Committee (pERC) makes these recommendations based on a drug’s overall clinical benefit, alignment with patient values, cost-effectiveness, and feasibility of adoption into the health system. Methods: In February 2016, pCODR launched a pilot process that allowed eligible clinicians (individually or as groups) not directly involved in the reviews to participate in the pCODR process, to provide: (1) input at the outset of a review; and, (2) feedback on the Initial Recommendation made by the pERC. Eligible clinicians are those who: (1) are actively practising physicians; (2) are members of a provincial cancer agency or similar body or a national cancer organization; and, (3) submit a declaration of conflict of interest. Results: As of March 31, 2018, 177 oncologists have registered to participate in the pCODR process. Of 43 submissions, 38 (88%) included clinician input. Fifteen submissions received individual input, and 33 received group input, the latter involving three to 13 clinicians or groups. Between April 2016 and March 2018, clinician input by tumour type was as follows: lung (n = 8), leukemia (n = 5), lymphoma (n = 5), gastrointestinal (n = 5), myeloma (n = 4), breast (n = 3), melanoma (n = 2), gynecological (n = 2), endocrine (n = 2), sarcoma (n = 1), and genitourinary (n = 1). Clinician input has answered several key questions, including current treatments, eligible patient populations, relevance to clinical practice, sequencing and priority of treatments, and companion diagnostic testing. Conclusions: Clinician engagement has provided value-added information on local issues from a practice perspective and insights into areas of unmet need. Continuous process improvement is important, however, and the pCODR program completed consultations in April 2018 to enhance clinician participation, proposing to: (1) customize the template that clinicians complete; and, (2) broaden the eligibility of clinicians to oncology pharmacists and oncology nurses.

Pan-Canadian Oncology Drug Review (pCODR): A unique model to support harmonization of cancer drug funding decisions in Canada.

41 Background: Unlike most other countries, Canada has a dedicated HTA process to review cancer drugs. pCODR, a program of CADTH, conducts thorough and objective evaluations of clinical and economic evidence; as well as considering clinician and patient perspectives, and using this information to make recommendations to the participating jurisdictions to guide their drug funding decisions. Previously, Canadian provinces had separate regional drug review processes to inform their local funding decisions. The pCODR process reduces duplication of effort by individual funders and ensures that reviews are done in a timely and consistent manner. Methods: In a retrospective review, we identified all anticancer drugs reviewed by pCODR from July 2011 to March 2018. Results: As of March 31, 2018, pCODR has issued 103 notifications to implement a final recommendation. Of note, 96% of the submissions include patient group input and 88% of the submissions include clinician input. The median time to complete a review is 146 business days. The pCODR Expert Review Committee has issued 21 negative recommendations, while the remainder were either positive recommendations (n = 10), or conditional recommendations (n = 72). The “condition” that must be addressed most frequently in the conditional recommendations is the cost-effectiveness of the drug. Over 75% of the 82 positive and conditional recommendations have received uptake from one or more participating jurisdictions. The concordance rates are as follows: Conclusions: With the implementation of the pCODR process, there is greater harmonization in cancer drug funding decisions and supports equitable access across Canada.[Table: see text]

Understanding the reasons for provincial discordance in cancer drug funding-a survey of policymakers.

Cancer drug-funding decisions between provinces shows discordance. The pan-Canadian Oncology Drug Review (pcodr) was implemented in 2011 partly to address uneven drug coverage and lack of transparency in the various provincial cancer drug review processes in Canada. We evaluated the underlying reasons for ongoing provincial discordance since the implementation of pcodr. Participation in an online survey was solicited from participating provincial ministries of health (mohs) and cancer agencies (cas). The 4-question survey (with both multiple-choice and free-text responses) was administered between 4 March 2015 and 1 April 2015, inclusive. Anonymity was ensured. Descriptive statistics were used to evaluate responses. Data were available from 9 provinces (all Canadian provinces except Quebec), with a response rate of 100%. The 12 responses received each came from a senior policymaker with more than 5 years' experience in cancer drug funding decision-making (5 from mohs, 7 from cas). Responses for 3 provinces came from both a moh representative and a ca representative. The most common reason for funding a drug not recommended by pcodr was political pressure (64%). The most common reason not to fund a drug recommended by pcodr was budget constraints (91%). The most common reason for a province to fund a drug before completion of the pcodr review was also political pressure (57%). Political pressure and budgetary constraints continue to affect equity of access to cancer drugs for patients throughout Canada.

Rationing cancer treatment: a qualitative study of perceptions of legitimate limit-setting

BackgroundGovernments are facing tough choices about whether to fund new, promising but highly expensive drugs within the public healthcare system. Decisions that some drugs are not sufficiently beneficial relative to their cost to merit public funding are often contentious. The importance of making decisions that stakeholders can understand and accept as legitimate is increasingly recognized and is commonly understood to be a crucial component for stakeholder support and successful implementation. Yet, little is known about clinicians’ perceptions of legitimate limit-setting. This study aimed to examine oncologists’ perceptions of the legitimacy of governmental decisions to deny patients access to new cancer drugs because effectiveness and cost-effectiveness of the drugs has not been demonstrated.MethodsSemi-structured in-depth interviews with 12 Norwegian oncologists were carried out. Data were interpreted with the use of theory driven thematic analysis. The analytical framework of Accountability for reasonableness aided data gathering and interpretation.ResultsThe participants endorsed the ideal of explicit criteria-based priority setting. Yet, when confronted with actual rationing decisions, they were far more equivocal. They advocated for increased access to drugs and were not always prepared to accept rationing of drugs they felt would benefit their patient. Distrust in the Norwegian centralised drug review process was found and different rationales were identified: i) Lack of engagement with the process, ii) Disagreement with the use of rationing criteria, iii) Lack of transparency and lack of dispute resolution procedures. Concerns about the wider implications of rationing decisions were reported. Most importantly, these related to negative impact on patient-doctor relationship of micro-level rationing and to inequities in drug availability resulting from privatisation of high-cost cancer treatment.ConclusionsDrawing on the analytical framework, we conclude that perceptions of legitimacy regarding rationing of high-cost drugs include procedural fairness. However, notions of substantive justice also seem to be important for accepting reasons given for decisions. Regulatory legitimacy may further warrant a more sophisticated theoretical account of second-order beliefs about the justifiability of rationing new technologies. These findings indicate a need for a broader concept of legitimacy than is commonly used in the literature on healthcare prioritisation.

PHP146 - The Frequency and Availability of Population-Specific Patient Reported Outcome Measures and Minimal Clinically Important Differences Among Approved Drugs in Canada

Patient reported outcome measures (PROMs) and minimal clinically important differences (MCIDs) are included in Canada’s Common Drug Review (CDR) process to approve new drugs. Often, the measures report on the health-related quality of life (HRQoL), but can also describe the symptoms, efficacy and harms important to patients. They can be generic or population/condition specific, validated or not. We examined the frequency, availability and accessibility of validated, specific PROMs and MCIDs reported in the CDR reports. We searched the Canadian Agency for Drugs and Technologies in Health (CADTH) on-line database for completed Common Drug Review, Clinical Review Reports (CDR-CRR) between November 2013 and February 2017. Two independent reviewers examined the reports and references for PROMs and MCIDs. Both reviewers separately categorized the PROMs and MICDs according to purpose, validation, availability and funding received. Discrepancies were rectified by consensus with a third investigator. One-hundred and five unique PROMs were extracted from 39 CDR-CRR, 57% with a HRQoL component. 91/105 (87%) referenced a validation study and 62/105 (59%) referenced a validation study in the study population of interest. Fifty-seven MCID references were extracted from 39 CDR-CRR. 34/57 (60%) were specific to the study population of interest, and 36% had a HRQoL component. 50% of PROM and 53% of MCID references were publicly available. PROMs and MCIDs referenced in CDR-CRR show similar trends. The majority are validated, but not necessarily in the study population of interest. Continued critical examination is required to evaluate new drugs specific to the population of interest.

What does meaningful look like? A qualitative study of patient engagement at the Pan-Canadian Oncology Drug Review: perspectives of reviewers and payers.

Objectives While there is wide support for patient engagement in health technology assessment, determining what constitutes meaningful (as opposed to tokenistic) engagement is complex. This paper explores reviewer and payer perceptions of what constitutes meaningful patient engagement in the Pan-Canadian Oncology Drug Review process. Methods Qualitative interview study comprising 24 semi-structured telephone interviews. A qualitative descriptive approach, employing the technique of constant comparison, was used to produce a thematic analysis. Results Submissions from patient advocacy groups were seen as meaningful when they provided information unavailable from other sources. This included information not collected in clinical trials, information relevant to clinical trade-offs and information about aspects of lived experience such as geographic differences and patient and carer priorities. In contrast, patient submissions that relied on emotional appeals or lacked transparency about their own methods were seen as detracting from the meaningfulness of patient engagement by conflating health technology assessment with other functions of patient advocacy groups such as fundraising or public awareness campaigns, and by failing to provide credible information relevant to deliberations. Conclusions This study suggests that misalignment of stakeholder expectations remains an issue even for a well-regarded health technology assessment process that has promoted patient engagement since its inception. Support for the technical capacity of patient groups to participate in health technology assessment is necessary but not sufficient to address this issue fully. There is a fundamental tension between the evidence-based nature of health technology assessment and the experientially oriented culture of patient advocacy. Divergent notions of what constitutes evidence and how it should be used must also be addressed.

Impact of the pan-Canadian Oncology Drug Review on provincial concordance with respect to cancer drug funding decisions and time to funding.

The pan-Canadian Oncology Drug Review (pcodr) was implemented in 2011 to address uneven drug coverage and lack of transparency with respect to the various provincial cancer drug review processes in Canada. We evaluated the impact of the pcodr on provincial decision concordance and time from Notice of Compliance (noc) to drug funding. In a retrospective review, Health Canada's Drug Product Database was used to identify new indications for cancer drugs between January 2003 and May 2014, and provincial formulary listings for drug-funding dates and decisions between 1 January 2003 and 31 December 2014 were retrieved. Multiple linear models and quantile regressions were used to evaluate changes in time to decision-making before and after the implementation of the pcodr. Agreement of decisions between provinces was evaluated using kappa statistics. Data were available from 9 provinces (all Canadian provinces except Quebec), identifying 88 indications that represented 51 unique cancer drugs. Two provinces lacked available data for all 88 indications at the time of data collection. Interprovincial concordance in drug funding decisions significantly increased after the pcodr's implementation (Brennan-Prediger coefficient: 0.54 pre-pcodr vs. 0.78 post-pcodr; p = 0.002). Nationwide, the median number of days from Health Canada's noc date to the date of funding significantly declined (to 393 days from 522 days, p < 0.001). Exploratory analyses excluding provinces with incomplete data did not change the results. After the implementation of the pcodr, greater concordance in cancer drug funding decisions between provinces and decreased time to funding decisions were observed.

Clarifying the Discussion Points in New Drug Application Reviews for Approval in Japan by a Government Advisory Council.

In Japan, the Pharmaceutical Affairs and Food Sanitation Council (PAFSC) of the Ministry of Health, Labour and Welfare conducts discussions during the final stages of drug application reviews based on reports from the Pharmaceuticals and Medical Devices Agency (PMDA). Any disagreements or points of contention raised during these discussions can result in delays to drug approval. It is therefore important to characterize the points of discussion in the PAFSC meetings to optimize the process and enable more efficient drug approval reviews in Japan. We investigated the recorded minutes of PAFSC meetings concerning 229 drug applications (comprising 164 new drug applications and 65 supplemental applications) between fiscal years 2012 and 2014. The discussion points were characterized according to their main topics, and the frequency of each topic was examined. Clinical trials were the most frequent topic of discussion. Issues concerning package inserts were also prominent because many required reconsiderations and follow-up after council meetings. In particular, additional precautions and further clarification regarding drug indications and dosage were major points for reconsideration and follow-up. The review process may be improved if the points identified in this study are taken into consideration during the drug review process by the PMDA.