Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.

The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.

Regulatory utility of pharmacometrics in the development and evaluation of antimicrobial agents and its recent progress in China.

Pharmacometrics is an emerging science that interprets drug, disease, and trial information in a mathematical fashion to inform and facilitate efficient drug development and/or regulatory decisions. Pharmacometrics study is increasingly adopted in the regulatory review of new antimicrobial agents. We summarized the 31 antimicrobial agents approved by the US Food and Drug Administration (FDA) and the 26 antimicrobial agents approved by European Medicines Agency (EMA) from January 2001 to May 2019. We also reviewed recent examples of utilizing pharmacometrics to support antimicrobial agent's registration in China, including modeling and simulation methods, effects of internal/external factors on pharmacokinetic (PK) parameters, safety and efficacy evaluation in terms of exposure-response analysis, refinement of the wording of product labeling and package leaflet, and possible postmarketing clinical trial. Ongoing communication among regulator, academia, and industry regarding pharmacometrics is encouraged to streamline and facilitate the development of new antimicrobial agents. The industry can maximize its benefit in drug development through continued pharmacometrics education/training.

An urgent call to raise the bar in oncology.

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

Assessment of the impact of Japanese-specific long-term safety data on new drug approval.

Under the International Council for Harmonization (ICH)-E1 guideline for drugs intended for chronic or repeated intermittent use in non-life-threatening diseases, data from 100 patients exposed for a minimum of 1 year are required to be included in the safety data base of a new drug application. In response to the recent globalization of drug development, the Ministry of Health, Labour, and Welfare of Japan requires that the data according to the ICH-E1 guideline should be collected from 100 Japanese patients by the administrative notice of Basic Principles on Global Clinical Trials (reference cases) by considering ethnic differences in safety between Japanese and foreigners. In this study, we assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports of new drugs from 2016 to 2020 that include safety data for 100 Japanese patients exposed to these drugs for a minimum of 1 year to see if the study data led to the detection of Japanese-specific safety issues. The result showed that the safety data from these patients provided only marginal value to identify Japanese-specific safety issues, and no drugs were subjected to regulatory measures. Based on these studies and the fact that Japanese-specific safety differences detected for a few drugs did not lead to adaptations of drug regulatory measures, we would like to propose not to make it a rule to collect safety data from 100 Japanese patients exposed at least 1 year, while keeping the ICH-E1 guideline.

Reliance: a smarter way of regulating medical products - The IPRP survey.

Introduction: A survey was conducted among national regulatory authorities' members of the International Pharmaceutical Regulators Programme (IPRP) to collect and share experiences of reliance approaches. Reliance allows formally, or informally, one regulatory authority to use assessments made by other regulatory authorities while remaining responsible for the final decision. Reliance is an essential concept to increase the efficiency of the global regulatory oversight of medical products by national regulatory authorities.Areas covered: This article describes the findings and recommendations from the IPRP survey. It shows that reliance in the area of medical product oversight is broadly accepted. The first part presents the acceptance and reasons for accepting reliance including the need for trust, then gives examples of the most common areas for reliance, and explains the difference between unilateral or reciprocal reliance. Finally, the article analyzes the lessons learned including challenges and opportunities for reliance on regulatory authorities to facilitate patient access in their jurisdictions.Expert opinion: Regulatory reliance facilitates regulatory approvals and allows to use resources in a more efficient way and ultimately serves patients by facilitating earlier access to quality-assured, safe, and effective medicines.

Physicians' attitudes towards accelerated access to medicines.

In recent years, a variety of 'accelerated access' schemes have been introduced by pharmaceutical regulators and funders globally. These schemes aim to overcome perceived regulatory and reimbursement barriers to accessing medicines - particularly for patients with limited time or therapeutic options. However, patient access to approved medicines is mediated by a number of third parties including regulators and payers, and physicians who act both as gatekeepers and guides to prescribed medications. It is therefore essential to know how physicians think about accelerated access as they are responsible for advising patients on and prescribing medicines made available via these pathways. We conducted semi-structured interviews with 18 Australian physicians focusing on their attitudes towards accelerated access. We identified three 'archetypes' of physicians: 'confident accelerators', 'cautious accelerators', and 'decelerators'. Although all acknowledged the potential risks and benefits of accelerated access, they disagreed on their magnitude and extent and how they should be balanced in both policy formation and clinical practice. Overall, our results illustrate the diversity of clinical opinions in this area and the importance of monitoring both the prescribing and clinical outcomes that result from accelerated access programmes to ensure that these are both clinically and morally acceptable.

Examining association between cohesion and diversity in collaboration networks of pharmaceutical clinical trials with drug approvals.

OBJECTIVE: Clinical trials ensure that pharmaceutical treatments are safe, efficacious, and effective for public consumption, but are extremely complex, taking up to 10 years and $2.6 billion to complete. One main source of complexity arises from the collaboration between actors, and network science methodologies can be leveraged to explore that complexity. We aim to characterize collaborations between actors in the clinical trials context and investigate trends of successful actors. MATERIALS AND METHODS: We constructed a temporal network of clinical trial collaborations between large and small-size pharmaceutical companies, academic institutions, nonprofit organizations, hospital systems, and government agencies from public and proprietary data and introduced metrics to quantify actors' collaboration network structure, organizational behavior, and partnership characteristics. A multivariable regression analysis was conducted to determine the metrics' relationship with success. RESULTS: We found a positive correlation between the number of successful approved trials and interdisciplinary collaborations measured by a collaboration diversity metric (P < .01). Our results also showed a negative effect of the local clustering coefficient (P < .01) on the success of clinical trials. Large pharmaceutical companies have the lowest local clustering coefficient and more diversity in partnerships across biomedical specializations. CONCLUSIONS: Large pharmaceutical companies are more likely to collaborate with a wider range of actors from other specialties, especially smaller industry actors who are newcomers in clinical research, resulting in exclusive access to smaller actors. Future investigations are needed to show how concentrations of influence and resources might result in diminished gains in treatment development.

Vaccine Safety.

The details of vaccine development, licensing, and monitoring have never been more important and relevant to the health care conversation in the United States. The potential exists for a preventive medicine such as a vaccine to cause harm, and physicians and patients need to understand the real balance of risks and benefits of immunization. Vaccines given in the United States undergo rigorous testing before licensure as well as extensive postlicensure safety monitoring.

Publicly accessible evidence of health-related quality of life benefits associated with cancer drugs approved by the European Medicines Agency between 2009 and 2015.

OBJECTIVE: Health-related quality of life (HRQoL) is one of the most important patient-relevant study end-points for the direct measurement of the benefit of cancer drugs. Therefore, our aim is to detect cancer indications with no published information on HRQoL at the time of European Medicines Agency (EMA) approval and monitor any reported HRQoL evidence updates after at least three years of follow-up. METHODS: We included all cancer indications that were approved by the EMA between January 2009 and October 2015. Our main sources of information were the EMA website, clinicaltrials.gov and a systematic literature search in PubMed. Information on HRQoL outcomes was extracted alongside evidence on median overall survival. RESULTS: In total, we identified 110 indications, of which more than half (n = 58, 53%) were lacking available information on HRQoL assessments at the time of EMA approval. After a monitoring period of at least three years, 24 updates were identified, resulting in 34 (31%) therapies where information on HRQoL was still not available. For the 76 therapies with reported information on HRQoL, cancer-specific instruments were mostly used (n = 49/76). Regarding cumulative evidence on median overall survival and HRQoL, 33 (n = 33/110, 30%) as well as 15 (n = 15/110, 14%) cancer drugs were lacking information on both study end-points at the time of approval and after monitoring, respectively. CONCLUSION: Our results demonstrate that there is an urgent need of routine re-evaluation of reimbursed cancer drugs with initially missing information on major outcomes. Standardisation of the typology and quality of HRQoL assessments need to be improved to allow better comparability of results.

Effective Market Exclusivity of New Molecular Entities for Rare and Non-rare Diseases.

BACKGROUND: Growth in development, approvals, and revenue of drugs treating rare diseases (orphan drugs) has been increasing over the last four decades, which has drawn substantial attention to these products. Much of this growth has been attributed to the incentives created by the Orphan Drug Act, which includes a seven-year exclusivity period for the approval of rare disease indications. OBJECTIVE: This study aims to compare the effective market exclusivity period of small molecule new molecular entities (NMEs) for rare (orphan) and non-rare (non-orphan) diseases approved by the U.S. Food and Drug Administration (FDA) from 2001-2012. While the overall length of a drug's effective market exclusivity period has been explored previously, there is little empirical research evaluating the differences in its duration between drugs for rare and non-rare diseases. METHODS: Data sources utilized in this analysis included the NME Drug and New Biologic Approvals Reports, Orange Book, Orphan Drug Product Designation Database, Drugs@FDA and IQVIA's National Sales Perspective. We computed the effective market exclusivity period for each NME as the time from NME approval until approval of the first generic competitor. We then regressed the effective market exclusivity period for each NME, on orphan disease status, and other NME market factors using a Cox proportional hazards model. Subsequently, we calculated regression-adjusted median effective market exclusivity periods for both orphan and non-orphan NMEs to estimate effective exclusivity extensions from orphan status. RESULTS: We find that only individual NMEs approved for the treatment of both orphan and non-orphan indications lower the hazard of generic entry (hazard ratio 0.464, p = 0.030) in comparison with non-orphan NMEs with a single indication. The associated additional median survival time for these NMEs is 1.9 years. CONCLUSIONS: NMEs' orphan status per se is not associated with a reduction in the hazard of generic entry and longer effective market exclusivity periods in comparison with non-orphan NMEs. Only NMEs that were approved for the treatment of both orphan and non-orphan diseases experience lower hazard of generic entry and longer exclusivity periods compared with non-orphan drugs with a single indication.