The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications.

The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis.

Too Important for the Bureaucrats: Rethinking Risk and Regulatory Presumptions in Times of Crisis.

The posture of American regulation of medicine is negative-we assume that a new drug is unsafe and ineffective until it is proven safe and effective.1 This regulatory posture is a heuristic normative principle, a specific instance of the so-called precautionary principle in public health law.2 It is defensible, if debatable, in many ordinary circumstances.3 But like many normative heuristics, this negative posture may compel suboptimal decision-making in emergencies, where context-specific decisions must be made and a range of unique values may apply.

How Science Is Driving Regulatory Guidances.

This chapter provides regulatory perspectives on how to translate in vitro drug metabolism findings into in vivo drug-drug interaction (DDI) predictions and how this affects the decision of conducting in vivo DDI evaluation. The chapter delineates rationale and analyses that have supported the recommendations in the U.S. Food and Drug Administration (FDA) DDI guidances in terms of in vitro-in vivo extrapolation of cytochrome P450 (CYP) inhibition-mediated DDI potential for investigational new drugs and their metabolites as substrates or inhibitors. The chapter also describes the framework and considerations to assess UDP-glucuronosyltransferase (UGT) inhibition-mediated DDI potential for drugs as substrates or inhibitors. The limitations of decision criteria and further improvements needed are also discussed. Case examples are provided throughout the chapter to illustrate how decision criteria have been utilized to evaluate in vivo DDI potential from in vitro data.

Chitosan-based microneedles as a potential platform for drug delivery through the skin: Trends and regulatory aspects.

Microneedles (MNs) fabrication using chitosan has gained significant interest due to its ability of film-forming, biodegradability, and biocompatibility, making it suitable for topical and transdermal drug delivery. The presence of amine and hydroxyl functional groups on chitosan permits the modification with tunable properties and functionalities. In this regard, chitosan is the preferred material for fabrication of MNs because it does not produce an immune response in the body and can be tailored as per required strength and functionalities. Therefore, many researchers have attempted to use chitosan as a drug delivery vehicle for hydrophilic drugs, peptides, and hormones. In 2020, the FDA has issued "Regulatory Considerations for Microneedling Products". This official guidance is a sign for future opportunities in the development of MNs. The present review focuses on properties, and modifications of chitosan used in the fabrication of MNs. The therapeutic and diagnostic applications of different types of chitosan-based MNs have been discussed. Further, the regulatory aspects of MN-based devices, and patents related to chitosan-based MNs are discussed.

Implications of Tennessee's Opioid Legislation for Neonatal Abstinence Syndrome.

Opioid use during pregnancy is on the rise in the United States. Neonatal abstinence syndrome (NAS), also known as newborn drug withdrawal, is a public health epidemic. Between 2004 and 2014, Tennessee experienced a fivefold increase in NAS hospitalizations, from 1.5 to 8.0 per 1,000 live births. Soaring increases in the number of newborns with NAS nationwide have caught the attention of many federal and state lawmakers, especially given the unknown burdens associated with medical and social services needed by those affected over time. Tennessee opioid-related regulations and laws enacted between 2000 and 2018 were systematically reviewed and analyzed to identify each law's purpose; effects on families and individuals; pros and cons in terms of social, practical, and legal factors; and implications for nursing practice. Our findings were that Tennessee's laws are intended to decrease the number of opioids prescribed, ensure access to continued prenatal care and substance abuse management for mothers with substance use disorders, and reduce the ease of obtaining opioids. We also found that Tennessee lawmakers have enacted laws and regulations aimed at decreasing the abuse of opioids, but not reducing the incidence of NAS. As new laws are considered, it is critical that health care providers and lawmakers work together to ensure that the developed and enacted laws strike a balance between safely managing the care of both pregnant women and their newborns without producing negative outcomes.

Reduced user fees for antibiotics under age 5 in Hungary: Effect on antibiotic use and imbalances in the implementation.

OBJECTIVES: In August 2016, new prescription guidelines were introduced in Hungary to reduce the co-payments for antibiotics among children aged 0-4. This study aims at analysing the implementation of this policy and its effect on the use of antibiotics. METHODS: The analysis is based on administrative prescription records between January 2010-February 2018, covering the entire population of Hungary aged 0-7. Spatial autocorrelation indices are calculated and settlement level regression models are estimated to analyse the spatial variation in the application of the new guidelines. The effect of reduced co-payments on antibiotic use is estimated with a difference-in-differences type model: the treatment and control groups are children aged 0-4 and 5-7, respectively; the treatment and control periods are August 2016-February 2018 and January 2010-July 2016, respectively. RESULTS: The new prescription guidelines are more widely applied in settlements with higher per capita income and lower unemployment rate. Adherence to the new guidelines is spatially clustered. A 10-15% decrease in the out-of-pocket costs of antibiotics is estimated to increase the consumption of antibiotics by about 5% (95% CI: 2.63%-7.55%). CONCLUSIONS: In the absence of clear enforcement mechanisms, the adoption of the new prescription guidelines is selective, contradicting the aims of the policy of making antibiotics affordable for the poor children. The results point to the possible role of physicians' information networks in the application of prescription guidelines. The use of antibiotics among children aged 0-4 is responsive to the price subsidy of antibiotics.

Phage Therapy Regulation: From Night to Dawn.

After decades of disregard in the Western world, phage therapy is witnessing a return of interest. However, the pharmaceutical legislation that has since been implemented is basically designed for regulating industrially-made pharmaceuticals, devoid of any patient customization and intended for large-scale distribution. Accordingly, the resulting regulatory framework is hardly reconcilable with the concept of sustainable phage therapy, involving tailor-made medicinal products in the global perspective of both evolutionary and personalized medicine. The repeated appeal for a dedicated regulatory framework has not been heard by the European legislature, which, in this matter, features a strong resistance to change despite the precedent of the unhindered implementation of advanced therapy medicinal product (ATMPs) regulation. It is acknowledged that in many aspects, phage therapy medicinal products are quite unconventional pharmaceuticals and likely this lack of conformity to the canonical model hampered the development of a suitable regulatory pathway. However, the regulatory approaches of countries where phage therapy traditions and practice have never been abandoned are now being revisited by some Western countries, opening new avenues for phage therapy regulation. As a next step, supranational and international organizations are urged to take over the initiatives originally launched by national regulatory authorities.

Policies to improve access to pharmaceutical products in shortage: the experience of Iran food and drug administration.

BACKGROUND: In the past decades, economic sanctions imposed on Iran for its nuclear program. The embargo made difficulty in foreign trade and led to lack of timely access to medicines. As the internationally-led sanctions caused to the shortage of medicine there, healthcare systems need to applied the new policies for maintaining health service quality especially in pharmaceutical sector. OBJECTIVES: This paper is about policies applied in Iran health system during the crisis reached its peak in 2012 as a good experience for guarantying access to pharmaceutical products. METHODS: Through interviewing experts and managers in pharmaceutical regulatory system, the implemented policies in targeted historical period were extracted, then quantitative data were analyzed to show the impact of the policies on the access and affordability of medicines before and after their implementation in Iran food and drug administration (IFDA). This paper tries to show strategies employed by to tackle the crisis caused by sanctions and to offer practical policies to make medicines more accessible at the time of crisis. RESULTS: In order to reduce the harmful effects of this crisis, IFDA proposed some changes at different levels ranging from organizational procedures to parliament legislations. The main achievements of IFDA were making drugs easily available are as follows, significantly reducing prices, decreasing the share of market regarding the imported medicines, facilitating the manufacture of domestic medicines, encouraging foreign investment in manufacturing drugs domestically, controlling the shortage of drugs, and finally giving financial support to all patients in general and to those patients who had problem paying for drugs in particular. CONCLUSION: These experiences which made the Iran pharmaceutical sector survive during the international sanctions, can be considered as a good example of resilience strategies in similar situations. Graphical abstract IFDA policies to improve access to pharmaceutical products in sanction.

A comparative analysis of the pharmacovigilance systems of Brazil, Spain, the European Union and the United States based on the information provided by their regulatory agency websites.

BACKGROUND: Pharmacovigilance (PV) plays an essential role in monitoring and raising awareness of adverse drug reactions (ADRs). Increasingly, ADRs are reported and PV information and activities are circulated via the Internet. PV actions are carried out by the Regulatory Agencies (RAs) responsible for medicinal products in each country. OBJECTIVE: The objective of this study is to ascertain and assess the operation and areas of competence of the PV system in Brazil and to compare them with those of Spain, the European Union (EU) and the United States (USA), through the information available on the websites of the RAs in each country. METHODS: A search of the information provided on the websites of these countries' RAs, establishing indicators to assess how far the information is available and accessible. RESULTS: The RAs we studied are similarly organised and they complied with most of the 38 indicators we defined to obtain and assess the information they provide on PV procedures and their systems for electronic reporting of ADRs. Brazil's RA, ANVISA, complied with 100% of the areas of competence analysed and with 92.11% of the indicators established for the study. CONCLUSIONS: Brazil's PV system, through ANVISA, achieves a good level of performance, both in itself and compared to the other RAs. There is room for improvement in three of the indicators analysed.

Does the Patent Linkage System Prolong Effective Market Exclusivity? Recent Evidence From the Korea-U.S. Free Trade Agreement in Korea.

This study evaluated the effect of the patent linkage system, fully introduced by the Korea-U.S. Free Trade Agreement in 2015, on patent challenges and the effective market exclusivity of new medicines in Korea. We used pharmaceutical approval data and pharmaceutical litigation data to detect new medicines and their counterparts, to collect patent challenges against new medicines, and to calculate effective market exclusivity for new medicines. Then, a nonparametric event history model was applied to statistically explain the duration of the market exclusivity of new medicines. Between 2007 and 2011, a total of 94 new medicines, consisting of 82 new chemical entities and 12 new biologics, were approved. The patent linkage system encouraged patent litigations to occur sooner, with a race to challenge the patents by various generic applicants. However, it was difficult to conclude that patent challenges had a significant impact on the prolongation of effective market exclusivity. The patent linkage system had a neutral effect on the effective market exclusivity of new medicines and encouraged patent challenges without abbreviating effective market exclusivity. In addition, this study highlights an important issue regarding biologics that has not been the subject of market competition, even for patent challenges.

Regulatory Capture in Pharmaceutical Policy Making: The Case of National Medicine Agencies Related to the EU Falsified Medicines Directive.

BACKGROUND: Regulatory capture describes the phenomenon in which regulators (e.g. medical agencies) protect the interest of the companies they regulate rather than the interest of the public. Not much is known about the mechanisms of this potential threat within the area of pharmaceutical regulation. OBJECTIVES: Through a comparison of two EU member states, the Netherlands and Denmark, this study aimed to investigate how regulatory capture could exist in pharmaceutical regulation. The EU Falsified Medicines Directive was used as the case, as it provided an opportunity for national medicine agencies to interact with various stakeholders. METHODS: The processes of negotiation and implementation of the directive were mapped by interviewing 23 stakeholder representatives and triangulated with relevant documents. A meaning condensation method was applied to show how stakeholders were involved with authorities, and the theory of regulatory capture was used to interpret how the two countries were susceptible to capture. RESULTS: The Danish Medical Agency was central in all relevant processes, whereas in the Netherlands, the Ministry of Health initiated the processes during the negotiation phase and, subsequently, three medical agencies shared responsibilities in the implementation phase. During the negotiation phase, the Dutch process was more focused on consensus among stakeholders while the Danish process focused on preparing the subsequent implementation. Neither member state prioritised transparency during implementation, but rather focused on timely implementation. CONCLUSIONS: The processes of EU negotiations and implementation of the Falsified Medicines Directive were handled quite differently in Denmark and the Netherlands. It is possible that regulatory capture could be prevalent in both member states as policy makers were only in limited dialogue with patients. EU countries must decide whether this technocratic approach is acceptable, or whether they should make a more concerted effort to include the public.

Abbreviated New Drug Applications: Generic Drug User Fee Amendments Act Analysis of Application Quality Metrics.

Implementation of the first Generic Drug User Fee Amendments of 2012 (GDUFA I) provided funding to the US Food and Drug Administration (FDA) for modernizing review of the FDA/CDER Generic Drug Program. Under GDUFA I, FDA agreed to reduce the backlog of pending generic Abbreviated New Drug Applications (ANDAs), improve the efficiency of generic drug review, and reduce the number of review cycles with the goal of reducing overall time to approval. This study presents a preliminary analysis of initial filing and regulatory first actions on ANDAs during GDUFA I cohort year 3 (CY3) and cohort year 4 (CY4). It highlights initial successes and areas of improvement in the ANDA review process for both FDA and ANDA applicants to improve the efficiency of providing the public with high-quality, affordable generic drugs.