Therapeutic Innovation & Regulatory Science

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.

Typography significantly influences the legibility and usability of patient information. This study investigated the implementation and changes of different typographic subjects in package leaflets used in the European Union.

A randomly selected sample of all German package leaflets investigated in 2005 was reanalyzed in 2015 for different important and predefined typographic subjects.

The 138 package leaflets revisited in 2015 showed significant increases in word count (average 2551 words), font size (1.43 mm x-height, 2.0 mm cap-height), line spacing (3.13 mm), use of text attributes (for example, lists in 94.2% and bold print in 83.2% package leaflet’s body text), use of light-condensed or condensed font (34.1%), and use of portrait format (81.9%) (P ≤ .015). Otherwise, line length significantly decreased to on average 62.6 characters per line (P = .012) and the classes of fonts used remained almost unchanged.

To achieve any further increase of package leaflet font size and other typographic improvements, a significant decrease in text volume is essential. To this end, replacing the current 840-word QRD template with a 200-word version would allow optimization of typography in all package leaflets, without deleting information essential for patients or incurring any unfavorable format increase.

Compliance of community pharmacists (CPs) and private general medical practitioners (GPs) with Malaysian Laws on Poisons and Sale of Drugs is crucial in encouraging rational supply of medicine to patients that will subsequently lead to rational use of medicine, especially controlled medicine and psychotropic substances. This study aims to identify the trend of yearly compliance rate of both CPs and GPs with the Malaysian Laws on Poisons and Sale of Drugs, and to quantify the effectiveness of disciplinary actions in improving their compliance level.

This is a retrospective observation study from the Sarawak state Pharmaceutical Enforcement Division (PED) inspection reports on CPs and GPs from January 1, 2012, to December 31, 2014. Descriptive statistics in numbers and percentages are used to present the results.

From years 2012 to 2014, the compliance rate of GPs increased from 34% to 51%, while the compliance rate of CPs remained almost constant, with a slight drop from 53% (2012) to 50% (2014). The most common noncompliance found among CPs is with the Poison Acts 1952 Section 26 Condition 2: “Records for the supply of preparations containing Pseudoephedrine, Ephedrine and Dextromethorphan,” and among GPs, it is the Regulation 12 of Poisons Regulation 1952: “labeling of dispensed medicines.” Warning letter is the most effective disciplinary action for both CPs (75% improvement) and GPs (67.8% improvement).

This study serves as a baseline that provides valuable insights to policy makers, researchers, and other stakeholders in developing better enforcement strategies.

Contract manufacturing of prescription drugs is perceived to be on the rise, as companies look to optimize manufacturing capacity by either outsourcing or manufacturing for others. The lack of transparency into these proprietary arrangements has led to concerns that outsourcing may result in an overly concentrated manufacturing base, making the system more vulnerable to drug shortages.

Using nonpublic, internal FDA data, we link 374 sterile injectable new drug applications (NDAs) and 797 abbreviated new drug applications (ANDAs, otherwise known as generics) with finished dosage form manufacturing facilities in which the drugs were made as of November 2014. We then examine which kinds of firms were outsourcing which products and for whom.

We find that NDAs were twice as likely to be outsourced as ANDAs: 39% versus 19%. Outsourced NDAs were just as likely to be made in the US as in Western Europe (45%), but outsourced ANDAs were mostly made in Asia (57%). Large application holders outsourced 10% of their application portfolio. They also manufactured for others—about 14% of applications they made were for others. Sixty-one percent of contract manufacturing firms were small and of those, 76% owned no applications. Because so much contract manufacturing of sterile injectables was being done by small players, there were no discernable differences in market concentration measures between application holders and drug manufacturers.

The landscape of sterile injectable contract manufacturing in 2014 was diverse, with small and large companies participating. This diversity resulted in a market similar in its concentration on the ownership and manufacturing sides.

There is a need for a collation and comparison of the content of the mobile medical applications (apps) to allow health care professionals to know precisely which app they can rely on to gain access to appropriate drugs references. This study aims to evaluate the features of mobile medical apps based on 3 major functions: Dosage recommendation, drug adverse Reaction, And Drug Interaction (DoReADI).

A review and comparison of mobile apps available in Google’s Play Store (Android system) and Apple’s App Store (iOS system) were performed. The comparison was based on the availability of options, especially DoReADI functionalities. The assessment criteria were as follows: requirement for an Internet connection, subscription fee charged, size of app, dose recommendation, drug indication, dose calculator, drug picture, dose adjustment, pregnancy safety, interaction checker, interaction classification, clinical teaching advice, contraindicated drug, black box warning, adverse effect, contraindication or precaution, as well as toxicology and pharmacology information.

Eight mobile medical apps were included and used to compare their features and functionalities. The 4 apps that scored the highest (14/17 points) are: Lexicomp^®, Epocrates^®, Micromedex^®, and Drugs.com ^®. Lexicomp and Micromedex do not provide the image of the drug and have an access subscription fee. Epocrates does not provide interaction classification and clinical teaching advice, and occupies a large space in the memory to be installed. Meanwhile, My Blue Book^® scored the lowest (9/17 points) because certain features such as toxicology information, drug interaction, clinical teaching advice, contraindicated drug, and black box warning were not included.

Based on the features assessment criteria of each mobile medical application, Lexicomp, Epocrates, Micromedex, and Drugs.com are the apps that scored the highest. Epocrates and Micromedex are useful for checking drug interactions. In addition, some of the apps have additional features for the DoReADI criteria, for example, dose calculator and interaction classification.

Pharmacovigilance of patient support programs (PSPs) has been the subject of debate, legislation, and guidance, and regulatory inspections over the last half-a-dozen years. PSPs often involve direct contact between patients or caregivers and health care professionals and are sponsored by marketing authorization holders (MAHs). PSPs have no scientific hypothesis under study, and are not governed by a protocol. Adverse events and suspected adverse reactions are expected to arise. Management of safety data is governed by a patchwork of incongruous guidelines worldwide, leaving room for varying interpretations.

A survey of MAHs was conducted to inquire about methods, techniques and scope of pharmacovigilance activities concerning PSPs and similar organized data collection systems. The survey was conducted over a 6-week period by contacting pharmacovigilance operations managers in a broad range of MAHs.

The survey was completed by 18 of 35 MAHs. The vast majority of MAHs (94%) conduct market research. Patient support programs were sponsored or supported by 89% of the respondents, with 67% of MAHs sponsoring or supporting disease management programs or social media resources.

Pharmaceutical industry responses to the challenge of pharmacovigilance of patient support programs are varied. In general there has been a consistent response to the European pharmacovigilance regulations and the accompanying guidance introduced in June 2012. As evidenced by the following survey results, many companies have adopted a risk-based approach first assessing each PSP for probability of AE generation, and then setting up a contract and processes to ensure appropriate collection, collation, and assessment of reports of suspected adverse reactions. At the same time, the survey results indicate that many companies are not as mature in their oversight of PSPs. The authors recommend collaboration within the industry to define and agree to industry standard approaches for oversight of PSPs and the adoption of evidence-based simplification of the current regulatory guidelines concerning safety monitoring and reporting, as the current burden is onerous, and over a period of several years has not yielded any information on medically important new risks. Specifically, the authors recommend the formation of a CIOMS Expert Working Group to spearhead this industry collaboration to find a better path forward.

Patients who are seriously ill and have run out of available treatment options may seek access to investigational agents that have not yet been fully vetted by regulatory agencies for safety and efficacy and approved for use in human subjects. Over time, a variety of terms have evolved internationally to denote mechanisms for providing access to such unapproved investigational agents. The lack of consistency in terminology used to describe this process is confusing at best and, at worst, possibly even detrimental to patients.

To highlight variation around the globe in terminology denoting pre-approval access to investigational agents, we conducted extensive Internet searches to locate specific legislation, guidance, or policy documents describing access mechanisms in numerous countries. We created a table of results intended to convey a sampling of international terminological diversity.

The profusion of terms used internationally to indicate pre-approval access to investigational agents is evident. We recommend a shift toward the use of “pre-approval access” as an umbrella term encompassing all forms of access to unapproved agents. We also recommend use of the phrases “individual/named patient regulatory routes for pre-approval access” and “group/cohort regulatory routes for pre-approval access” to differentiate between pre-approval access programs designed for single patients, versus those designed for groups of patients.

There is a pressing need to revisit and better align pre-approval access terminology at the international level. Adopting the umbrella term “pre-approval access” may be a useful strategy for initiating and promoting harmonization of terms to reduce potential confusion by patients and health care decision makers regarding experimental treatment options.

Assessing the benefit-risk profile of a medicinal product is a complex but fundamental activity that sponsors and regulators must perform throughout the product’s lifecycle. In order to improve the transparency and consistency of the decision-making process, regulators and sponsors alike are increasingly applying a structured approach to benefit-risk assessment. However, to our knowledge, there has been little practical guidance in the published literature regarding how to embed such a process organizationally. This paper seeks to address this gap.

Using a case study approach, we describe (1) how to integrate a lifecycle approach to structured benefit-risk assessment within a biopharmaceutical company; (2) key issues to anticipate during implementation, and (3) best practices and lessons learned to date.

Based on our experience, key prerequisites for successful implementation included the selection of a structured benefit-risk assessment (SBRA) framework; application of a “core” approach to conducting SBRA with an accompanying template; development of a supporting standard operating procedure; and cross-functional team training. Common implementation challenges encountered were (1) facilitating cross-functional team adoption of SBRA nomenclature and analytic methods, including the use of a value tree and effects table, and (2) applying the SBRA framework to different products with heterogeneous data sources.

Conducting transparent, systematic benefit-risk evaluations is an emerging “best practice” for medicinal product lifecycle management. Our experience using such an approach resulted in improvements in the consistency, quality, conciseness and strategic value of our benefit-risk assessments, and increased transparency and harmonization in the communication of the product benefit-risk profile.

A breakthrough therapy designation is intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious condition.

The Center for Drug Evaluation and Research (CDER) at Food and Drug Administration (FDA) analyzed 364 breakthrough therapy designation requests received from program inception on July 9, 2012, through June 30, 2016.

Of the 364 requests received during this time, CDER granted 133 (37%), denied 182 (50%), and the sponsor withdrew 49 (13%) before CDER made a decision.

This analysis provides information on the distinguishing characteristics of the drugs seeking this designation and the decisional factors used by CDER to either grant or deny breakthrough therapy designation requests. This paper provides greater transparency into the CDER decision process, so the public can better understand how breakthrough therapy designations are determined.