Therapeutic Innovation & Regulatory Science

The isotretinoin risk management program iPLEDGE places requirements on patients and providers to ensure that the benefits of isotretinoin therapy outweigh the risks. Such burdens have the possibility of limiting patient access through mechanisms such as lowered physician participation.

In this study, we utilized prescription claims data to examine changes in patient and provider participation in isotretinoin therapy with iPLEDGE implementation. We examined the change in utilization among patients not targeted by iPLEDGE (male patients) to assess the program’s impact on access. We also examined whether provider participation in isotretinoin therapy varies by specialty and isotretinoin prescribing history.

Patient access to isotretinoin decreased in the period immediately following iPLEDGE implementation, but recovered to pre-iPLEDGE levels in the succeeding months. In addition, therapy completion rates increased with iPLEDGE implementation, suggesting that patients less committed to isotretinoin therapy may be self-selecting out of therapy. Lastly, iPLEDGE resulted in decreased participation by low-volume, general practitioners, while high-volume, specialists’ participation was largely unchanged.

We found that participants responded to iPLEDGE’s burdens in predictable ways. Insufficient anticipation of potential iPLEDGE rollout issues initially disrupted patient treatment and resulted in far fewer patients starting therapy. Over a longer term, isotretinoin utilization and therapy completion increased and isotretinoin prescribing shifted toward high-volume, specialist providers. We argue that these changes are predictable based on the burdens iPLEDGE imposes on patients and prescribers and may not be inconsistent with the goals of the risk management program.

To evaluate essential medicines utilization in community health institutions to identify problems hindering the implementation of the Essential Medicine System at community level in Beijing, China.

A total of 20 community health centers in Beijing were surveyed during September 2014 regarding stocking situation and utilization status of essential medicines. Opinions about essential medicines utilization were solicited from clinical staff at these centers. Average outpatient health expenditure was obtained from the Beijing Municipal Health Bureau to evaluate the financial impact.

During our study, an average of 377 species of essential medicines was stocked by the community health institutions, accounting for 53.9% of Beijing Essential Medicine List, and 61.6% of the total medicines in the institutions. First-aid and low-price essential medicines were frequently out of stock. The average expense per outpatient visit increased yearly from 2009 to 2013. Feedback from clinical staff revealed patients’ negative perception of the essential medicines and major concerns about its quality.

Our study found both the list and supply of essential medicines could not meet the clinical needs of patients at community health centers adequately. Furthermore, some existing drug policies had restricted the service capacity, thus affecting the centers’ function and bringing additional negative impact on essential medicines utilization. Financially, the inadequacy of essential medicine to meet clinical need and poor supply of many low-price drugs contributed much to the rise of average drug expenses, limiting the role of essential medicines to improve the quality of care at the community level.

The purpose of this study was to determine how well patients could correctly recognize and comprehend the various information items in over-the-counter (OTC) medications package leaflets in Saudi Arabia.

Leaflets from 20 most commonly sold OTC medications were examined by experts to evaluate the leaflet layout, language, and content. The same leaflets were also evaluated by patients who had their medicines dispensed at 2 hospitals and 8 community pharmacies in Al Kharj, Saudi Arabia. A questionnaire was used for the patients’ examination.

A total of 479 questionnaires were included in the study. Each package leaflet was examined by at least 20 participants. The results indicate poor comprehensibility, for many items, particularly items regarding “drug interactions” and “contraindications.”

The participants had some difficulty recognizing and comprehending certain information items in the package leaflets that are supplied with OTC medications in Saudi Arabia.

Because of its structure and complex manufacturing process, every biotherapeutic product (BTP; medicinal products made by or derived from living organisms and produced by biotechnology) adheres to stringent quality assurance and control requirements, in addition to extensive nonclinical and clinical study data. Similarly, copy products of original biotherapeutics (termed as “biosimilars”) are subjected to equally strict regulatory control. BTPs have been registered in Malaysia since the 1990s; however, registration of biosimilars started only in 2008.

This research aims to compare evaluation practice on biosimilar and novel BTPs at the Biological Product Registration Section in Malaysia. Evaluation activities were studied in terms of evaluation questions, evaluation timeline, nonclinical and clinical requirements, and local requirements on product label (including package insert). Six biosimilar product dossiers and 6 novel BTP dossiers evaluated in 2013-2015 were sampled. Parameters for comparison were determined and analyzed using data collection forms. Specific to the biosimilar products, the evaluation practice on labels and package inserts were dissected and described in a qualitative arm of this research.

Generally, the registration requirements of novel BTPs and biosimilar products are in agreement with international regulatory practices. However, some labeling and package insert requirements, and registration conditions are unique to the Malaysian regulatory context.

Study findings revealed some similarities and differences in current evaluation practice (timeline and requirements) for biosimilar versus novel BTPs. The findings of this research also provide an insight on current evaluation practice on biosimilar product labeling.

An addendum to the International Conference on Harmonisation E9 (ICH E9) guidance document (Statistical Principles for Clinical Trials) is currently under development. The aim of the addendum is to promote harmonized standards on the choice of estimand (a well-defined measure of the treatment effect that is being estimated) in clinical trials and to describe a consensual framework for planning, conducting, and interpreting sensitivity analyses of clinical trial data.

In order to help understand current practices relating to the choice of estimands and sensitivity analyses for clinical trials, the ICH E9 working group developing the addendum conducted a survey with a primary focus on clinical trials involving drugs, vaccines, and biologics. The survey was distributed electronically between May 19, 2015, and June 11, 2015, to various stakeholder groups within ICH, including industry, regulatory, and academic communities. A total of 1305 respondents participated.

Of the 1305 respondents 547 (42%), 344 (26%) and 283 (22%) were from Europe, USA and Japan respectively. Over half of the respondents work in pharmaceutical companies, and approximately a quarter of respondents noted oncology as the primary therapeutic area they work in. Over half of the respondents (595, 55%) noted the treatment effect being estimated was ‘in the entire target population of patients regardless of whether they will take treatment as instructed’. The most common methods for handling missing data in primary analyses were mixed-models repeated measures (555, 56% respondents) and last observation carried forward (549, 55% respondents). The majority of respondents (816, 83%) noted they conducted sensitivity analyses to estimate treatment effects in different ways compared to the primary analysis by using alternative assumptions (627, 78%) and/or using alternative statistical methods (616, 76%).

The survey results have provided useful information to the ICH E9 working group on current practices on the choice of primary estimands for measuring treatment effects in confirmatory clinical trials, and approaches used to select sensitivity analyses.

To confirm the effectiveness of sivelestat, a clinical trial was conducted comparing sivelestat with conventional treatment in an open, nonrandomized, multicenter study of patients with systemic inflammatory response syndrome (SIRS)–associated acute lung injury. The primary endpoint was ventilator-free days (VFD).

This study adopted a “cluster entry” method to control for patient selection bias arising from the unblinded and nonrandomized clinical trial. Thus, all patients in the same hospital during the same entry period entered the same treatment arm, and entry periods did not overlap. In the primary analysis of VFD, adjusted mean VFD values were compared between groups using the inverse probability of treatment weighted (IPTW) method, based on propensity score, for control of confounding factors.

There were 374 patients in the sivelestat group and 168 in the conventional therapy group. The primary analysis confirmed that sivelestat was effective (between-group difference of adjusted mean was 3.5 [2-sided 95% confidence interval, 1.3-5.8]; P = .0022).

In general, a study where all patients in the same cluster enter the same treatment arm has within-cluster correlations, which need to be considered in the study analysis. However, in analysis using the IPTW method, it is usual to use a robust variance estimator, the sandwich variance estimator, which is consistent regardless of whether the specification of within-cluster correlation structure is correct. Thus, in the analysis using the IPTW method, it was found that it was not necessary to adopt any other adjustment method for within-cluster correlation.

Traditionally, sample size considerations for Phase 2 (Ph2) trials are based on the desired properties of the design and response information from the trials.

This work extends that of Patel et al (2012) to design Ph2 trials based on program-level optimization (ie, optimizing the entire Ph2/3 trial design strategy). It describes a framework to evaluate the impact that several Ph2 design features have on the probability of Phase 3 (Ph3) success and the expected net present value (eNPV) of the product. These factors include the Ph2 sample size, decision rules to select Ph3 dose(s) and sample sizes, as well as number of Ph3 trials. Using neuropathic pain as an example, simulations illustrate the framework and show the benefit of including these factors in the overall decision process. Patel et al considered one dose of test drug in each of exactly two Ph3 trials. This work extends that to consider 1 or 2 doses in each of 2 Ph3 trials and, if needed, 1 or 2 additional Ph3 trials to substantiate the usefulness of the second dose.

We found that employing a quantitative algorithmic strategy to choose 1 or 2 doses for Ph3 based on trial results does not substantially alter the eNPV compared to a strategy of always taking 2 doses to Ph3, if appropriate. Similar to the findings by Patel et al, for 1 Ph3 dose, we found that Ph2 sample size can be optimized at small to modest sizes when allowing for the possibility of taking 2 doses to Ph3. We found that choice of number of Ph2 doses depends on the magnitudes and shapes of the true underlying efficacy and safety dose-response curves.

Simulating a sequence of clinical trials can inform trial design and drug development strategy.

Fixed-dose combination (FDC) drugs have been an attractive product in pharmaceutical markets because of their unique advantages, but general guidance directing the clinical development of FDC drugs is not yet available in the US.

All drug approval reports of FDC products approved by the US FDA from January 2010 to December 2015 were intensively analyzed to investigate the regulatory requirements of the US FDA.

Through analyzing 63 approved FDCs out of 655 New Drug Application (NDA) approvals, it was found that completion of the full phases of clinical trials was not always required for approval by the FDA, which indicates that some phases of clinical studies can be possibly exempted, if justified.

The results imply that pharmaceutical companies can accelerate FDC development and enter the market earlier if scientific regulatory rationales are established.

The use of smart and/or wearable devices for collection of electronic data in clinical trials has recently become a strong tool with which to collect patients’ data in a timely manner. Electronic collection of patient data will necessitate comprehensive data analysis involving huge-scale datasets in the future. However, it is still unclear how to validate and qualify computerized systems used to collect and/or manage electronic clinical data when smart and/or wearable devices are involved.

We (a special interest group of Good Automated Manufacturing Practice Japan Forum [GAMP Japan]) investigated and designed a data-flow model for a clinical data management system involving smart and/or wearable devices, and suggested an approach for the validation of such a computerized system. The appropriateness of applying GAMP5 to the validation of a clinical data management system involving smart and/or wearable devices was also reviewed.

A regulated company should have policies and standard procedures for validating computerized systems in clinical systems. When a sponsor engages a contract research organization (CRO) for clinical data management, the sponsor should assess the CRO to confirm their capabilities. The sponsor also needs to check whether the CRO assesses device manufacturers as sub-suppliers. When the CRO intends to conduct sub-supplier assessment with a device manufacturer, a risk-based approach can be taken.

We believe our method of system validation will be applicable to and will facilitate various clinical trials that involve smart and/or wearable devices.