Therapeutic Innovation & Regulatory Science

Current clinical trial labels are designed primarily to meet regulatory requirements. These labels have low patient and site utility, few are opened, and they have limited space and small fonts. As our world transitions from paper to electronic, an opportunity exists to provide patients with information about their investigational clinical trial product in a way that is more easily accessible, meets Health Authority requirements, and provides valuable additional information for the patient and caregiver.

A TransCelerate initiative was launched to understand the current regulatory and technology landscape for the potential use an electronic label (eLabel) for investigational medicinal products (IMPs). Concepts and an example proof of concept were developed intended to show the “art of the possible” for a foundational eLabel and a “universal printed label.” In addition, possible patient-centric enhancements were captured in the eLabel proof of concept. These concepts were shared with Health Authorities as well as patient and site advisory groups to gather feedback and subsequently enhance the concepts.

Feedback indicated that the concept of an eLabel provides value and concepts should continue to be pursued. While the Health Authorities engaged with did not express issues with the use of an eLabel per se, the reduction in the content on the paper label is not possible in some geographic locations due to existing regulations.

There is nothing that prevents transmitting the label electronically in conjunction with current conventional labeling. While there are still some regulatory barriers that need to be addressed for reducing what is on the paper label, advancement toward a more patient-centric approach benefits stakeholders and will enable a fully connected patient-centric experience. The industry must start now to build the foundation

The quality of data from clinical trials has received a great deal of attention in recent years. Of central importance is the need to protect the well-being of study participants and maintain the integrity of final analysis results. However, traditional approaches to assess data quality have come under increased scrutiny as providing little benefit for the substantial cost. Numerous regulatory guidance documents and industry position papers have described risk-based approaches to identify quality and safety issues. In particular, the position paper of TransCelerate BioPharma recommends defining risk thresholds to assess safety and quality risks based on past clinical experience. This exercise can be extremely time-consuming, and the resulting thresholds may only be relevant to a particular therapeutic area, patient or clinical site population. In addition, predefined thresholds cannot account for safety or quality issues where the underlying rate of observing a particular problem may change over the course of a clinical trial, and often do not consider varying patient exposure.

In this manuscript, we appropriate rules commonly utilized for funnel plots to define a traffic-light system for risk indicators based on statistical criteria that consider the duration of patient follow-up. Further, we describe how these methods can be adapted to assess changing risk over time. Finally, we illustrate numerous graphical approaches to summarize and communicate risk, and discuss hybrid clinical-statistical approaches to allow for the assessment of risk at sites with low patient enrollment.

We illustrate the aforementioned methodologies for a clinical trial in patients with schizophrenia.

Funnel plots are a flexible graphical technique that can form the basis for a risk-based strategy to assess data integrity, while considering site sample size, patient exposure, and changing risk across time.

Site identification, site selection, and study start-up have become the focus of improvement by organizations conducting clinical trials.

To examine and measure the process from site identification through site activation, Tufts Center for the Study of Drug Development (CSDD) conducted a comprehensive survey among pharmaceutical organizations, biotech companies, and contract research organizations (CROs). Responses from over 400 unique companies were gathered and analyzed.

The results indicate that the start-up process is on average 5 to 6 months in total duration, and cycle times across all activities, including site identification, site selection, and study start-up, are faster for repeat sites than for new sites. Comparisons between sponsor and CROs indicate that CROs completed all site-related activities 6 to 11 weeks faster than sponsors. Other areas impacting cycle times were examined, including centralized versus decentralized functions, investment in technology, and organizational strategies that improve cycle time efficiency and performance.

Tufts CSDD will explore this area in future research to gather additional insights into other factors that may be associated with speed and efficiency.

The US Food and Drug Administration (FDA) ensures clinical trials meet regulatory/ethical standards through inspections. If FDA Investigators observe potential violations of regulatory requirements during an inspection, a firm will receive a Form FDA 483, Inspectional Observations. Violations cited have resulted in the death of human research subjects, prosecution of research personnel, and denial of approval for new medical products. Objectives included the standardization of Violation Themes cited for analysis by inspection firm type, geographic location, and Violation Theme citation to provide insight into regulatory violations.

Cross-sectional analysis of citations published in public databases between October 1, 2005, and September 30, 2015, by the FDA for inspections under the Bioresearch Monitoring program. For each inspection citation, the main measure was the Code of Federal Regulation cited coded into a standardized Violation Theme for citation analysis.

Under the Bioresearch Monitoring program, 3281 inspections received a Form FDA 483 in 2007-2015. FDA inspections have increased over this period but the rate of Form FDA 483 issuance has decreased. On average, Sponsor-Investigators received 4.41 citations per inspection compared to clinical researchers alone receiving 2.21. One-third of violations were related to adherence to investigational procedures followed by informed consent and study records issues.

In the last decade, the number of violations observed under the Bioresearch Monitoring program has decreased; however, significant improvements can still be made regarding adherence to study procedures, the consenting of human research subjects, and creation of adequate and accurate study documentation.

The US Food and Drug Administration (FDA) ensures that clinical trials meet regulatory and ethical standards through inspections of researchers, also known as clinical investigators. Inspections with significant regulatory/ethical violations may result in regulatory actions, such as a warning letter or a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). Objectives included the standardization of regulatory violation themes cited by the FDA for novel analysis of published regulatory actions rate issued by study intervention type, violation theme by intervention type, and violation theme variation between regulatory action type.

Cross-sectional analysis of regulatory actions from October 1, 2006, to September 30, 2015, for inspections of researchers. For each FDA regulatory action, the main measure was the Code of Federal Regulations cited coded into a violation theme. Data were paired with FDA’s published researcher inspection metrics to perform fiscal year analysis.

The FDA conducted 6375 domestic inspections of researchers in 2007 to 2015: 360 had significant regulatory violations, and 194 received published regulatory actions. Since 2007, rates of significant deviations have decreased. Medical device researchers had higher rates of warning letter issuance than did biologic product researchers. In contrast, medical device researchers had lower rates of NIDPOE issuance as compared to rates of biologic or pharmaceutical researchers. Lack of researcher supervision and submission of false information were cited more frequently for NIDPOEs.

Researcher compliance has significantly improved as evidenced by medical device researchers having the lowest rate of the most significant noncompliance. Disqualification is more likely to occur when researchers fail to supervise the trial or false information is submitted.

To apply “user testing” to maximize readability and acceptability of a Clinical Trial Results Laypersons Summary—a new European requirement.

“User testing” (using questionnaire and semistructured interview) assessed whether people could find and understand key points. Findings were used to improve content and design, prior to retesting. Participants had a range of levels of health literacy and there was a higher education group. Participants accessed the summary on screen. In round 1 we tested 12 points of information. In round 2 a revised summary addressing round 1 findings was tested, leading to a third final version.

In round 1, 2 of 12 points of information did not reach the target and interviews raised further format and content issues (some distracting technical explanations and inability to find or understand the 2 main study purposes). These findings informed revisions for the version tested in round 2, with 2 different points not reaching the target (inclusion criteria relating to duration of seasonal allergies and how researchers found out about participants’ symptoms). Identified problems in both rounds were addressed and reflected in the final version. Despite improvements, participants did not consistently understand that summaries were intended for the public, or to only interpret results of single trials in the context of additional trials. All readers, including those with higher education, found the clear and straightforward language acceptable.

Applying “user testing” resulted in a largely health-literate summary suitable for people across a range of backgrounds.

New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets.

A tripartite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included.

Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US (P < .01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as “useful,” “acceptable,” and “trustworthy,” whereas Japan was clustered with intermediate to negative responses such as “neither” and “untrustworthy.”

Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan.

Juvenile animal testing has become an established part of drug development to support safe clinical use in the human pediatric population and for eventual drug product label use.

A review of European Paediatric Investigation Plan decisions showed that from 2007 to mid-2017, 229 drugs had juvenile animal work requested, almost exclusively incorporating general toxicology study designs, in rat (57.5%), dog (8%), mouse (4.5%), monkey (4%), pig (2%), sheep (1%), rabbit (1%), hamster (0.5%), and species not specified (21.5%). A range of therapeutic areas were found, but the most common areas were infectious diseases (15%), endocrinology (13.5%), oncology (13%), neurology (11%), and cardiovascular diseases (10%). Examination of major clinical indications within these therapeutic areas showed some level of consistency in the species of choice for testing and the pediatric age that required support. Examination of juvenile animal study findings presented in product labels raises questions around how useful the data are to allow prescribing the drug to a child.

It is hopeful that the new ICH S11 guideline “Nonclinical Safety Testing in Support of Development of Pediatric Medicines” currently in preparation will aid drug developers in clarifying the need for juvenile animal studies as well as in promoting a move away from toxicology studies with a conventional design. This would permit more focused testing to examine identified areas of toxicity or safety concerns and clarify the presentation/interpretation of juvenile animal study findings for proper risk assessment by a drug prescriber.

Nonstandard product information leaflets (PIs) may lead to medication errors. We assessed the completeness, and compatibility of, essential information against reference sources in selected PIs of medicines used in Sri Lanka.

Hundred PIs each were used to assess completeness and compatibility of information, respectively. Availability of essential information was checked against drug regulations of the country. Clinical facts were matched against the British National Formulary and/or Australian Medicines Handbook for compatibility. PIs were categorized as “compatible” if all facts stated under each clinical information type were mentioned in at least one of the references; “partially compatible” if only some facts mentioned under each clinical information type were available in at least one of the references; and “totally incompatible” if none of the facts stated in each clinical information type were mentioned in both references.

Of the 100 PIs, 28% did not include at least one of the essential information required by the regulations. Pharmacokinetic data, duration of treatment, overdose, and special dosage information were frequently missing. Nine types of clinical information in PIs matched with reference sources resulted in 900 cross-matches. Among the cross-matches, 80 (8.9%) partial compatibilities and 8 (0.9%) total incompatibilities were encountered. Nearly half (48%) of the PIs had at least one incompatibility.

Some PIs lacked important medicines information and were incompatible with known references. PIs need to be carefully prepared by medicine manufacturers and meticulously reviewed by regulatory authorities for accuracy and completeness.

The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA’s regulatory framework. Gaps exist between patient advocates’ knowledge of the agency’s processes and FDA’s need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making.

Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants’ perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes.

The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA’s patient experience data requirements. A conceptual model of this regulatory process was developed.

Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics.

Children with congenital cochleovestibular abnormalities associated with profound hearing loss have few treatment options if cochlear implantation does not yield benefit. An alternative is the auditory brainstem implant (ABI). Regulatory authority device approvals currently include a structured benefit-risk assessment. Such an assessment, for regulatory purposes or to guide clinical decision making, has not been published, to our knowledge, for the ABI and may lead to the design of a research program that incorporates regulatory authority, family, and professional input.

Much structured benefit-risk research has been conducted in the context of drug trials; here we apply this approach to device studies. A qualitative framework organized benefit (speech recognition, parent self-report measures) and risk (surgery- and device-related) information to guide the selection of candidates thought to have potential benefit from ABI.

Children with cochleovestibular anatomical abnormalities are challenging for appropriate assessment of candidacy for a cochlear implant or an ABI. While the research is still preliminary, children with an ABI appear to slowly obtain benefit over time. A team of professionals, including audiological, occupational, and educational therapy, affords maximum opportunity for benefit.

Pediatric patients who have abnormal anatomy and are candidates for an implantable auditory prosthetic require an individualized, multisystems review. The qualitative benefit-risk assessment used here to characterize the condition, the medical need, potential benefits, risks, and risk management strategies has revealed the complex factors involved. After implantation, continued team support for the family during extensive postimplant therapy is needed to develop maximum auditory skill benefit.