Quality, reliable data is the key to successful drug development. From the initial preclinical data, the plan to bring a drug to market is built upon the foundation of solid, reliable data that demonstrates safety in a human patient population.

In this journal, we lead you on the complex, multi-step data journey for Phase I clinical trials, from conceptualization and initial protocol development, collection and analysis, through final regulatory submission. We highlight best practices and approaches to mitigate challenges, and show how integration and collaboration build the strongest datasets for your drug development program.

In Issue 29 of The Altascientist: 
•    Protocol development
•    Data management
•    Statistical support
•    Analysis and reporting

Clinical Trial Protocol Development—The First Important Step

Developing a protocol is the first step in making your study design a concrete, actionable plan to generate data for regulatory submission. Meticulously documented and validated, a well-designed protocol provides the structure for the trial activities that will generate the data to support the study objectives; it is integral to the success of any drug development program.

The credibility of the data from the clinical trial is mainly dependent on the trial design. The trial design in the protocol defines the endpoints and study type (double-masked, placebo-controlled, parallel design), and includes detailed information about the investigational product (IP), the anticipated duration of subject participation, and the sequence and duration of all trial periods, including follow-up. Discontinuation criteria are also key elements for data-driven decision-making during study conduct.

In addition, the protocol includes the description of the analysis and statistical methods to be employed, including timing of any planned interim analyses and quantification of the approach, such as selection criteria for analysis populations (all randomized, all dosed, all eligible, etc.), sample size, calculation of power of the trial, and clinical justification. Finally, the protocol details procedures for reporting any deviations from the original statistical plan, and the use of any excess, missing, or spurious data. 

Once the study protocol is final, it becomes the foundation for additional and more detailed study documents, including the Data Management Plan (DMP) and Statistical Analysis Plan (SAP). Here, the first steps of the data journey truly begin.

How Altasciences Will Support Your Clinical Trial Data

At Altasciences, we take pride in the way we handle your data and facilitate your journey. We have a talented, experienced, and integrated team, whose collaborative efforts ensure that your data is collected and managed with the utmost speed, efficiency, and respect for quality.

Following rigorous processes and standard operating procedures and leveraging a deep and broad knowledge of CDASH and CDISC guidelines, we ensure that your critical trial data is delivered in a regulatory-compliant format. Our PK and PD experts ensure that all analyses are carried out with rigor in a timely fashion so that the data is thorough, accurate, and actionable. When you partner with us, you need never be concerned about the quality, security, or accuracy of the data you present in support of your drug development program.
 

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Liquid-filled hard-shell capsules (LFHCs) are a popular formulation for oral solid delivery of chemical drugs and nutraceuticals. Often selected for drugs with poor solubility/bioavailability, LFHCs also have applications in a number of other situations, including specific benefits during early-phase clinical development.

In Issue 28 of The Altascientist, you will find: 
•    Applications of LFHCs
•    The production process
•    The role of excipients
•    Other advantages of LFHCs
•    A case study
•    How Altasciences can help

Applications for Liquid-Filled Hard-Shell Capsules in Your Drug Development Program

The use of modern drug discovery approaches, such as combinatorial chemistry and high-throughput screening, as well as structural understanding of drug-target binding by X-ray diffraction and molecular modelling, has resulted in an increasing percentage of highly potent lead compounds.

The majority of these compounds have high-melting points and poor aqueous solubility, which directly impact their dissolution and bioavailability. In an LFHC, readily metabolized lipid-based solutions are used as liquid carriers, providing for optimized absorption of the active pharmaceutical ingredient (API).

LFHCs offer several advantages for handling these challenging APIs, including: 
•    improved safety in processing and administration of potent drugs
•    ease of administration
•    flexible application
•    abuse-resistant formulations

How Altasciences Can Help With Your Liquid-Filled Hard-Shell Capsule Formulations and Manufacturing

Altasciences has a proven track record and thorough expertise with LFHCs, having completed numerous projects over the years, for a wide range of clients. Our highly knowledgeable experts will assist you in determining the most appropriate and efficient program parameters, from batch size to excipient selection and capsule composition, color, and banding options. Our skilled operators use state-of-the-art machinery for every step of the process. We perform comprehensive process validation prior to manufacture, identifying and correcting any potential issue before it becomes a problem. We provide 100% manual inspection of the finished capsules and take pride in doing the job right the first time, every time.

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Ophthalmic medications have a particular set of challenges that can impact their speedy and successful path to market. From prototype formulation through preclinical testing, early-phase clinical and manufacturing and development, ophthalmic drug development presents with specific and unique complexities. It is best to entrust drug development to a partner with regulatory knowledge, technical expertise, and a thorough understanding of the market in this growing therapeutic area. From current reality to future trends, being at the forefront of ophthalmic drug development delivers tangible benefits to sponsors.

In Issue 27 of The Altascientist, we dive into all areas of ophthalmic drug development, including: 
•    Prototype development, formulation, and manufacturing 
•    Preparing for first-in-human studies 
•    Species and strain selection parameters 
•    Routes of administration 
•    Specialized ocular assessments and equipment 
•    bioanalysis
•    Phase I clinical research
•    Phase II to commercialization

Three case studies are also included!

Navigating the Complexities of Ophthalmic Drug Development

The global market for ophthalmic drugs was valued at USD 36.7 billion in 2020, according to Grandview Research. The compound annual growth rate (CAGR) is expected to be 6.4% from 2021 to 2028. The acceleration in market growth is influenced by increasing awareness of eye-related diseases and advancements in related technology. The aging of the population, as well as the impact of COVID-19 ocular involvement, are also contributing factors. Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population.

Drug development in the ocular space has specific challenges. The eye is a multi-faceted organism and has many barriers to drug delivery. Formulation and delivery options must be expertly planned and developed to overcome those barriers and ensure that the maximum bioavailability is achieved without negatively impacting vision or the physical structure of the eye. Planning of preclinical studies must consider the appropriate animal species for the route of administration and therapeutic area of the investigational drug. Some species are more appropriate for certain routes of administration, while others have relevant retinal mutations that can be leveraged in ocular development.

Clinical trials need to be carefully designed by knowledgeable specialists with significant ophthalmic experience. The delicate nature of the eye and the importance of subject safety are key considerations. Just as importantly, the bioanalysis of trial samples necessitates the use of bioanalytical techniques created especially for the often uncommon and frequently fragile matrices involved. Finally, understanding the regulatory environment and related guidances, as well as proactive and appropriate discussions with relevant agencies when warranted, are critical components of the pathway and can help ensure a seamless experience.

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The Clinical Data Interchange Standards Consortium (CDISC) is a worldwide organization for data standardization, ensuring that drug research data delivers the maximum value for sponsors, regulatory agencies, and patients. Data that is accessible, compatible, comparable across regions, and reusable for meta-analysis or reanalysis, serves to improve our understanding of human therapeutics by providing meaningful, efficient research data for the entire global drug research community. Implementing standards to collect, structure, and analyze data makes it easier to aggregate information and take advantage of big data.

In Issue 26 of The Altascientist: 
•    Introduction to standardization and its benefits
•    Client considerations for nonclinical and clinical data standardization
•    Case Study — Realized Efficiency
•    Case Studies — Legacy Data Conversion
•    The future of CDISC and data strategy

Why is Data Standardization in Drug Development Important?

There is tremendous value in standardizing and sharing data: organizations across the globe that are using CDISC standards produce faster, more efficient research, and pave the way for more breakthroughs that amplify the power of data, in both the short- and long-term.

“Adherence to data standards is integral to successful and efficient drug development for our clients,” says Nicole Maciolek, Vice President, Research Services, Medical Writing and Scientific Affairs, at Altasciences. “We are experts in applying CDISC standards, from preclinical SEND to clinical CDASH, SDTM, and ADaM. We are proud to be Gold members of the CDISC consortium, and to bring the advantages of standardization to all the data we deliver.”

Data that is presented in a well-organized, templated fashion is easier for regulatory reviewers to understand and interpret, which limits requests to sponsors for clarification or resubmission. The CDISC standards cover all types of data, from nonclinical to Phase III, across therapeutic areas, and are required for all studies supporting marketing authorization.

Sponsors benefit from data that is of high quality, easy to interpret, and leads to sound, swift go/no-go decisions. Regulatory bodies benefit from a smooth, consistent process that allows them to analyze all the data submitted in the same way, without concerns about the organization or interpretation of data that may be structured differently.

How Altasciences Ensures Compliance With CDSIC Data Standards

We ensure that our team is always up to date with the latest trends and guidelines in regard to CDISC standards. We utilize a suite of proprietary validation checks, as well as Pinnacle 21 Enterprise version technology, to load, review, and validate SDTM and ADaM data and Define.xml files. Our CDISC experts are available on a per-project or full-time equivalent (FTE) basis, according to your needs. Our team has converted data from clinical trials, in diverse therapeutic areas, to CDISC-compliant SDTM and ADaM datasets, as well as designed CDASH-compliant forms and databases for streamlined data management and reporting.

Click here to learn more about our clinical data management capabilities.  

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The structure of an early-phase drug development pathway is not set in stone. In fact, certain studies that are generally considered Phase I do not have to be conducted before Phase II commences. Conversely, some studies that are typically done in Phase II can be advanced into a Phase I combined protocol to have access to key data earlier in the program. Early Phase I studies have become increasingly complex in order to gather comprehensive data related to safety and drug pharmacology. Having early access to trial results and data helps inform decisions later in the development journey, can support funding opportunities, and helps solidify the overall plan around sound data.

In Issue 25 of The Altascientist: 
•    Timing of early clinical pharmacology studies
•    Phase I combined protocols 
•    Special populations 
•    Resource allocation 
•    Examples of flexible Phase I study timing

Designing Early Clinical Pharmacology Studies

Phase I clinical pharmacology studies of an investigational drug are designed mainly to investigate safety and tolerability at a range of doses (where possible, develop target therapeutic dose range) and characterize the pharmacokinetics (PK) and pharmacodynamics (PD).

Therapeutic exploratory studies are required milestones, while clinical pharmacology studies include both mandatory and conditional studies. Conditional studies need only be conducted where specific safety data must be acquired for regulatory approval. These studies can sometimes be scheduled at different stages of the program, depending on the specifics of the investigational product. In some cases, such studies can be waived with supporting data.

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Conducting ethnobridging studies locally, during Phase I clinical trials, in the target population, can reduce drug development timelines by the number of years typically needed to complete clinical development in the target region, as compared with North America or Europe. A Phase I ethnobridging strategy allows you to recruit patients in “global” safety and efficacy trials (Phases II and III) without repeating Phase I development in that region and population.

In Issue 24 of The Altascientist: 
•    The importance of Asian ethnobridging in clinical research
•    Bridging requirements per the ICH E5 Guidance
•    Strategic program considerations per the ICH E7 Guidance
•    Accelerating Asian drug development
•    Language requirements for global clinical trials
•    Altasciences’ expertise and experience with ethnobridging

The Importance of Asian Ethnobridging in Clinical Research

Over 60% of the world’s population is considered part of the diverse group of ethnicities commonly referred to as Asian, with each ethnicity having a distinct genetic profile. A 2019 systemic review identified 49 different ethnic categories that were classified as “Asian” in pharmacogenetic studies. Within Asian subgroups, the known differences in pharmacogenetics are generally previously identified variants, which are significantly more or less prevalent in Asians as compared to other populations.

Two identified intrinsic factors that affect drug metabolism are that Asians are more commonly poor metabolizers of cytochrome P450 (CYP) 2C19, and carriers of the human leukocyte antigen (HLA)-B*15:02 allele. The relative risk increase was shown to vary between genes and drugs but could be more than 100-fold higher in Asians. The resulting adverse events that are more prevalent in Asians range from reduced drug efficacy to severe cutaneous skin reactions.

Extrinsic factors (e.g., diet and lifestyle), socioeconomic factors, environmental influences (e.g., amount of sunshine, and air and water quality), as well as differences in medical practice, may have an impact on the pharmacokinetics (PK) of certain drugs in Asian populations.

Because of these differences, drugs were generally developed in Asia on a timeline that was different from the Western regions of the world. By the late 90s and early 2000s, a drug development time-lag of as much as eight to 10 years was observed by consumers for drugs (many for the most critical indications such as cancer and heart disease) to reach Asian markets.

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