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International Clinical Trials

The Final Step

Once a sponsor has completed research on clinical trials, and believes enough evidence is available on the safety and effectiveness of the new drug, the final step of the development process is to submit an application to regulatory authorities to gain approval for marketing the product. The application must contain data outlining the technical specifications of the product, as well as statistical analysis demonstrating the safety and efficacy of the new molecular entity as evidence of the acceptable benefit:risk profile.

Application Models

Developing these applications can be costly and timeconsuming. By starting the product development process with the eventual marketing application in mind, sponsors can streamline development and more efficiently submit new products for consideration by the regulatory authorities. The end-to-end standards provided by the Clinical Data Interchange Standards Consortium (CDISC) can help optimise not only individual clinical trials, but also the marketing application process.

While many companies are familiar with the study data tabulation model (SDTM) and analysis data model (ADaM), the protocol representation model (PRM) and clinical data acquisition standards harmonisation (CDASH) standards are not as well known, and have seen less adoption in the industry. Yet both of these standards offer the promise of increased efficiency in the overall clinical development programme, as well as the eventual marketing application process.

Additionally, planning early and periodically about what needs to be included in the integrated summary of safety (ISS) and integrated summary of efficacy (ISE) – two documents required for marketing applications in the US – can help ensure that upon successful completion of clinical studies, all the data needed to convince the FDA that the product is safe and efficacious will be available.

Protocol Representation Model

The PRM was developed to support the generation of one overall protocol development database, to serve as a single-sourced downstream electronic content piece to aid with all clinical study documents for a programme.

With PRM, companies need only start from scratch on the first protocol for a compound’s programme, rather than developing de novo a separate protocol for each individual study because protocol information is stored in one data library. It also facilitates standardisation across studies, leading to more straightforward analyses when it is time to develop the ISS and ISE for the marketing application. The tool enables one to observe additional efficiencies through a reduction in both review cycle time and protocol amendments.

While PRM requires an investment of time at the outset, the model can save significant time for all subsequent studies – making it more attractive for new molecular entities, rather than compounds with previously initiated studies. A great potential for efficiency exists – taking information, quantising and then capturing it in a database for repetitive use in a series of protocols is a good idea – but the industry has not yet seen significant adoption of the model.

This low adoption rate can be attributed to several factors – primarily the requirement for a sponsor to implement a major process change to initiate protocol development. This learning curve, as well as the fact that only 10-20% of compounds entering human studies eventually make it to the market, gives companies pause for thought when asked to modify established processes for early stage activities. At the outset of a programme, protocol development teams need to consider PRM as an option, with biostatisticians, data managers and regulatory scientists serving as advocates to convince traditional protocol initiators of PRM’s advantages in order to facilitate the eventual regulatory compliant SDTM and ADaM data requirements.

Long-Term Cost and Time Efficiency

CDASH describes CDISC’s basic recommended data collection fields for 18 domains found in most clinical studies, including demographics, adverse events and other key data points that will eventually be included in the marketing application. CDASH is also being extended into a host of therapeutic areas to capture therapeutic areaspecific data. If data is gathered in the CDASH format, it will be easier to get it into the required SDTM and ADaM formats. Although some conversions may still be needed when using CDASH, there will be fewer, the process will be faster, and it will be less expensive. The FDA will require all studies initiated after December 2016 to be CDISC-compliant.

While there may be initial cost savings by not capturing data in CDASH format, if conversion is required these savings are lost entirely, as time for conversion is introduced and costs are increased in the long run. Sponsors must weigh up these risks early to help prepare for a smooth marketing application process.

ISS Submissions

Planning for ISS submissions is difficult at the outset – there is no good way to know exactly which safety concerns may present themselves during the course of development. Each product class has different safety concerns, and each individual product may have its own specific toxicity to consider. In general, neural, cardiovascular and respiratory considerations are among the most concerning safety events. However, nonclinical toxicology and Phase 1 studies are the ideal time to start identifying target organs that might arise as safety concerns.

The ISS must report back on all relevant safety signals. CDISC standards keep the variables associated with safety signals, their values and their meanings consistent, which makes it easier for sponsors to combine studies and data from subgroups – key factors in a successful ISS.

ISE Submissions

Where ISS submissions log every relevant safety consideration, ISE submissions offer a targeted look at efficacy and require a great deal more specific analysis. Every product is different, so the most important data points to consider will vary significantly from one compound to the next. However, key across all new products are the primary clinical endpoints the sponsor has agreed on with regulatory authorities. Presenting clinically meaningful results as demonstrated by the statistical significance of these primary clinical efficacy endpoints is important in determining if the product is approvable.

When drafting an ISE, these primary clinical endpoints results can be pooled from multiple studies, providing a powerful statement of efficacy – as long as the data being pooled was collected in an analogous fashion from a homogeneous population. Trials that are designed similarly – such as a group of studies utilising the PRM, for example – have a greater chance of enrolling compatible subject populations with the assessments of identical clinical endpoints.

Pooling data from two or more studies with similar subject populations and identical clinical endpoints provides more statistical confidence than analysing each study separately. For example, combining two large Phase 3 studies with similar subject populations and identical clinical endpoints with 800 subjects each allows an ISE to analyse 1,600 subjects, rather than 800 from each study. The FDA requires two adequate and well-controlled studies for each drug – by combining the results, more robust evidence of efficacy can be gathered.

If ISE analyses are not examined until the marketing application is being drafted, it might be too late in the development process. By considering the end analysis from the beginning of development, sponsors can evade problems with combining data, and avoid conducting studies that do not directly address the marketing label. The result is a much more convincing argument of the benefits and risks of the product seeking marketing approval.

Start at the End

By beginning with the end in mind – what the final, printed label on the compound will look like – and utilising the full complement of CDISC standards, companies can improve the efficiency of clinical development programmes and the marketing application process. By using the PRM, CDASH, SDTM, and ADaM throughout the development programme, sponsors can ensure that variables have the same meaning and attributes across studies, thereby facilitating the pooling of data and ease of assembly of marketing applications.

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David Shoemaker is the Senior Vice President of R&D at Rho, where he ensures efficient compliance with applicable regulations and guidance documents. He holds a BSc in Chemistry from Trinity College in Connecticut, US and a PhD in Physiology and Pharmacology from Duke University.
David Shoemaker
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