Questions to Consider From the Beginning:
Drug development is a time and resource expensive proposition and most if not all companies pursuing such a path must find ways to make the greatest progress as fast as possible within their resource limitations. This article intends to help the reader understand some of the necessary considerations to achieve this efficiency by providing answers to these questions:
- How do we utilize limited time, money and talent to achieve the most value the most efficiently? How do we focus these resources on the critical questions and risks or opportunities?
- How do we assure that expended resources are delivering the intended product?
- How do we prepare for our final or intermediate submissions as the work are being conducted minimizing the turnaround time?
- How do we organize, manage, store and maintain the integrity of our data?
Keeping the End in Mind From the Beginning:
What are the attributes of a therapeutic product that are needed to achieve a successful launch and commercialization? How do the current marketed products stand up? What are the products in the development pipeline and how will they differ in hurdles and potential? Keeping the end in mind from the beginning is a fundamental requirement to achieving the ultimate goal effectively. Of course at first there are goals that must be met on the way to keep the ball rolling and the funds coming. How do these intermediate goals impact the ultimate success or failure of the intended product?
There are many approaches to creating a map for the final product profile. The FDA and industry have worked together to provide guidance on an approach to build and to discuss final product characteristics that will ultimately determine product labeling called the Target Product Profile. This can be used for discussions with regulators during the process of development to assure both the agency and the sponsors are on the same page especially during BLA and NDA preparation meetings. A separate article is provided that discusses this approach.
Each component of the TPP represents a question and a problem that need to be addressed about a new product and these can be prioritized and must be answered in an appropriate development sequence. In addition to development questions that lead to direct labeling statements are those questions that are inherent in the process or tasks. For example, safety and tolerability for single low doses of a new agent need to be established before studies on efficacy in patients following multiple doses can be endeavored. The degree of efficacy in comparison to the most appropriate standard of care at the time has a much higher priority and will impact to a much greater extent the ultimate success of a product than storage and handling instructions. Prioritization is key, which problems represent the most significant risk to ultimate success versus simple issues that must be addressed at the appropriate time as a matter of course.
To generate the answers to these development questions (some affecting directly the potential for a drug while others merely are required along the way) the appropriate studies need to be designed and conducted. Studies can be simple or complex, nonclinical, clinical or CMC. In some cases, exploratory studies must be combined with confirmatory studies to achieve a strong answer to a specific problem and achieve regulatory approval standards. A development plan represented in graphical or tabular form such as a Gant chart is essential. A method that I like uses a graphical representation of a sequence of decisions in a Bayesian network where each node can be assigned a cost based on the study design and a priori probabilities for potential outcomes. The model can be customized to specific therapeutic areas and calibrated by training with historical data. Using this approach one can diagnose where the product is most likely to fail to meet the desired profile and where the greatest cost efficiency exists, e.g., which study will reduce the most risk for the lowest cost? The object is to utilize this development map to target resources where they impact risk for success the most. This should allow achieving the ultimate target while helping to keep money flowing in as the probably of overall success increases.
As development progresses, this prior assumptions on the risks to development are updated with new results of studies, changes in the standing of competition or understanding of the disease or medical practice. The TPP can be updated as a result and used in discussions with regulatory agencies to assure that development is converging on the desired product profile.
How Do We Prepare for Intermediate and Final Submissions?
The information generated during the development of drugs and devices must be placed into the right format for a final market approval submission. It makes sense to place this information in a format and database that matches the regulatory requirements from the beginning, e.g., the eCTD, such that reprocessing and quality control costs are minimized. Any time data must be reformatted this introduces the opportunity for error and the requirement for quality control. This takes time and money.
A step in this direction is preparing for an IND or CTA submission using the same format. If submitting an electronic IND, the only choice of format is the eCTD format. A recent FDA presentation at the DIA is helpful to orient new comers to this format which continues to evolve. The electronic CTA in Canada is also in the eCTD format whereas in EU and other European and Asian countries CTAs are reviewed nationally and require specific national formats. After May 5, 2017, all FDA submissions must be in electronic format following the issuance of a binding guidance on eCTD submissions. Exemptions to these requirements include devices being developed under Center for Biologics Evaluation and Research. For the FDA, these submissions under 10 Gb are submitted to the Electronic Submissions Gateway (ESG). The current USA standard is the Module 1 (3.3 DTD) format. Once a submission is made to this standard all subsequent submissions must meet that standard as well.
Health Canada accepts electronic Clinical Trial Authorizations (CTA) in the same eCTD format. Going from IND to CTA or vise versa is readily accomplished by substituting a Module 1 according to Canadian requirements.
In the EU, the Clinical Trial Directive of 2004 initiated a process to harmonize a multi-national electronic CTA format. Whereas Market Approval Applications are in the eCTD format, CTAs are still national along national requirements for documentation.
The NDA or ANDA and MAA are in the same format, just with a lot more data on clinical studies and quality control, etc. Consequently starting down this path maintaining records in the eCTD format from the beginning means significant reductions in preparation time and expense. The current version of the eCTD in the EU is the Module 2, Version 3.2.2. The ICH is currently conducting a process to generate M8 V4.0.
There are a number of companies out there offering eCTD templates which are Microsoft Office compatible, already fully loaded with XML and Module 1 requirements for the USA, Canada, EU or Japan and able to generate the final PDF formatted electronic submission. Software is available that allows this information to be maintained and ready for incremental updates all the way through to market application. In addition, some of these offer the ability to convert to other formats including national CTAs.
How Do We Maintain Electronic Records and Signatures?
Sponsors are not only required to generate a large number and variety of documents but also to maintain records that can be audited by the FDA if and when needed. Converting to a completely electronic system of record keeping, quality control, signature and submission leads to very time and resource efficient business processes when compliant with 21 CFR Part 11. For countries where paper records are still required, these can be easily generated as secondary copies.
In a world where small companies including biotechnology companies cannot afford to have all the required talent and capability in house, having electronic documents and processes available through the Internet greatly reduces the burden of establishing collaboration and a distributed work force. Obviously, security needs to be tight for information that is highly confidential but there are good companies to help establish this at reasonable expense. There are services available to evaluate and audit web sites and systems once established.
The electronic and Internet based world of today allows small companies to leverage their talent and resources through very efficient processes and compete with big PhRMA companies that have significantly greater resources. We would be happy to consult with you to help you work through this approach.
Thomas W. Stephens, Ph.D. has 28 years of pharmaceutical development preceded by 12 years of in vitro diagnostic experience with emphasis in research, regulatory, project management and administration. In his spare time Tom pursue various interests including astrophotography, underwater photography, swimming, gardening and cooking.