Filing an investigational new drug application (IND) is a complicated process, and submitting to more than one regulatory body at a time adds a layer or two of complexity. However, taking the requirements of multiple countries at once can save a great deal of time and avoid rework down the road.
Outsourcing-Pharma (OSP) recently spoke with Mark Walker (MW), senior technical director of toxicology at WuXi AppTec Laboratory Testing Division, about the ins and outs of global IND application submission. With 25 years of preclinical toxicology and drug development experience under his belt, he holds a unique, informed perspective regarding the field.
OSP: Please tell us about your company.
MW: WuXi AppTec provides a broad portfolio of research and development (R&D) and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,000 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.
For drug developers, the laboratory testing division (LTD) of WuXi AppTec is a well-integrated group of functional units that focus on drug and biotherapeutic ADME, metabolite identification studies, bioanalysis, in vitro studies for potency and selectivity, and all in vivo studies required for investigational new drug (IND) applications to one or more agencies (i.e., FDA, NMPA, MHLW, or EU countries).
WuXi AppTec has several core strengths to provide customers, but what is great about the LTD it has the ability to conduct drug development programs for submission to the global marketplace. Our global facilities have all services needed to perform analytical, bioanalytical and specialized pharmacodynamic assays; these capabilities truly provide a multidisciplinary R&D service provider that offer various efficiencies, such as access to additional laboratory locations and redundancies that minimize changes of service disruptions or temporary resource limitations.
Further, our supply chain and materials transfer team is experienced with international permitting requirements and function as a center of excellence for WuXi AppTec.
OSP: What trends are you seeing in the early stage submission process? When did these trends gain momentum?
MW: More of our clients are working in a virtual setting and have limited to no capacity to conduct activities beyond lead optimization and selection. Outsourced research organizations and testing laboratories are becoming a more comprehensive partner in the drug development process.
In response, companies are enlisting their help for more significant portions of the overall project plan, such as manufacturing and CMC development, analytical method optimization and initial efficacy studies in transgenic test systems.
Other trends are generally due to adjustments from new regulatory expectations and interactions during the planning phases. The number of drug development entities aware of the importance of early discussions with the FDA is growing, and more companies are addressing in vivo studies sooner to avoid unnecessary experimentation or duplication of efforts.
Also, developers have been using smaller preliminary studies with a more targeted scope to more specifically evaluate mechanisms of action before the pre-IND meeting.
OSP: Please explain the process of dual filing global IND submissions and its purpose.
MW: First, drug developers are encouraged to proactively plan regulatory filing pathways, according to the requirements of each governing body where they intend to submit their IND package. This integrated and complementary scope of work can then be refined through a dialogue initiated with involved agencies to maximize the toxicological and clinical relevance of the data that is generated from the study plans.
After authorities conduct a cooperative review process, developers incorporate necessary feedback to the preclinical studies, accounting for any differences in study type or design. These steps minimize delays in the review process. For example, the relevant agencies can share information and resolve potential issues before they result in a loss of time and money. From this point on, drug developers begin the testing processes that support global IND submissions.
The dual filing process supports a streamlined path to approval with multiple agencies, and these gained efficiencies can save a developer valuable time and money. Additionally, the final IND package may grant the ability to perform first in human studies in numerous populations, with a significantly larger patient population.
OSP: What makes dual filing particularly relevant under current market conditions?
MW: Globalization has resulted in greater heterogenicity in the human population, and there is a growing opportunity to serve more patients with an urgent need for life-saving therapies. Also, there are unique biochemical differences in drug metabolism and inherent biodiversity of our world’s population increase the need to understand how a drug causes it desired pharmacologic effects, while understanding what toxic effects may occur.
There are also many logistical advantages to dual filing, as it provides the ability to evaluate more diverse patient populations, which will influence clinical trial design. Additionally, dual filing has fostered regulatory and scientific cooperation between countries, a valuable result for the industry and a positive impact on global health.
OSP: Why would a drug developer consider global IND submission? Are there particular compound or company categories that would benefit most?
MW: Many mid-to-large-sized pharmaceutical companies have a global footprint and can improve the penetration of new therapies by leveraging their presence in these marketplaces with a dual registration.
Alternatively, smaller biotechnology companies frequently approach the development of their molecules as marketable assets. For them, using a dual filing strategy makes the drug more valuable to other companies with greater size and resources.
Drugs that have a significant impact on the health and welfare of people around the globe, like those intended to treat cancer, neurodegenerative disorders, infectious diseases, and immunomodulatory drugs should be considered for submission to more than one authority. Using a dual or global drug registration strategy promotes international cooperation and drives harmonization efforts to bring therapies to more patients.
OSP: What steps should drug developers take if they are filing to multiple regulatory bodies?
MW: Drug developers should consider global filing in the early planning stages of their development plan. Weigh the opportunities and potential challenges to using this approach and determine how to manage the asset if the IND is approved.
Then, identify expertise gaps in regulatory affairs and safety assessment program design. Services of specialized consultants (i.e., regulatory affairs, biologics or small molecule development) are encouraged for their experience and skills in global registration.
Lastly, drug developers should become familiar with the regulations and guidance of each country where they are submitting the IND, as this enhances their understanding of how to anticipate any unique requirements.
OSP: What key differences in regulatory submission requirements should be considered for global IND packages?
MW: Varying regulatory requirements leave global submissions vulnerable to the details. Some agencies may require studies that are typically needed after IND approval, so careful attention to the scope of the IND program is essential. There may also be additional requirements for tabulating the salient elements of the study design and results (such as eCTD tables or report format).
Global INDs generally have a slightly larger work scope, and studies may need to address gender representation and reproductive toxicology earlier in the process. Therapies meant for unique populations (i.e., juveniles, pregnancy or lactation, infectious diseases, and oncology) may have different requirements based on the potential for developmental toxicity or residual, off-target toxicities.
Global IND packages proactively and explicitly address the regulatory compliance of all countries of submission. Submissions should focus on any differences in terminology, the roles and responsibilities of key personnel, study design elements, and documentation practices. Be sure to clarify the report format and submission process for each authority.
OSP: Are there common pitfalls you’ve witnessed during the dual filing process? Have these changed in the past year?
MW: The most common issues that arise with dual filings are insufficient planning and preparation, and bringing subject matter experts into the partnership too late in the process. These experts are needed to avoid incomplete assumptions and inaccurate budgeting, which both can lead to significant delays in the overall product development timeline.
When developers do not account for enough time for a proactive dialogue with regulatory agencies, delays occur due to insufficient communication. Finally, it’s essential to ask the question about the intended fate of the drug, because too often, the decision to seek dual registration is made after initiating critical studies.
The past year has been challenging and unique in many ways, unrelated to trends in the pursuit of global registration. The important achievements toward international harmonization of best practices have made the process less cumbersome. Since guidance has become more consistent, we have observed an increase in global filings, likely related to business plans and target populations.
OSP: What advice can you give to developers planning for global IND submissions?
MW: It’s important to approach the development of a new drug with an eye on the future; as with any business decision, there should be an analysis of the short, intermediate, and long-term goals for both the therapeutic focus and the most relevant marketplace for a new therapy. All of these decisions have a financial and resource impact, and making informed choices early on will not only minimize missteps, but will also lead to a clear understanding of your marketing plans.
Those planning global submissions should conduct a thorough gap analysis of their drug development progress, because there are real differences in the expectations of different regulatory bodies. Also, there are times when the scientific expertise (as it relates to safety assessment) regulatory submission experiences are not sufficient to meet your goals. Eliciting the help of experts in the field make this process more efficient, objective and targeted ultimately driving success.