Mark Walker - Senior Technical Director of Toxicology at WuXi AppTec Laboratory Testing Division
Introducing a new drug candidate to market is a complex and time-intensive process that can cost pharmaceutical companies $1 billion and more than a decade of research and development. Coupled with the fact that only about 11% of new drugs make it from discovery to clinical trials - and only about 1% of them ever make it to consumers’ medicine cabinets - drug development is clearly a risky endeavor.
Every drug candidate must demonstrate safety and efficacy to gain U.S. Food and Drug Administration (FDA) approval, but not all drugs are created equally. A drug’s therapeutic area will often determine the length of time and financial investment needed for development. For example, oncology and immuno-modulatory drug candidates typically require greater resources than dermatology ones, but no drug development process should be considered risk-free.
Product reformulation, safety/efficacy concerns and unforeseen ADME characteristics can derail a program during early-phase development. But one of the most overlooked, and perhaps most perilous, risks to any drug development program is poor team management and ineffective partnership.
Following fundamental de-risking tips like protecting timelines, having the right leaders in place, knowing where to start and putting together a submission strategy, drug developers can mitigate risks and improve the quality of preclinical work.
Protect the Development Timeline
One of the most significant steps in a drug development timeline is progressing a molecule into the pivotal clinical trial stage and filing an Investigational New Drug (IND) application with the U.S. FDA.
IND packages require exhaustive safety and efficacy data about each molecule, including any information gathered during discovery, development and initial testing. U.S. FDA regulators will expect to see all available data related to purity, potency and stability of the drug, as well as any data garnered during DMPK/ADME studies. Regulators will also expect any salient information related to manufacturing the drug, including any substances that may have been present and detailed descriptions of processes used. Finally, the IND application should include detailed plans and rationale for executing clinical trials and information about the clinical investigators tasked with conducting them.
Drug developers bring various levels of experience to this stage, and like any project that requires collaboration, the quality of the team often determines the outcome of the game. If everything goes smoothly, a molecule’s IND program should take about 12-15 months to complete. The timeframe operates like a Gantt chart - projects and processes are moving in parallel to achieve a single goal. One of the biggest mistakes developers make when constructing the timeline is failing to anticipate delays, errors or unfavorable test results. Building in reasonable time buffers can mitigate challenges like these and allow developers to recoup time in future stages.
Laboratory testing partners can help protect the timeline by providing their experience. Understanding molecule sensitivities and analytical methods - especially when it comes to dosing concentration and systemic exposure - requires significant time and expertise. Planning for these time-intensive processes can make or break a test program timeline. Moreover, producing and scaling the first molecules can be a delicate and expensive undertaking. When the time comes for in vivo studies, laboratory partners should understand how to purify the molecule and develop sufficient quantities to conduct those tests. Letting a laboratory partner handle the technical work and set expectations for testing outcomes alleviates a burden for developers and generates an achievable timeline.
However, sometimes even the best, most thorough timelines get derailed. Failing to understand the expectations for manufacturing and purifying molecules is one of the primary reasons this happens. Likewise, failing to understand the absolute quantities of the molecules needed or quality standards to meet can cause significant delays.
Factors that could potentially derail an entire program occur when fundamental steps are missed or ignored. For example, suppose a developer realizes too late that they cannot scale manufacturing or that they cannot optimize the technique needed to obtain a specific molecule. In either case, the impact on the program could be disastrous.
Identifying and working back from important dates is another way developers and partners can protect the timeline. Whether the dates are regulatory deadlines, anticipated test results or recurring payments (for developers working with venture capital firms), knowing when certain milestones need to be met can help pave the path forward.
Appoint Strong Leaders
Building the right internal and external partnerships helps de-risk a drug development program by defining clear roles, identifying success metrics and establishing accountability. Part of building an agile team is appointing a leader - or a leadership group - and empowering them to make fundamental decisions that may impact overall program success. That said, the leader (or leadership group) must value input equally.
For example, leaders must voice and address concerns about pharmacokinetics or biodistribution as soon as they appear, as they can impact every subsequent step. Conversely, test article selection may only happen early in the process but can massively impact the program timeline if not given its due consideration. The primary goal of any drug development team should be to have everyone working in concert and ready to collaborate if and when problems arise. A collective sense of humility does not hurt, either.
Overconfidence within appointed leaders can make team dynamics more challenging and stall development. Self-aware leaders should always be asking themselves if they have the right pieces in place. They should continuously monitor internal and external capabilities to ensure the team they have built can complete the tasks necessary for success. For example, in-house regulatory specialists or toxicologists may be rare for all but the largest drug developers. Leaving those members off the development team becomes a serious problem if those services are needed to move the program forward. Situations like this are where external partners can be extremely valuable in filling gaps in knowledge and expertise.
The amount of time and money invested in developing a drug requires team leaders who are equal parts strong, savvy and self-assured. They need to inspire and motivate their teams to ensure everyone is hyper-focused on achieving program goals.
Start With the Right Strategies
There is no denying the impact a strong leader can have on a drug development program. Their experience, personality and vision are crucial to success. One of the most important qualities of having a clear vision is knowing where to begin. Starting with the right studies and processes will answer any glaring questions and identify fundamental flaws before the molecule gets too far down the development pathway.
De-risking a drug development program should always start with chemistry, manufacturing and controls (CMC). Knowing how to match, manufacture and purify a therapy beyond the tiny original amount used for testing is essential for determining the path forward. The most promising test results do not mean much if the drug cannot be manufactured or purified in a financially and biologically responsible way.
In vitro and in vivo studies like ADME and DMPK studies can be very informative in developing early-stage insights. ADME studies will reveal a drug’s behavior in a biological system and demonstrate how the behavior may differ from species to species. Making species-based assumptions using outdated strategies or because it is “standard industry practice” is a mistake that IND-enabling studies like these can correct.
DMPK studies consider biotransformation and other pharmacokinetic properties to assess drug safety. Key findings in these studies include the time it takes for a compound to clear the human body without producing harmful side effects or dangerous exposure levels.
Regulators will be most interested in a compound’s relevance to human populations, thus each step in ADME and DMPK studies builds toward that understanding. The efficacy and toxicity data generated during IND-enabling studies cause much of early-phase drug development failure. Regulators require these data as part of an IND application, so these studies ultimately support safety by helping developers decide on the feasibility of moving forward with their molecule.
Preformulation is another valuable early-phase strategy for identifying fundamental areas of concern with a drug candidate. Preformulation work identifies and characterizes the physicochemical properties of a compound. It helps ensure the volume and composition of a molecule are biologically compatible with human patients. For example, the best cancer drug ever created is not viable if it does not dissolve in substances found in the human body.
Preformulation requires unique expertise to understand which chemical components are compatible with the human gastrointestinal (GI) tract or can be injected into the skin without damaging cells. This work also helps establish formulations that protect biologics from being metabolized too quickly.
Basically, pre-formulation work seeks to develop the formulation to get a compound to the right place without producing toxicity or destroying the drug during absorption and distribution. Preformulation requires a wealth of experience, so developers who do not possess the capability in-house may find collaborating with a laboratory partner particularly useful.
Figure Out Where to Submit
After establishing the timeline, building the internal and external teams and appointing the right leaders, it is time to kick off the test program. But often, knowing where to start depends greatly on what has already been done. Developing specific molecules can be filled with high expectations or market demand, but the key consideration should always be whether it meets its therapeutic target.
Establishing a regulatory strategy, including knowing which agency and department to submit to, can also influence program design. Laboratory testing partners can help developers navigate the regulatory landscape, but resources are available for those needing additional information. The U.S. FDA’s Office of Infectious Diseases (OID) facilitates and fosters early communication between regulators and sponsors. It can provide pre-IND advice on issues related to:
- Required data to support the rationale for testing a drug in humans;
- Design of nonclinical pharmacology, toxicology, and drug activity studies, including design and potential uses of proposed treatment studies in test article models;
- Required data for Investigational New Drug (IND) applications;
- Initial drug development plans
- Regulatory requirements for demonstrating safety and efficacy
Developers will submit to either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) based on the product’s molecular structure or mechanism of action. Knowing which U.S. FDA center to submit to will help developers design their program, prepare for the pre-IND meeting and develop the overall strategy.
CDER regulates most protein-based biotherapeutics, including monoclonal antibodies and their derivatives (i.e., bispecifics and antibody-drug conjugates), fusion proteins, endogenous replacement therapies and nanoparticles. CBER, on the other hand, regulates all cell, tissue, and gene therapies, bacterial and viral products, blood and blood products and vaccines.
Orphan drugs, or those used to treat extremely rare diseases, are an emerging priority for the U.S. FDA. Orphan drugs undergo an additional step in the regulatory pathway given their priority status. Sponsors can request orphan-drug designation for their drug product, or the U.S. FDA can choose to grant the designation based on the product’s therapeutic target. Once a product is designated an “orphan drug,” it undergoes the same scientific review process as other drugs - but sponsors receive various tax and financial benefits upon approval.
Take Advantage of the Opportunities Available
There is a tendency among drug developers to want to blaze new therapeutic trails alone. While admirable, isolation is not the answer when it comes to drug development. Collaboration with partners and scientific community members can provide invaluable guidance and alleviate procedural and regulatory headaches. Developers working in rare or unmet-need diseases will likely find incredible support in the scientific community.
Finally, developers need to be realistic after taking stock of organizational capabilities and identifying gaps in knowledge or expertise. It is not worth wasting valuable resources on a testing program that is missing key components, or worse, is fundamentally flawed.
The Final Word
The drug development process is designed to produce a safe, efficacious drug that meets regulatory requirements and provides a health solution. With all the moving parts inherent in early-phase development, uncertainty and risk are everywhere. Derailed timelines, dysfunctional teams and inconsistent molecules are all possibilities. But developers need to understand that they are not alone. An experienced laboratory testing partner can help identify problems, sidestep pitfalls and successfully navigate the regulatory landscape.
About the Author
With more than 25 years of preclinical toxicology experience, Dr. Mark Walker provides technical and scientific support, enhancing WuXi AppTec’s ability to handle technical questions with a quicker response rate for our international clients. Dr. Walker’s professional focus and strength are in primate toxicology and integrative toxicology program design and regulatory interactions for Investigational New Drug (IND) applications.
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