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Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.
Mark Egerton, PhD, chief executive officer of Quotient Sciences, shares insights on a new approach to accelerate drug development, which integrates formulation development, real-time adaptive GMP manufacturing, and clinical research within a single platform.
As the pharmaceutical industry faces increasing pressure to accelerate drug development, many contract development organizations are recommending early development programs. In this Q&A, Mark Egerton, chief executive officer of Quotient Sciences, discusses current roadblocks in the traditional drug development process and explains how productivity can be improved and timelines shortened by implementing a new approach the company refers to as Translational Pharmaceutics.
PharmTech: What can delay novel therapeutics from getting to market?
Egerton: There are many factors that can delay the development and eventual commercialization of novel therapeutics. One of the most intractable factors is the conventional trial-and-error approach to new drug development, under which the drug developer typically decides upon a fixed formulation type and two to three dosage strengths in the preclinical phase, often before completion of toxicology studies.
To advance the molecule into first-in-human (FIH) clinical trials, the drug developer then must invest significant quantities of drug substance, which may be in scarce supply, in preparation of large batches of each of these dose strengths as a means to provide sufficient quantities and flexibility of drug product to cover the early development program. When that molecule fails toxicology, or if the selected drug product format turns out to be suboptimal following clinical dosing, the drug developer must start all over again, which will require obtaining regulatory approval for a redesigned trial with a modified formulation or dosage strength. Each iteration of redesign, resubmission, and re-evaluation can significantly delay marketing authorization and commercialization.
PharmTech: What are the challenges in developing novel therapeutics?
Egerton: One of the biggest challenges in today’s environment is the sheer competitiveness of the marketplace, in which it is imperative for innovator companies to deliver first- and/or best-in-class medicines. That pressure has increased the emphasis on new molecular targets and disease mechanisms that offer the potential to deliver breakthrough therapies. However, due to the very nature of translational science, the majority of investigational programs will fail at or before proof of concept (POC), resulting in high attrition rates in Phase II.
PharmTech: What are the current roadblocks in the traditional drug development process? What strategies can be implemented to remove these roadblocks?
Egerton: Some of the most significant roadblocks in the traditional drug development model are of an organizational nature. Current organizational structures and processes are such that many innovator companies and service providers have consolidated into two vertically integrated supply chains: one focused on the making of test materials (drug substance and product) and the other focused on testing of those materials (preclinical and clinical). This strong demarcation of ‘make’ and ‘test’ functions, which has given rise to the contract development and manufacturing organization (CDMO) and contract research organization (CRO) industries, is suboptimal in terms of supporting early development because the transfer of drug product(s) between the two channels can be cumbersome and complex. For example, generation of sufficient stability data to achieve an extended shelf life and to accommodate the logistical inefficiencies between manufacture and dosing can result in significant delays.
Early development also requires considerable investment to manufacture a range of dose strengths at quantities to cover all eventualities in a clinical trial. In an outsourcing situation, the provision of drug product may require up to four different suppliers to cover drug substance supply, formulation development, clinical trial manufacturing, and packaging. The resulting siloed supply chain thus presents a significant management burden and timeline risk, especially when the chain breaks down and the incumbent suppliers are not focused on devising a solution.
Fortunately, horizontal integration of the ‘make’ and ‘test’ supply chains-by which these functions are outsourced to a single supplier-can enable the rapid and seamless manufacturing-to-clinic transfer of drug product, with manufacturing often completed within a 24- to 72-hour period prior to dosing. This approach, which we call Translational Pharmaceutics, can reduce development timelines and expenditures, in some cases by up to half of those of conventional approaches. More importantly, horizontal integration can encourage innovative thinking in the early stages of development, especially for processes preceding FIH studies or for subsequent optimization of the drug product prior to full development.
Another notable early-stage obstacle is the difficulty of forecasting the pace and location of patient recruitment. This can be especially challenging in the orphan and rare disease space, as well as for pediatric indications requiring small-scale, innovative POC trials. Rather than pursue the conventional approach of producing a large batch of product with an extended shelf life, horizontal integration can overcome this obstacle by enabling the manufacture of drug product on a per-patient basis. Under the Translational Pharmaceutics approach, a recruiting physician can contact the drug developer as soon as an eligible patient is identified, whereupon the manufacturer can produce the product for that patient, and deliver it to the physician for dosing within 14 days of patient identification.
Additionally, drug development programs can be derailed by poor solubility, an issue that affects more than 70% of small molecules in the industry pipeline. Under the conventional approach, a drug developer must make a judgment call as to which formulation technology to apply in the clinical setting based upon laboratory or preclinical data. However, horizontal integration of the ‘make’ and ‘test’ functions provides the flexibility to take multiple technologies into a trial, allowing the drug developer to choose the most appropriate technology to take forward, based on thorough analysis of clinical data.
PharmTech: How do you accelerate the drug development process and how can productivity be improved?
Egerton: Horizontal integration of the ‘make’ and ‘test’ supply chains allows for the adaptation and fine-tuning of the manufacturing process to the specific needs of a clinical trial. That is a key benefit that can yield significant reductions in the amount of drug product that must be manufactured (and, by extension, in the amount of resource, including drug substance, which is consumed in a trial), as well as in the lead time for manufacturing, ultimately condensing the drug development timeline.
A major advantage of horizontal integration is that the drug product dose and formulation can be adaptive in real time in response to clinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Armed with the timely analysis of those data, the outsourcing partner can go back to the manufacturing unit to produce the modified drug product, dose to subjects in the trial, and evaluate the clinical data anew. By repeating that cycle as often as every 14 days, the outsourcing partner can use the clinical data to intricately adjust the formulation such that by the end of the early development program, the customer has a drug product that is optimized for progression to the later stages of development and commercialization. Indeed, implementing the 14-day ‘make-test’ cycle can shave six months or more off a typical formulation development timeline.
PharmTech: What are the drivers and advantages of outsourcing drug development to CROs and CDMOs?
Egerton: To a great extent, the current wave of outsourced drug development has been driven by mega-mergers that in many cases have resulted in R&D budget cuts, site closures, and loss of in-house R&D personnel and know-how. Many large pharmaceutical organizations have recently entered into multi-year, multi-compound strategic outsourcing partnerships by which major elements of operational responsibilities and resources are transferred to a service provider, sometimes in conjunction with R&D facilities. For an innovator company, a major advantage of outsourcing to CROs and CDMOs is that the company can direct its investment toward attainment of key development milestones, rather than toward an internal infrastructure that may be underutilized.
PharmTech: How do you optimize and validate a formulation?
Egerton: The conventional approach to the development of improved drug product formulations uses separate CDMO and CRO providers to develop candidate formulations of a drug that can then be screened in preclinical and ultimately clinical studies. This approach results in longer development times and requires acceptance of (poorly predictive) preclinical PK data to determine which systems to take forward into a human study.
By contrast, Translational Pharmaceutics can accelerate access to clinical data more readily and allow accurate decision making in formulation evaluation. This application of Translational Pharmaceutics can also be used to optimize formulation composition by interrogating a formulation design space within a clinical study. This approach builds upon established International Council for Harmonization Q8 principles and allows products from any point within a continuous formulation composition space to be evaluated without having to submit multiple amendments to a regulatory authority.
PharmTech: Why is it important to integrate formulation development and adaptive GMP manufacturing with clinical research?
Egerton: Horizontal integration of formulation development, real-time adaptive GMP manufacturing, and clinical testing is especially advantageous in the early stages of drug development (defined as FIH through to POC). When a sponsor can outsource all these functions to a single partner that offers these capabilities under a single roof, with a single project manager, an integrated early development program can significantly ease the sponsor’s management and contracting burdens.
The integrated approach also addresses a major shortcoming of the conventional, multi-vendor outsourcing approach: the lack of operational or ‘know-how’ synergy between vendors, which can stymie innovation. Rather, under the integrated approach, the formulation development and drug product manufacturing specialists understand exactly what the clinical trial personnel need, and vice versa, fostering a consistent exchange of information.
PharmTech: Can you give an example of how the Translational Pharmaceutics platform was used in a development project?
Egerton: In one example, a sponsor development team was challenged to identify a new oral formulation of one of their compounds. The new formulation needed to be able to overcome solubility-limited absorption to improve bioavailability compared to the formulation used for FIH trials.
A formulation development program was conducted that identified spray-dried dispersion formulations as ideal for the compound, which were confirmed as superior to the preceding formulation through discriminatory dissolution testing. A series of demonstration batches of candidate formulations was manufactured under GMP to provide data for submission to the regulatory authority. Approval to commence recruitment for the clinical study was received in 14 days.
The candidate formulations were manufactured in real time and dosed to 10 healthy volunteers in a crossover trial, with significant improvements in bioavailability observed. In this program, the first subject was dosed with the new formulation just 20 weeks from commencement of formulation development. The total project duration from initiation to completion of the clinical phase was 28 weeks, minimizing the impact of the formulation program upon the development plan, thereby delivering both time and cost benefits.
Supplement: Partnerships in Outsourcing 2018
When referring to this article, please cite it as A. Siew, “Accelerating Early Drug Development with Translational Pharmaceutics,” Pharmaceutical Technology Partnerships in Outsourcing 2018 Supplement (February 2018).