Over the past 15 years, the pharmaceutical R&D ecosystem has experienced a dramatic increase in the number of companies involved in drug development—from roughly 1,200 companies in 2001 to more than 3,600 in 2016—as well as in the number of therapeutic molecules in development—from approximately 6,000 in 2001 to well over 13,000 in 2016.¹

Yet as R&D spending has increased enormously, the industry continues to grapple with the problem of poor R&D productivity, as the majority of molecules entering drug companies’ pipelines fail to achieve marketplace success. Those failures are a major driver of the skyrocketing cost of developing and securing marketing approval for a new drug, which the Tufts Center for the Study of Drug Development recently estimated at $2.6 billion.²

As a result of the decline in R&D productivity, many drug developers are seeking new ways of making drug development more efficient and cost-effective through innovation, new technologies and process evolution. Those efforts have generated an explosion of multiple outsourcing initiatives over the last 10 years that have driven fundamental change in how the industry is structured.

Strategic change in the marketplace is largely occurring because most of the larger pharmaceutical companies are sourcing an increasing proportion of the new molecules in their pipeline from smaller entrepreneurial biotech companies, sometimes up to 50%.³ Consequently, there is a significant expansion in the number of biotech companies, often funded by venture capital, that are focused on a business model of developing a molecule through to the proof-of-concept (POC) stage, and then selling or licensing the molecule to a pharma partner. These companies have streamlined internal fixed cost operations to ensure that the majority of their capital is spent on value-enhancing drug development activities.

Outsourcing to siloed vendors
In addition, outsourcing has become increasingly tactical, as pharma companies continue to outsource specific functions that historically were handled in-house. As a result, outsourcing companies have become siloed along functional disciplines, spawning a profusion of firms that focus solely on activities such as discovery chemistry, discovery biology, preclinical toxicology and safety, clinical testing, and formulation development and manufacturing.

To progress a drug development program in the conventional outsourcing approach, the developer must therefore engage with multiple vendors—an imperative that creates a significant management burden, as there is little, if any, communication between vendors. For example, the contract development and manufacturing organization (CDMO) will seldom, if ever, talk to the contract research organization (CRO), and may have a limited understanding of the clinical trial design and endpoints the customer aims to deliver against. Similarly, the CRO may have little understanding of where the drug product is coming from, or of the product’s strengths and weaknesses in terms of how it performs in a human system.

This very labored and siloed approach results in very little operational or “know-how” synergy between vendors, compromising the pharma company’s ability to innovate the drug development process. Yet despite the limitations of this conventional approach to outsourcing, the process has remained essentially unchanged for the last 10 years.

Horizontal integration for synergistic service delivery
Fortunately, the early stages of drug development—defined as first-in-human through to POC—are particularly amenable to implementing an integrated platform that ties together formulation development, real-time adaptive GMP manufacturing and clinical testing. When a sponsor can outsource all these functions to a single partner that can offer these capabilities under a single roof, with a single project manager, an integrated early development program can significantly ease the sponsor’s management burden, as well as the contracting burden.

The integrated approach solves the problem of know-how synergy, as 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 and interplay into single projecting.

Horizontal integration of “make” and “test” supply chains allows the outsourcing partner to adapt and fine-tune the manufacturing process according to the specific needs of the clinical trial (see Figure 1). At Quotient Sciences, we have developed 14-day “make-test” cycles for our integrated Translational Pharmaceutics platform, in which the drug product is manufactured on Day 1 and dosed in the clinical trial on Day 2, or shortly thereafter. We can then evaluate the clinical data, and on the basis of that evaluation, decide how to modify the drug formulation composition or dosage strength. We can then go back to the manufacturing lab and produce the modified drug product, dose the modified product and evaluate the clinical data anew.

This integrated approach is even more powerful when the range of drug products that can be manufactured and dosed in a clinical trial is extended by the use of a multidimensional “design space” in the regulatory submission. A design space also overcomes some of the weaknesses of the conventional approach, under which a company whose manufactured drug turns out not to work in the clinical trial setting must start all over again and obtain regulatory approval for a redesigned trial with a modified drug formulation or dosage strength.

A design space allows the drug developer to inform a regulatory agency that the exact formulation and dose of the drug product to be tested are as yet undetermined but will fall within a certain range. The company can then obtain pre-approval to test any product within that range of parameters, without having to secure approval every time the company adjusts the dose or formulation. That flexibility then allows the company to manufacture and dose the first product, evaluate the clinical data and repeat the process with as many different products as necessary, as long as they fall within the design space, to identify a product with an optimized dosage strength and formulation composition.

The design space concept dates to 2007 when Quotient first proposed it to the UK Medicines and Healthcare products Regulatory Agency (MHRA). That first design space was two-dimensional, with dosage strength (low to high) along one axis and composition of the formulation excipient (also low to high) along the other axis.

Today, the concept is even more flexible and can comprise up to five dimensions. For example, in a multi-particulate product, it is possible to vary particle size (small, medium, large), along with different types of coating (polymer-coated vs. uncoated) and with coats ranging in different thickness. We now routinely include the design space in regulatory submissions to the MHRA and are in dialogue with the Food and Drug Administration (FDA) regarding bringing this concept to the U.S.

Time and cost benefits
Implementing this integrated approach can shave six months or more off a typical drug development timeline. For a drug product that is forecast to generate $500 million to $1 billion in annual revenues, such a time savings can save the customer millions of dollars per day.

Drug developers see direct cost savings, for example, because the integrated approach enables a limited amount of drug substance to go further than in a conventional program. Our process yields significant reductions in the amount of drug product that must be manufactured and, by extension, in the amount of drug substance that is consumed in a trial, as well as in the lead time for manufacturing. Typically, the integrated approach requires less than 15% of the drug substance that is used in a conventional early development program. That is an important advantage for a company with a molecule in the early stages of development, when the availability of a drug substance can be so limited that it must be rationed out to cover different activities.

One of the challenges of early-stage clinical trials is that the pace and location of patient recruitment can be difficult to forecast, especially in the orphan/rare disease space, as well as for pediatric indications requiring small-scale, intensive POC studies. In a conventional drug development program, the drug developer will likely be forced to produce large batches of product with an extended shelf life so that sufficient quantities of drug are always available whenever, and wherever, trial participants appear. That approach requires significant up-front investment and can lengthen the lead time of the overall program.

By contrast, the integrated approach enables manufacture of drug product to be adapted to the precise demands of the clinical trial. Where necessary, manufacturing can even occur on a per-patient basis. In an integrated program, a recruiting physician can contact the drug developer as soon as an eligible patient is identified, whereupon the manufacturer can start making drug product for that patient and deliver it to the physician for dosing within 14-days of patient identification.

Currently, the integrated approach works for small molecules designed for oral, inhaled or dermal delivery and is particularly well-suited for molecules with poor solubility—an issue that affects more than 70% of small molecules in the industry pipeline.⁴ Unlike the conventional approach, in which the drug developer must make a judgment call as to which solubilization technology to take into the clinical setting, the integrated approach is flexible enough to allow the sponsor to take multiple technologies into a trial and use clinical data to select the most appropriate technology with which to move forward.

Another advantage of the integrated approach is that the drug product dose and formulation can be modified in real time in response to clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) data. Dosing and formulation adjustments, informed by clinical data, can thus help the drug achieve an exposure profile that, ideally, delivers a positive therapeutic effect for 24 hours, thereby enabling once-daily dosing.

With 14-day cycles, we can use clinical data to intricately design the drug product 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.

Future directions
Whereas the integrated model is most appropriately applied in the early stages of clinical development, it also has potential applications in the later stages. At Quotient, we increasingly field inquiries from clients that would like to take the outputs of our early-stage Translational Pharmaceutics services to help them scale up their drug manufacturing processes as a means to support their later-stage activities.

Indeed, once our later-stage capabilities are more fully developed, we envision forging relationships with a large number of customers, working with them throughout their entire clinical development timeline, from the early stages all the way through to commercialization. As more drug developers realize the cost- and time-saving benefits of early-stage integration of drug development and manufacturing, we expect to see rising demand for these services as an end-to-end, all-stages offering, thereby streamlining these processes throughout the clinical development cycle. 

References

1. Informa Healthcare (2016). Blockbuster Trends and Rising Stars of Global R&D: Pharmaprojects Pharma R&D Annual Review 2016.
2. DiMasi, J.A., Grabowski, H.G., Hansen, R.W. (2016). Innovation in the pharmaceutical industry: new estimates of R&D costs. Journal of Health Economics, 47, 20-33.
3. Schuhmacher, A., Germann, P., Trill, H., Gassmann, O. (2013). Models for open innovation in the pharmaceutical industry. Drug Discovery Today, Vol. 18, 23-24.
4. Hauss, D.J. Oral lipid-based formulations. Advanced Drug Delivery Reviews 59 (2007) 667-676, and Quotient internal data.

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Mark Egerton, PhD, joined Quotient as chief executive officer in August 2005. With more than 20 years of experience in the pharmaceutical and biotech industry, Mark has worked in a range of organizations including large multinational pharmaceutical companies as well as private venture funded biotechnology companies. Mark began his pharmaceutical R&D career at Novartis (then Sandoz) in Switzerland and then AstraZeneca in the U.K.