The route a new drug takes to market is long and costly. Time and money saved along the way by improving processes is valuable. Bearing in mind that the cost, both in terms of time and lost market opportunity, when a drug fails in late-stage development is so significant, it is very important to be able to predict problems early in development and either 'develop issues out' or move on to more promising candidates. In this environment, companies are well advised to invest more time and analysis in earlier stages of clinical development in order to reduce costly late-stage failures.
So what are some of the issues facing drug developers today?
Oral drug administration and simplified dosing, ideally once-a-day, is the holy grail for many companies. Research has consistently shown that once-a-day administration positively impacts on patient acceptability, and improves compliance and commercial success. But it does present significant development hurdles. Many candidate compounds exhibit less than ideal pharmacokinetics and a modified release (MR) dose form is often required. The number and complexity of variables driving the choice to develop a MR formulation, and the number of options available once that decision has been made, make this a very challenging process.
Developers have long relied on making and testing different formulations, comparing the results and then modifying and retesting. Following in vitro characterisation, formulation prototypes are traditionally tested in animal models first, with a smaller number then going forward into man, following regulatory approvals. But as costs rise and timelines are compressed, this two-stage iterative approach is becoming less viable. In addition, data suggests that the initial animal models are often a poor predictor of a drug's performance in man (Fig.1).
New approaches are now emerging to help. Specialist early development companies with integrated GMP/GCP facilities offer rapid and flexible make-test protocols, and can manufacture a new formulation and test it in-clinic within 24 hours. This can reduce the time to develop a new dosage form by as much as 50 per cent, and significantly reduce costs. Fig.2 presents a comparison of the traditional approach and an alternative model in which formulations are administered to volunteers in the clinic within 24 hours of manufacture.
Where issues of bioavailability arise in these initial clinical studies, a new human data-driven approach can help to move development forward (Fig.3). The combination of Enterion regional absorption studies that provide a detailed picture of drug absorption, and intravenous microdosing studies that probe questions of absolute bioavailability, metabolism and drug-drug interactions, provide a reliable basis for decision making concerning a candidate drug.
This is a combination of new thinking and new technology. The technology is important (see box), but the power of the approach is realised through know-how and interpretation. We work hard to turn the early clinical data on a compound into valuable knowledge that informs the later stages of development.
So what difference can this approach make?
By carrying out regional absorption studies in a small number of human volunteers, it is possible to map drug absorption windows (Fig.4), understand solubility and permeability issues and evaluate gastrointestinal (GI) metabolism and transport for a new drug.
Microdosing of intravenous (iv) tracer 14 C-drug with simultaneous administration of non-labelled therapeutic dose by the intended extravascular route (oral, dermal or inhaled, for example) provides the opportunity to define full pharmacokinetics, volume of distribution, absolute/relative bioavailability and establish the metabolic fate of a prospective drug in man.
Drug-drug interactions, the routes and rates of elimination and potential 'developability' issues can also be evaluated.
These factors are usually assessed late in development. The lack of a clear regulatory requirement for the data, the need to manufacture an iv dose and the high cost of conventional studies have combined to provide a barrier to including this work in early development stages.
Now, innovative protocols and trial design allow these issues to be addressed early, and with minimal incremental cost. For example, by administering an iv 'tracer' microdose alongside ascending dose studies, researchers can effectively 'piggy-back' a study using Pharmaceutical Profiles ivMicrotracer on to their initial clinical trials.
In a significant move, regulators have accepted that tracer studies of iv formulations can go ahead without the extensive preclinical safety package normally required to support an intravenous regulatory submission.
Clinical studies at Pharmaceutical Profiles are performed under Medicines and Healthcare Regulatory Agency (MHRA) regulations.
Figures released for August 2008 show the average MHRA response time for clinical trial applications (CTAs) submitted is just 12.9 days (see www.mhra.gov.uk).
It's true that we are in the early stages here, but both industry and regulators are very receptive. Drug development looks set for radical change over the next few years. Many expect that the combination of rapid manufacture and early clinical evaluation will significantly reduce timelines, cut costs and lead to clear decision-making. This new paradigm is supported by innovative technologies such as Enterion for drug absorption studies, and ivMicrotracer for absolute bioavailability and metabolism studies.
As a result, development professionals now have the ability to effectively direct formulation strategies - informed by solid data from clinical studies in man.
Following completion of a programme designed to assess the suitability of a candidate for MR formulation, a director of one leading pharmaceutical company recently commented that the work Pharmaceutical Profiles had completed allowed them to put the idea of MR formulation 'to bed' approximately six months earlier than would have determined in the lab.
As a ballpark estimate, if you consider the compound under evaluation has the potential to be a billion dollar drug, then every day of launch delay costs around US$3.3million. Saving six months translates into sales in the region of $600million.
- Dr Andrew Rankin is Chief Scientific Officer, Pharmaceutical Profiles, Nottingham, UK. For more information, visit www.pharmprofiles.co.uk.
