Potential & Requirements for Clinical Translation
John Waterton1

1University of Manchester, United Kingdom


This presentation discusses clinical translation of novel agents. Firstly, the conventional diagnostic drug development pathway is outlined. Then six unconventional pathways are introduced and illustrated with examples from MR and other diagnostic imaging modalities.

Clinical Translation Overview

Novel agents are first characterised in vitro and, if promising, evaluated in animals, then translated into man. It seems difficult to justify the cost and ethical burden of chemistry and animal work, unless the ultimate goal is to improve human health.

Substances and devices introduced into the human body are strictly regulated by bodies such as CFDA (China), EMA (Europe), FDA (US), or MHLWPMDA (Japan). Approximately 95% of substances approved by regulatory authorities are therapeutic drugs. The rest are diagnostic drugs, mainly imaging contrast agents and tracers. Diagnostic imaging drugs have been approved for MR, CT/radiography, SPECT/scintigraphy, PET, ultrasound, and the optical imaging modalities.

Regulators have three concerns: Safety; Efficacy; and Quality. They need evidence that the medical benefits of the agent outweigh any risks or harms to patients who receive it, and evidence of consistent high manufacturing quality (Good Manufacturing Practice, GMP). Other diagnostic modalities which use innovative chemistries, e.g. immunohistochemistry or in-situ hybridisation, face lower regulatory burdens, because they do not expose patients to any risk of toxicity.

In Clinical Development the first milestone (translational gap 1) is regulatory approval to start clinical trials: Investigational Medicinal Product (IMP) or Investigational New Drug (IND) approval. The second milestone (translational gap 2) is regulatory approval to manufacture and sell the new agent: the Marketing Authorisation (MAA) or New Drug (NDA) Application approval.

A conventional pathway to market for new agents

1. A for-profit company acquires intellectual property (IP) to the agent, through either in-house discovery research or inlicensing;

2. The company raises funds for Development, either internally or from the financial markets;

3. The company demonstrates Safety and Efficacy (from clinical trial findings) and Quality (GMP) to regulators’ satisfaction;

4. Cost-effectiveness is often a fourth hurdle. The company must satisfy the payer that the benefit to patients (e.g. in Quality-adjusted Life Years, QALYs) outweighs the cost of the product e.g. in €/QUALY.

5. After regulatory approval, the company can sell the agent at a profit to radiologists or other healthcare professionals for diagnostic imaging of their patients. The company may only promote the product for indications approved by the regulator. Additional sales occur if the product is used “off-label” in other indications. Profits repay and reward the original investment. Most profit is made during the exclusivity period before patents expire.

6. If sales are low, the product is withdrawn from market.

7. If sales are high, generic competition may drive down prices after patent expiry.

8. Nanomedicines may retain effective exclusivity even after patent expiry because of confidential manufacturing "know-how".

Common contrast agents did follow this pathway1,2, but there are challenges:

  • Diagnostic agents, unlike therapeutics, do not benefit patients directly. Patients benefit indirectly if they are directed down a better care pathway. Hence it can be difficult to quantify the true benefit of a diagnostic to patients. If care pathways change (e.g. due to new treatments) the benefit of the diagnostic may disappear.
  • Regulators have become more concerned about risks of chronic toxicity from diagnostic imaging agents. Identification of rare delayed adverse events needs large trials with long follow-up, increasing development costs.
  • MR platforms change. Agents whose relaxivity is optimised at one field strength may become less effective as other field strengths are introduced.
  • The capabilities of non-contrast MR increase continually, and may overtake the putative new capability offered by the new agent.
  • Even if existing contrast agents are less specific than the new agent, if the old agents are sensitive and cheap (generic), they may out-compete the expensive new agent.
  • Diagnostic imaging competes with other diagnostic modalities. It is difficult for MR to compete on cost or safety grounds with sensitive, specific and inexpensive biomarker modalities such as circulating free DNA in oncology.

In response to these challenges, several alternative pathways to impact have been devised.

A. “The non-proprietary NDA”

Here, for IP or other reasons, there is no prospect of exclusivity after approval, and therefore no incentive for investors to fund the development. Instead, development is funded by government agencies or entities who do not expect a direct financial return on their investment. This approach worked for PET tracers such as fludeoxyglucose-18-F (FDG3,4).

B. “The everlasting IMP”

Similar to A, but with no intention of ever seeking marketing (MAA/NDA) approval and therefore no possibility of marketing for patient care. Instead, the agent is used under IMP/IND or similar authority solely in clinical trials. The substantial GMP costs are covered by the triallists. This is actually normal in PET, for example consider 11C-raclopride5 or 18F-fluoromisonidazole6.

C. “Raiding the Pharmacopoeia”

Here, a foodstuff or drug previously approved in a different indication is adopted as an imaging contrast agent. There are many successful MR examples such as iopamidol7, ketamine8, oxygen9,10, xenon11, glucose12, fructose13, or pyruvate14.

D. “Companion diagnostics”

Here, a proprietary therapeutic is co-developed with a proprietary imaging companion diagnostic. The regulatory authority requires that patients undergo the imaging diagnostic test before the therapeutic can be given. This case has favourable health economics, driven by the companion therapeutic. One disadvantage is that if the therapeutic development fails, it likely destroys the diagnostic development too. Imaging examples include: vintafolide plus etarfolatide15; [90Y]-ibritumomab plus [111In]-ibritumomab16; MM-302 plus [64Cu]-MM-30217.

E. “Unrelated therapeutic indications”

Here, an investigational MR diagnostic agent also happens to have therapeutic potential in an unrelated indication, and so the agent can be developed as a therapeutic. A couple of MR examples are tempol (radioprotectant18) and ferumoxytol (chronic kidney disease19).

F. “Theranostics”

Similar to E, but now the agent is diagnostic and therapeutic in the same indication. An obvious opportunity in nuclear medicine (e.g. 131I-iodide20), but capicitibine21 provides a possible MR example.


Clinical translation and development of novel molecular probes requires at least as much ingenuity as their design.


No acknowledgement found.


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Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)