Complex, innovative and novel: a recipe for successful drug development

As our Centre for Drug Development celebrates its 25^th birthday, we recognise the unique role Cancer Research UK plays in supporting early studies of anti-cancer therapeutics.

We look at some of the major achievements over the last 25 years, how the landscape of drug development has evolved and the impact our work is making internationally. As we enter the next quarter century of the charity’s support for drug development, we’re well placed to support the increasing breadth of therapeutics and are excited about the future potential for developing new treatments to improve the outlook for cancer patients.

A bleak history

For anyone unlucky enough to have been diagnosed with cancer in 1980, prognosis and treatment were very different to today. Cancer therapy relied on surgery, radiotherapy, and adjuvant chemotherapy with cytotoxic drugs, and whilst some of these treatments were very effective (and are still in use now), their side-effects could be horribly toxic.

The commercial arguments for making new anti-cancer drugs weren’t very strong; cancer was a terminal illness, and there wasn’t much profit in making drugs that patients would only take for a few months before they died. The first steps towards understanding the molecular basis of cancer were being taken, but the era where drugs targeted against particular molecules could become billion-dollar blockbusters was yet to dawn.

Breaking down barriers between bench and bedside

Many of the classic cytotoxic chemotherapy drugs, such as vincristine and cisplatin had been discovered in academic labs, and in the UK the Cancer Research Campaign (CRC, one of the precursor charities to CRUK) funded three major drug discovery labs – at the Institute of Cancer Research in London, the Paterson labs in Manchester, and Aston University in Birmingham. However, there was a big barrier between the lab bench and the clinic: promising candidates had to get from pre-clinical studies into phase 1 and 2 trials designed to demonstrate safety, dose, and efficacy before most drug companies would be interested, and the logistics – the facilities for bulk synthesis, toxicology, formulation and early clinical trials management – were missing.

To address these challenges, a funding committee was set up in 1982, the Phase I/II Clinical Trials Committee. Chaired by the dynamic and inspirational medicinal chemist Professor Tom Connors, the committee comprised key players involved in anti-cancer drug design, together with the clinicians who sought to use the new agents. Once the Committee approved a project, our Formulation Unit, established by CRUK at the University of Strathclyde, got the drug into a form suitable for clinical use and manufactured supplies; the CRC-funded Clinical Trials Data Centre at Charing Cross Hospital helped develop and manage the Phase I/II trial protocol and collect the trial data; and pre-clinical toxicology testing was undertaken. Potential drugs, many of which, as first-in-human compounds, would have been considered too risky a commercial proposition for a drug company, sped through the programme.

Birth of the CRUK Centre for Drug Development

By 1992, the Phase l/ll Clinical Trials Committee had acquired a reputation for fast tracking compounds into the clinic, with 32 drugs tested, and one, temozolomide, showing exciting activity against glioma. The nature of the drugs was changing too: targeted therapy was now the buzzword, and the Committee was considering proposals to test biological agents such as monoclonal antibodies, as well as rationally designed small-molecule drugs.

So that drugs could be taken into commercial development with as little delay as possible, a new expert resource was set up to ensure that all trials met the international standards of Good Clinical Practice. Under its first Director, Dr David Secher, the Drug Development Office (DDO) – the precursor to today’s CRUK Centre for Drug Development (CDD) – undertook to manage and coordinate development of all the drugs approved by the Phase I/II Clinical Trials Committee and the data management team was moved from Charing Cross Hospital to the DDO. In 1998 the DDO established the New Agents Committee, which took over the role of the Phase I/II Clinical Trials Committee in considering new applications.

In 2004, with the arrival of the EU Clinical Trials Directive, the DDO’s role became even more critical. Prior to 2004, academic clinical trials were conducted under light touch DDX (Doctors’ and Dentists’ Exemption) rules, which assumed these two groups would run trials that were in the best interests of their patients; however the new EU regulations were far more stringent. Whilst the DDO was already complying with established good clinical practice (GCP) quality standards, the requirement for the preparation of detailed scientific information in the form of Investigational Medicinal Product Dossiers (IMPDs) signalled a need to increase the scientific expertise in the DDO. The DDO, renamed the Centre for Drug Development (CDD) in 2015, now stands as a fully integrated, multidisciplinary development function that is globally unique in the non-commercial sector.

Expert navigation in a complex landscape

Today, led by Dr Nigel Blackburn, the CDD, staffed by 120 people, has a portfolio of around 25 drugs in development. The CDD works in close collaboration with the researchers, scientists and clinicians in our UK-wide Experimental Cancer Medicine Centres (ECMC) network, providing specialist expertise on every aspect of preclinical and clinical development for a portfolio of increasingly complex drug candidates. Once new projects pass the stringent scientific review of the New Agents Committee, which also factors in assessment of novelty and likelihood to deliver patient benefit far in to the future, a multidisciplinary CDD team assembles to design and deliver pre-clinical studies and clinical trials in close collaboration with experts in our ECMC network. It’s the CDD’s proud boast that they’ve never failed to get regulatory approval for a drug submitted to the UK’s regulatory body, the Medicines and Healthcare Products Regulatory Agency (MHRA).

A recipe for present and future success

Not surprisingly, the portfolio managed by the CDD has changed considerably over the years. Nowadays, the majority of CDD projects are collaborations with industry, forged through the innovative Clinical Development Partnerships scheme. The agents under investigation have also changed drastically. Now, more than half of the CDD portfolio are biological drugs – vaccines, antibodies, radiopharmaceuticals, cell therapies, viruses and recombinant proteins – a development that would have astonished the pioneers in the 1980s. The CRUK Biotherapeutics Development Unit, now located in a new start-of-the-art building opened in 2010, undertakes the manufacture of these highly complex biological drugs for early phase clinical trials.

At CRUK we are also tackling the challenge of how to run trials of combination therapies. Frequently, ideal drug partners belong to different companies, and there has been little appetite for joint testing. Commercially-sponsored trials involving drugs paired with radiotherapy have also been a rarity. Through the Combinations Alliance, a joint initiative between CRUK, the ECMCs and a growing number of pharmaceutical collaborators, combination ideas involving novel or marketed drugs, radiotherapy and/or chemotherapy are trialled in the ECMC network. Currently, 14 trials are open with six more being set up – five of these trials are radiotherapy combinations and one immunotherapy combination.

Throughout all this change, the underlying philosophy of the CDD has remained the same – to bring drugs that otherwise may not have been developed into clinical trials, to bring benefit to patients in need of new medicines.

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