Bringing new drugs to market is a very expensive business: typically it can cost over €500 million and – given time limitations on patents – the pharmaceuticals company then has just 5-10 years or so to recoup its investment and make a profit for most therapeutic areas.
Because companies need to maximise the potential sales opportunities for their products, before patents expire, it is vital to obtain approval and relevant product licences for the new drug in as many geographies as quickly as possible. Understandably, regulators in each country want evidence that a new drug is efficacious and safe for their particular populations, so it is essential that clinical trials are held simultaneously among a wide range of ethnic groups and patient lifestyles. This is a key reason why we are seeing clinical trials take place on a global scale with parallel and competitive patient recruitment in many regions. This requires improved planning and information from all parties involved to manage such complex projects with maximum efficiency and cost effectiveness.
Four phases of testing
Following preclinical testing within the laboratory, a new drug often progresses through four phases of testing. The first phase is usually a very small-scale (proof of concept) study with a handful of volunteers in a single location. Phase two involves tests to establish the optimum dose – which could involve studies in a dozen or so countries and perhaps up to 50 hospitals/investigator sites worldwide. Phase three is the major clinical trial stage to provide greater information to support a licensing application. This can involve many thousands of patients across perhaps 50 countries with 300 hospitals or more, each managing anything from five to around 300 patients. Finally, there is the ”Post-Marketing Surveillance” phase with a need for ongoing pharmacovigilence – continued monitoring of the trial.
In addition, the past few years have seen significant tightening in regulatory controls. There is now a raft of regulations and there is continued expansion of centralised laboratory testing, increasing the logistics complexity as patient samples are returned from the investigator sites to regional locations.
Many of the regulations on medication have originated from the EU but several are being adopted globally. These regulations embrace not just manufacturing processes and storage controls, but also the need for a ”Qualified Person”, for example, to take responsibility for ensuring compliance to drug production processes and integrity of product distribution throughout the supply chain.
Clinical trials are usually ”double blind” to reduce the chances of bias in patients or practitioners. This means that none of those involved know whether a particular patient is being given the active test drug, a placebo, or increasingly the active comparator (current ”best in class” medicine) with which the new product is being compared. Patients are generally enrolled into a trial by their consultants who use a voice or web response system (IVRS or IWRS) to register patient details, hospital location and so on. This information goes to a central global database and the patient is then assigned to one of the test groups. Patients are ”randomised” (number coded) to either an active or comparator patient group and the appropriate coded medication pack, for such group, assigned centrally so that no one involved in day-to-day running of the trial knows whether a particular patient is receiving active or placebo medication, thus maintaining the integrity of the trial.
This model presents several logistical challenges. First, it is obviously important to have the correct packages of medication (which are uniquely numbered and in a scrambled sequence) for each individual patient in the right place at the right time. Secondly, because the drug is still at an experimental stage, often there is limited stability data, which results in a high proportion of chilled (2-8oC) storage and distribution and comparatively short expiry/retest dates. Thirdly, medicines have to be distributed to a wide range of geographies at the time of year to meet study start; be it Riyadh to Siberia in summer or Sydney to Anchorage in winter – and distributed to the right place at the right time.
Medicines – active or placebo – are allocated centrally to each individual person in the trial with practitioners then advised which numbered package to dispense to which patients. Obviously accurate picking is important – but so too is the ability to rectify any mistakes quickly and efficiently. It is estimated that around 70 per cent of clinical materials produced for research trials are never used due to inefficiencies in forecasting demand in the supply chain. It is difficult to predict the pattern of patient recruitment to a trial so the traditional method of sending supplies in advance to a particular geography is wasteful and expensive – but with previously poor supply chain disciplines it has often been the only option available.
Truly global supply
Because of the global nature of trials and the relatively few numbers of patients in each geography, consignments shipped are generally small, so it is not cost effective to send a chilled truck to each trial site. Instead thermally insulated forms of packaging are needed: isothermic units that can maintain the drugs at the correct temperature regardless of the many different external climates they must pass through to reach their destination, for example in some regions regulatory controls require the need to assure temperature data in transit. The same applies to any storage facility as the consignment passes through customs and staging posts on its way to the trial site.
Typically pharmaceutical companies want a responsive supply chain with the drugs to reach their destinations within 24 or 48 hours: 72 hours can be just about acceptable for more difficult geographies, but speed is definitely of the essence. This is not a problem with the single EU market, but as soon as customs and cross-border traffic become involved successful distribution from a central single global or regional depot becomes totally unrealistic.
Contract Research Organisations
Until now pharmaceutical companies have largely depended on CROs – Contract Research Organisations – to manage their clinical trials. These are usually full service providers which have often been established by former pharmaceutical company executives. They manage the packaging and distribution of medicine and may also process research information and statistical data involved in the trial. These CROs are not logistics specialists and, as the demands of global clinical trials increase, they are finding it more difficult to manage the complexities involved. They ”bundle” logistics services using a number of third parties, thus increasing complexity and cost – occasionally at the expense of quality and responsiveness.
It is an area where 3PLs can not only fill a vital need, but also provide additional value added services. It is estimated that the global market for clinical trials logistics is worth around €1.4 billion a year and is growing at a conservative 16 per cent p.a. It is thus a very attractive business for 3PLs with a healthcare specialist knowledge to enter. It’s also an area where we can apply the skills and experience gained in handling other demanding supply chain models – from the environmental controls on chilled food to the short lead times of automotive products and high value electronics – to help streamline clinical trials management and thus improve product development and lifecycle management for the pharmaceutical companies.
From a pharmaceutical company perspective, however, logistics would seem to be of far less significance. On average only around 2-3 per cent of a pharmaceutical company’s overheads go on distribution. Telling the CEO you can halve this is thus unlikely to impress. More important is to point to the improvements in clinical trials management enabled by better logistics, improving utilisation of medication which is in short supply and designing an agile supply chain to reduce supply times, improving patient recruitment and compliance and bringing a new product to market at speed and thus into profitability.
Just as important for any 3PL entering this market is to have an established global network operation. That not only means good distribution to the countries involved in trials, but chilled pharmaceutical grade warehousing facilities in each of these geographies. It can take seven days to get through customs in Brazil, for example, and many parts of central and South America are almost as challenging. Equally, it can take 16 days to obtain an import licence in Israel and Russia and the Ukraine are both very challenging. Because patients are being recruited into trials competitively (each site does not have a defined number of patients but recruits as quickly as it is able within the study inclusion criteria) it is often very difficult to predict what the demand for medication – active or placebo – is likely to be. Supporting a just-in-time approach with minimal local stocks is vital – especially in the early stages of trials when supplies of experimental drugs can be limited. In some markets it is important to have local warehousing facilities, in others good relationships with customs departments to ensure fast tracking for these vital supplies: such attributes and understanding are only really deliverable by logistics companies with an excellent understanding of these geographies. Local regulations also change frequently, so keeping abreast of the right number of packing list copies, import licenses, certificates of origin and all the other vital paperwork required is essential.
Unless a company is continually working in these markets it is very easy to get the basics wrong and so increase import processing times significantly, thus leading to a delay in getting the right package of medicine to the right patient at the right time.
Full service Clinical Research Organisations may be experts in the regulatory nuances of clinical trials, but they do lack logistics expertise and in today’s global market that is what pharmaceutical companies need.
Chris Tierney is business development manager for clinical trials logistics at DHL Exel Supply Chain. Chris.email@example.com
- It is estimated that the global market for clinical trials logistics is worth around €1.4 billion a year and is growing at a conservative 16 per cent p.a.
- It is important to point to the improvements in clinical trials management enabled by better logistics, improving utilisation of medication and designing an agile supply chain to reduce supply times, and bringing a product to market at speed.
- When it comes to strategic outsourcing, cost and service benefits can be taken for granted – the key factor to look for is innovation. www.supplychainstandard.com
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