With the increasing popularity of biologicals in clinical trials, difficulties are emerging when it comes to adhering to good distribution practice guidelines and multinational regulations. Clinical Trials Insight meets Rafik Bishara, chair of the Pharmaceutical Cold Chain Interest Group, to discuss strategies for the timely and safe delivery of biological products to trial sites.
The surge across the global biological medicines market over the last decade has been nothing short of remarkable.
Today, it is estimated that over a third of biopharmaceutical research and development activities carried out by the pharmaceutical industry are comprised of biologics, drugs that can be made up from proteins and nucleic acids, as well as cells and tissue.
Industry experts are confident that by 2016, ten of the top 20 bestselling drugs in the world will be biologics, and by 2018 they could account for almost half of the top 100 drugs by revenue.
There has subsequently been aspike in demand for biopharmaceutical clinical trials, bringing with it a set of logistical hurdles for pharma companies and trial sponsors.
First off, one needs to consider that in spite of their increasing popularity, awareness around biologics – in a clinical trial setting, at least – is still relatively limited. Sponsors are faced not only with high costs to finance trials, but also have to navigate the quandary of limited drug candidates.
An efficient supply chain management and logistics model is essential. In particular, these products require robust cold chain practices to ensure their therapeutic value is not compromised.
Industry bodies appear to be aware of the complexities of biologics in clinical trials. The FDA has issued a series of good distribution practice guidelines; and on a smaller, national scale, groups such as the US Pharmacopeia are drawing up a chapter on the handling, storage and distribution of biological clinical trial materials (CTMs). The latter is set for imminent publication.
While challenging, Rafik Bishara, current chair of the Pharmaceutical Cold Chain Interest Group – which operates within the Parenteral Drug Association (PDA) – believes pharma has made considerable strides in adhering to biologics guidelines.
"I am confident that the pharmaceutical and biopharmaceutical industries are doing their utmost to comply with the new and continuously changing demands and regulations with regards to how to handle, store and distribute clinical trial materials," he says.
Handle with care
But Bishara admits that is far from easy. The main hurdle, he says, when working with new clinical entities of a biological nature – such as vaccines – is maintaining the safe and efficient handling and storage of temperature-sensitive products.
"You need to ask the question: how is the clinical trial material being stored and does the clinical investigator have the proper storage facility?" says Bishara. "For example, if it says 2−8°C on the label that means the product needs to be refrigerated.
If it says to store below 30°C that means room temperature. Are those label conditions being followed by the investigator? You need to know."
Another salient factor to consider is the continuing globalisation of the clinical studies sector. Sponsors are now commonly faced with the task of transporting biological products to a large number of sites spread across several countries, contributing to the shorter availability of more complex products.
The requirement to source expensive comparators and meet varying patient demands in an international supply chain is no small undertaking. According to Bishara, the only way sponsor companies can achieve seamless delivery is through a more ‘glocalised’ approach.
"For a successful clinical trial, the industry – meaning pharmaceutical, biotechnology and vaccine manufacturers – need to familiarise themselves with the global regulations," he explains.
"We need to think globally and act locally. So, for example, if a UK company is planning to conduct clinical trials in Mexico, it needs to be aware of regulations respective to Mexico, while making sure that distribution of the product from the home nation is as safe as possible."
Ensuring the timely and safe delivery of products to trial sites remains the crux of the issue for pharmaceutical companies. For Bishara, handling, storage and distribution represent a triumvirate of metrics by which this can be gauged.
"You need to be able to determine whether there is any weak link in the supply chain, such as at the points of airport handling and customs clearance," he says.
"The industry needs to be aware of mapping the supply chain, which is about knowing where the weakest link is and addressing it so it doesn’t become a liability. This goes back to safe handling, storage and distribution, which form part of good clinical practice in clinical trials."
Specialised supply chain management technology
Making use of specialised supply chain management technology can certainly help in this regard.
Such systems – usually comprising material resource planning and interactive response technology – is able to provide bespoke (as opposed to cloud) real-time data to stakeholders, removing some of the age-old logistical headaches associated with running global clinical trials.
In effect, these tools enable sponsors to retain tight control over trials, while at the same time reducing timeframes and costs, and – most vital of all – matching clinical supply to patient demand.
"Risk assessment software is also a great tool to have," says Bishara. "It allows you peace of mind that when your clinical trial material is shipped out, it will reach its destination – whether that be the investigator, study nurse, institute or hospital – in a timely manner in the right condition. It offers a safeguard against mishandling."
Bishara believes biopharma clinical trials sponsors and investigators are spoilt for choice when it comes to data capture technologies – and consultancy services – already available on the market. Nonetheless, he believes take-up rates could be better.
"The tools are already there and developed well enough," he says. "That applies to the likes of ICH [International Convention of Harmonisation], which provides guidance over what to do and how to do it. It’s important to be familiar with and follow these recommendations."
The rise of biosimilars
So, what’s next for biologics in clinical trials? A growing trend in recent years has been the development of biosimilars – essentially identikit biologicals with the same active properties, but marketed after the patent expiration of existing drugs.
Driven by lower costs associated with these drugs, market demand is forecast to rise, creating new opportunities for biosimilar clinical development.
However, biosimilar manufacturers – unlike those that produce small-molecule generic drugs – are currently required to run comparator trials, during which their compounds are contrasted against originator drugs.
This, in turn, can constitute a major obstacle, as it often means that manufacturers have to obtain their competitors’ products for comparison – which companies naturally attempt to obstruct.
Furthermore, the timeframe for biosimilars is even narrower than for the clinical development of other medicines, because of the race to market before biologics patents expire.
Due to the aforementioned difficulties associated with producing biosimilars, some companies have opted to develop new-generation biobetters – new molecular entities related to existing biologics, but with improved safety, manufacturing and efficiency attributes.
In addition to carrying obvious advantages for patients, these improved drugs represent a better return on investment for developers. According to the Biotechnology Information Institute, there are currently 452 biobetters in development.
But returning to biologics, we are in the midst of a sea change. According to the Pharmaceutical Research and Manufacturers of America, in the US alone there are currently 907 biologics in development, with the view to targeting more than 100 diseases in the near future.
How such materials are handled in the clinical environment will remain crucial in terms of biological medicines making it successfully onto the marketplace. For that to happen, pharmaceutical companies will need to keep their powder dry and ensure they are in complete control of their respective supply chains.
Rafik Bishara is the current chair of the Pharmaceutical Cold Chain Interest Group (PCCIG), which operates within the Parenteral Drug Association (PDA). He spent 35 years with Eli Lilly and Company as director, quality knowledge management and technical support. Bishara’s current focus is on supply chain integrity and security.
The biggest biological players in 2014
- Humira − $12.54 billion: AbbVie’s adalimumab is a TNF-inhibiting, anti-inflammatory drug. It reduces inflammation in a range of conditions such as rheumatoid arthritis and Crohn’s disease.
- Remicade − $9.24 billion: Johnson & Johnson subsidiary Janssen Biotech’s infliximab was approved for the treatment of psoriasis, Crohn’s disease and arthritis.
- Rituxan − $8.68 billion: Roche-manufactured rituximab treats non-hodgkins lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis.
- Enbrel − $8.54 billion: etanercept is another TNF inhibitor that treats autoimmune diseases like arthritis, psoriasis and ankylosing spondylitis. It is co-marketed by Pfizer and Amgen.
- Lantus – $7.28 billion: insulin glargine is a long-acting basal insulin analogue that controls blood sugar levels of those with diabetes.