Volume 7 Issue 572 Journal for Clinical Studies

Drug companies must focus on quality if they are to reap the benefits - and reduce the risks - of comparator clinical studies. The pharmaceutical industry’s expectation for comparative effectiveness research continues to increase as international governments battle to contain rising healthcare costs - with payers, physicians and patients increasingly seeking evidence of how treatments compare in safety, efficacy and also value (HEOR: health economics and outcomes research) - the industry’s use of comparator trials is growing. The model for pharma R&D is changing, but so too is the regulatory environment that governs it.

In the past, in order to achieve regulatory approval, pharma companies have conducted clinical trials that compare investigational drugs to placebos. But in a competitive and cost-conscious commercial environment, where demonstrating value has become a primary objective, clinical studies must also include an active comparator if companies wish to claim superiority against competitors.

And in many cases, a compelling value proposition that can underpin market access and commercial success may hinge on robust comparative evidence. As a result, the trend towards active controlled, non-inferiority and equivalence trials has gathered significant pace.

But as the emphasis on comparative effectiveness research intensifies, companies know that to maximise the opportunity, they must develop robust systems and processes that enable them to source, acquire and supply clinical trial comparator drugs safely and optimally. It is a major challenge being played out against a very testing backdrop.

The global sector is under sustained pressure to increase the speed - but reduce the cost - of drug development, and at the same time remain compliant with stringent regulations designed to protect patient safety. In recent years, those regulations have been tightened further. New legislation in the EU Falsified Medicines Directive along with major revisions to Good Distribution Practice (GDP) guidelines in Europe and the Human Medicines Regulations 2012 in the UK and FDA in the US, are having significant implications for both the drug industry and companies involved in clinical trials supplies.

So the question for pharma companies is clear but critical: in a global market where the demonstration of comparative effectiveness can yield a significant competitive advantage, how do you source quality comparator drugs for clinical trials, safely, reliably and effectively? The commercial benefits are huge, but the implications of getting it wrong are - potentially - even greater.

Sourcing Comparators: Key Considerations Sourcing commercial drugs for clinical trials is fraught with risk - both in terms of financial and reputational damage for pharma companies. The quality, credibility and guarantee of supply are key imperatives. Common issues such as missing supply

deadlines, not being able to provide documentation to support licence applications or failing to assure the appropriate storage conditions in drug transportation can set a clinical trial back significantly - with subsequent economic costs, and implications for shareholders, patients and clinicians.

The supply of comparator drugs is a highly dynamic process that encompasses a range of important factors. Sourcing strategy, price and supply availability are important.

Likewise, documentation, lead times and, ultimately, the legitimacy of supply are even more crucial.

Developing and implementing a comparator sourcing strategy that mitigates risk, assures quality and remains compliant with evolving regulations is therefore critical.

Companies must determine whether they use single or multi-country sourcing from an authorised distributor, or source directly from a manufacturer. In recognition of the growing importance of comparator trials, pharma companies are gradually beginning to demonstrate a greater willingness to share documentation with competitors - but co-operation between manufacturers remains variable. Although some companies are naturally reluctant to make a drug, or documentation, available to a competitor who wishes to prove the superiority of their medicine, many now recognise the mutual benefits of greater transparency.

Equally, whether drugs are sourced singularly or locally, availability and volume is vital. Whilst small quantities are often available at a country level, it can be the case that there is insufficient volume to supply a larger trial. Once again, this can have significant repercussions - not least in extended delays, inflated lead times and, as a consequence, increased development costs.

Price too remains a major driver. As firms look to the supply chain for opportunities to drive down costs - and consider procuring cheaper comparator drugs from the open market - the increased focus on price could become a catalyst for an ill-advised compromise on quality. Sourcing a comparator from the open market or through complex supply chains may deliver short-term savings, but if quality or quantity is not assured, it could have expensive implications in the long term.

These implications could not only be bad for pharma companies and shareholders, but also, more importantly, for patients. It is now recognised that there are risks of falsified medicines in the legalised supply chain and reducing the complexity of that supply chain is one way of assuring that the right quality product is procured.

Sourcing directly from the original manufacturer or primary wholesalers of the manufacturer - via a specialist comparator supplier - is, of course, one of the safest and most effective means of sourcing quality.

The Incomparable Benefits of Assured Quality in Comparator Trials

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Sourcing from Outside the EU The most effective suppliers will have a full knowledge and understanding of the legislative environment that regulates the safe distribution of medicines. And they will have robust processes and systems in place that can not only prove and guarantee the highest standards of service, but also demonstrate similar proof of professional ethics and compliance amongst their supplier-base.

In a global marketplace, where comparator drugs can be sourced from all over the world, regulatory compliance is paramount - and it’s a complex regulatory picture. The EU Clinical Trials Directive (CTD) stipulates that a Qualified Person (QP) must sign off the release of every batch of products made for clinical trials, including cases where those supplies emanate from outside Europe.

Furthermore, the QP needs to be able to provide documentation which could prove that any imported products are compliant, equivalent to the EU’s Good Manufacturing Practice (GMP) - or, in the event that this cannot be determined, assure quality through obtaining sufficient information that the manufacturer is registered and approved under an equivalent system to the EU, and ensure that each imported batch is subject to appropriate tests to support confirmation of the correct quality.

The Falsified Medicines Directive also places much emphasis on the knowledge of the complete supply chain, from active substance supply through to finished product.

Sourcing from Within the EU When sourcing within the EU, the process is much more straightforward. In simple terms, a designated QP must confirm that every batch of medicinal product complies with the EU GMP and with the marketing authorisation; therefore, a comparator product sourced in the EU has had those checks performed.

However, recent revisions to EU GDP have once again strengthened the regulations. Ensuring that comparator drugs measure up is crucial in the long term, placing even greater emphasis on suppliers’ ability to maintain the traceability of every batch of product - and committing them to developing comprehensive audit and documentation processes that validate compliance throughout the life-cycle.

The latest EU GDP guidelines were enforced as recently as September 2013, and bring GDP much closer to GMP. They mandate companies to ensure a robust system of quality management is in place, to include the formal review of processes and measurement performance. There must also be a formal quality risk management system which can monitor and manage:

• Complaints and recall• Deviations • CAPA • Audits • Self-assessment • Emerging regulations • Changes in business environment and objectives.

The revised GDP guidelines also outline the legal responsibilities for key personnel, such as the Responsible Person (RP), and the need for all staff to be trained in GDP - including the EU Falsified Medicines Directive. In addition, key requirements include those around documentation - including items such as quality agreements within the distribution network. Also, areas around Falsified Medicines and Transportation have all been updated.

Moreover, the revisions make extended provisions for the use of brokers. Brokers are generally involved in activities related to the sale or purchase of medicinal products - though they never physically handle them. Evidence shows that a number of recorded cases of counterfeit medicine within the EU have involved brokers.

Under the terms of the guidelines, brokers must now not only be registered, but also comply with all other requirements for wholesale distributors, even though they have no product stores in their premises.

In truth, the use of brokers in sourcing active compounds for clinical trials can expose pharma companies to costly and unnecessary risks. The most effective comparator suppliers will have a demonstrable pedigree in engaging with credible suppliers, and will have developed sustainable relationships built on trust.

The Checklist for Quality With the pharma industry’s deployment of comparator trials growing steadily, companies have a duty to protect patient safety by ensuring they do all that they can to ensure they use only the highest quality comparator drugs. The ramifications of sub-standard or counterfeit products entering the supply chain are significant. As a consequence, the most reputable suppliers of clinical trial comparators will focus exclusively on quality, be fully cognisant of - and compliant with - global regulations, and ensure that they partner only with suppliers that can demonstrate equivalent standards and ethics.

Fundamentally, suppliers of clinical trial comparators have an obligation not only to ensure that their own processes are infallible, but also to perform due diligence on their suppliers too.

This requires conducting a bona fide analysis that the company supplying the medicine is legitimate. Do they have a licence to supply? Can they demonstrate that they have been inspected by an appropriate health authority? Can you be confident that they understand regulations such as GMP and GDP? And crucially, can they certify that the goods they are supplying are genuine and safeguard patient care?

The Future The pharmaceutical legislative environment continues to evolve. Moreover, regulations in the Falsified Medicines Directive, GDP/ GMP and the UK Human Medicines Regulations 2012 do not operate in isolation - they are part of a rich tapestry of legal frameworks that combine to support the safe development, manufacture and distribution of medicines for humans. Despite their undoubted importance, knowledge of these regulations - and their implications - can vary across the industry.

Volume 7 Issue 574 Journal for Clinical Studies

This can certainly be the case in some of the more commercially-focussed parts of pharmaceutical operations where, quite understandably, the focus on marketability, sales and profit is the primary concern.

But best practice examples show that the most successful comparative effectiveness strategies have been developed in companies where there is greater collaboration between commercial and quality assurance (QA) teams.

Certainly, commercial executives that work closely with QA to understand the regulatory environment are often best-placed to overcome the common challenges of comparator studies, and design trials that can help generate vital value-based evidence quickly and efficiently.

The biggest challenges in the effective management of comparative effectiveness research largely emanate from a failure to identify the most reliable partners to source high-quality comparator drugs. In a value-based economy, comparator trials are rapidly becoming the gold standard for drug companies desperate to demonstrate the superiority of their products. Data from such trials can significantly enhance a value proposition and generate key evidence to help brands achieve market access. But when managed poorly, comparative effectiveness studies can have damaging repercussions. For some companies, the current means of acquiring clinical trial comparators are inefficient, unpredictable and can leave operations vulnerable to unnecessary risk.

When comparators are sub-optimally sourced on the open market, it can lead to delays and supply disruptions. Failure to guarantee supply can have substantial downstream costs, with expensive implications for clinical trial operations, production and manufacturing, labelling, and distribution. In the process, development costs increase, speed to market is massively

compromised and profitability takes a major hit.

The damage to ROI is significant; furthermore, instances where sub-standard or counterfeit medicines get into the supply chain not only bring companies into major disrepute but, most important of all, can risk patient safety. And these are risks that are not worth taking.

The industry’s reliance on comparator studies is only likely to increase as marketers seek more sophisticated data to demonstrate brand superiority. But pharma companies must do all that they can to ensure their hard-earned reputations are not brought into disrepute by substandard practices in the procurement of comparator drugs. That is a huge price to pay for working with a supplier.

For best practice, drug companies should seek comparator partners that are fully cognisant of the regulatory environment and have processes and systems that can guarantee - and prove - compliance.

Saving money on a comparator in the short term may ultimately compromise quality further down the line - with highly expensive implications. The most effective suppliers of clinical trial comparators will be those that don’t bring you into disrepute - but instead focus on delivering the very best.

In a market characterised by comparisons, the benefits of quality are incomparable.

Dr Bashir Parkar is the Managing Director of BAP Pharma, who are a leading supplier of comparators for clinical trials. Bashir has worked in the pharmaceutical industry for more than twenty-five years, having held a variety of senior positions in both the scientific and commercial arenas. bashir@bappharma.com

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