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European Pharmaceutical Contractor

Look Before You Leap

As the volume, size and complexity of clinical trials in emerging markets reaches record levels, the demand for reference drugs – or so-called comparators – is soaring, putting supply chain professionals under pressure to source sufficient quantities of these products against tight timeframes and budget constraints.

In the competitive biopharmaceutical and pharmaceutical industries, comparators are increasingly being used in clinical trials to establish whether an investigational drug is more effective than an existing product – a differentiating factor that can be a prerequisite for formulary listing, healthcare reimbursement and even licensure.

Supply Uncertainty


While the growing demand for comparators is easy to explain, meeting the demand is not quite so straightforward. In a survey conducted in 2014, for example, respondents repeatedly raised the issue of comparators, with nearly one in four identifying comparator sourcing as a serious concern (1).

The same survey brought to light the apprehension surrounding supply chains in emerging markets. Explanations for this uncertainty were attributed to the challenges faced in sourcing comparators within these regions, magnified by the numerous obstacles to logistics and supply. In these countries, problems range from coping with language barriers and choosing reliable sourcing specialists, to guarding the integrity of the supply chain, managing evolving regulatory requirements and transporting temperature-sensitive drugs in tropical climates.

Overcoming these hurdles requires an integrated and strategic approach to comparator sourcing. Today – with two decades of globalisation under our belts – the one thing supply chain managers are certain of is that there is no one-size- fits-all solution for supply issues in emerging markets.

Trial Expansion


First, to provide some context. In the late 1990s, the biopharma industry embraced globalisation as a prescription for high drug development costs and sluggish research output. The industry found relief in many countries located in emerging regions of Africa, Asia, Central and Latin America, Eastern Europe and the Middle East.

Some of these countries offered remedies that included lower clinical research costs, rapid recruitment of naïve patients in targeted areas of research, and supportive regulatory environments. Another compelling incentive for sponsors was the opportunity to establish footholds in highly populated markets poised for economic development. A good example is China, where so many trials have taken place that the Chinese Food and Drug Administration (CFDA) now stipulates that firms must first be registered there (2).

The expansion of the clinical trial universe to incorporate emerging markets has ultimately been a resounding success. As of July 2015, the worldwide registry of clinical trials listed more than 194,000 such trials occurring in 190 countries – a number that has been climbing steadily (3). Today, clinical studies take place in over 30 countries, a large proportion of them characterised as emerging.

Two decades ago, sponsors considered many markets outside of North America, Western Europe and Japan as emerging, but perceptions are shifting. In an informal survey conducted in 2014 among supply chain professionals, the top three ranked emerging market destinations for trials were China, India and Russia. In the same poll, respondents revealed which emerging markets they found to present the most difficulties ‘from a clinical trial supply perspective’. The problematic nations identified were: Brazil (45.5%), China (42.4%), Russia (39.4%), India (18.2%), Turkey (15.2%), Mexico and Nigeria (both 12.1%) and Indonesia (9.1%). The other countries specified (21.2%) were mostly located in the Middle East and Africa (1).

Sourcing Advantages


There are many advantages to be gained by sourcing comparator drugs in emerging markets:
  • Value – as a rule, sourcing comparators in regions such as Asia and Latin America is less expensive than sourcing the same products in North America or Europe. Due to differential cost, local sourcing of comparators is preferred for open-label trials. Oncology trials, of which 80-90% are open-label, offer a good example: oncology drugs are considerably less expensive to source in emerging regions than in North America or the EU
  • Product availability – although it appears counterintuitive, sometimes a sufficient supply of comparator is available only in emerging regions. This could happen if the manufacturer of a product – slated for use in a competitive trial – tries to prevent or delay sourcing, thus erecting hurdles to trial initiation. In such cases, supply chain managers may not be willing or able to source comparators on the open market
  • Potential regional packaging and labelling advantages – while most comparators sourced in emerging markets are used for trials in those same countries, it may be cost-effective to source them in one emerging market for use in another region. This can, however, present regulatory issues. The ability to source comparators within an emerging region and label them in a single language for use across multiple countries provides ease of sourcing, and eliminates the need for many country-specific packs. Examples include packs labelled in Arabic for use throughout the Middle East, or Spanish-language packs for Latin America
  • Import restriction – the issue of sourcing in-country is not always a matter of choice. Import restrictions in some emerging markets – such as China, Russia and Ukraine – make it necessary to source study drugs locally. Sourcing drugs through the open local market reduces timelines, as well as the logistical and regulatory burdens required to import product
Operational Hurdles

There are a myriad of sourcing challenges to overcome in emerging markets, and clinical supply chain managers must do everything possible to mitigate them.

Business Partners

It is impossible to conduct a global clinical trial without an efficient, compliant and secure supply chain. In emerging regions, here are some of the most common obstacles:
  • Lower quality standards – some suppliers in emerging markets do not meet the same North American and European quality standards or requirements. For example, due to either a lack of understanding or concern, suppliers may not consistently adhere to temperature controls for cold chain products during storage and transportation. This is an issue of particular concern in emerging markets with tropical climates and limited infrastructure
  • Risk of counterfeit product – drug counterfeiting is a proliferating worldwide problem that affects both developed and developing countries. Over the past few years, an increasing number of counterfeits have been observed, with China being a major source. The WHO has estimated that up to 30% of drugs sold in parts of Asia, Africa and Latin America are counterfeit (4,5)
  • Documentation issues – product paperwork, such as certificates of analysis, can be difficult to obtain from some suppliers or may only be available in the local language. Documentation provided by a supplier is necessary for import/ export purposes, should a product need to be exported for repackaging and re-imported to a country for a clinical trial
  • Contractual and financial concerns – language and cultural differences in some Asian countries can lead to misunderstandings with suppliers about contractual issues. Translating a contract into the native language and carefully explaining its provisions to a potential supplier can help. Caution must be taken if a contract proposal is signed and returned too quickly. In such instances, it is likely that the supplier does not fully understand, or is unconcerned about meeting the terms. In addition, many suppliers decline to sign confidentiality agreements, and it is imperative to undertake financial background checks on suppliers, as pre-payment is often the standard way of doing business in emerging markets
  • Logistical issues – aside from sourcing drugs, choosing the right partner for freight and transportation can prevent a supply chain from unravelling. Some vendors with excellent on-paper qualifications may nonetheless fail to deliver – literally. It is important to vet courier companies carefully and monitor their performance within certain countries
Selecting Partners
Direct sourcing from the manufacturer is almost always the preferred route of supply because it offers the shortest and most transparent supply chain. Sometimes, however, sourcing from an innovator is neither feasible nor desirable for a number of reasons: the manufacturer is not present in those countries; stock is not available within the study timelines; or the quantities of comparator required are too small. As noted earlier, a sponsor may also not want a manufacturer to know about plans for a competitive clinical trial.

Under these circumstances, supply chain managers must turn to wholesalers or distributors to obtain comparators. Given the issues, it is important to work only with suppliers that have been carefully selected and vetted through a rigorous qualification process.

The qualification process should consist of multiple parts, including risk assessments of both the supplier and country of sourcing. Criteria for suppliers should include: reputation and referrals, licences, capacity, pricing and benefits, economic status and financial stability.

The country of sourcing is important because some markets are considered ‘safer’ than others. Such perceptions derive from international guidelines based upon the following considerations: level of Good Manufacturing Practice; Good Distribution Practice and Good Clinical Practice requirements; legal provisions on marketing authorisation; regulatory inspection of manufacturer and distributors; import control; licensing; and sanctions for violation of codes of conduct. A further method of assessment computes the frequency with which counterfeit drugs have been documented in the country, using information from the WHO and the International Medical Products Anti-Counterfeiting Task Force.

Product Availability and Pricing Considerations

It is easy to make assumptions about the availability of comparators, but for commercial and regulatory reasons, not every drug is available – in ample supply – in every market:
  • Drug availability – if availability is scarce, it may be impossible to source a particular comparator in certain emerging markets. Some governments decline to licence expensive drugs because they either cannot afford to do so or simply do not want to reimburse the cost. As an alternative, such governments will turn to generic products or lower-cost competing drugs. The bottom line is that, in some cases, it may be impossible to source a desired comparator locally, and so importation is the only option
  • Establishing equivalency – it is important to bear in mind that sourcing comparators from multiple countries requires data establishing product/dose equivalency
  • Pricing differences – when it is available locally, comparators are usually (but not always) less expensive to source in emerging markets than in the EU or North America. Costs may be higher in some parts of Asia and are almost always higher in the Middle East. In fact, the cost of comparators in the Middle East and North Africa region, which extends from Morocco to Iran, can be even higher than in Europe. Furthermore, volatile currency values – stemming from economic or political instability – can cause costs to go up or down rapidly. This significantly raises the likelihood of price increases for resupplies
Rules and Regulations
Faced with an increasing influx of clinical trials, some emerging markets are struggling to create the necessary infrastructure, while others are finding it difficult to build upon that already in place. As a result, there can be a mixed bag of unclear regulations which fluctuate, and although they are scheduled to change, resist all attempts to do so. Some examples include:
  • China’s reputation for bureaucracy is based on a complex web of government policies and regulations that constantly evolve. Conducting clinical trials here requires a great deal of patience. It can take as long as 24 months for the CFDA to approve a trial application – a delay that has a knock-on effect on supply plans (6)
  • Having previously announced plans to introduce export restrictions for pharmaceutical wholesalers, Turkey recently disclosed that it would not introduce these limits anytime soon
  • In one Eastern European country, the planned cancellation of an export restriction has been postponed repeatedly
The situation in some countries may be further complicated by political instability, as it has in Ukraine due to ongoing tensions with Russia. It is therefore worthwhile to keep up-to-date with current affairs in emerging regions; it is better to be prepared and plan for the risks of changing circumstances, than to be caught off-guard.

Some further points to note include:
  • Value-added tax (VAT) always requires consideration when the comparator is locally sourced and will not leave the country. VAT regulations differ from country to country, so it is important to keep up to speed with the latest rules to ensure compliance
  • Free trade zones (FTZ) – manufacturing and packaging supplies in FTZs, such as those in China and India, confer tax and duty-free status for studies taking place outside of these countries
  • Bovine spongiform encephalopathy (BSE) – to import products containing gelatin and/or lactose derivatives, the US, EU and some other countries require proof that the products are BSE-free
  • Invoices pro-forma – these documents state the value of clinical material in a shipment and are required for importation and re-importation, as well as when sourcing from third-party suppliers
Regional Idiosyncrasies
Among the most obvious obstacles to sourcing in emerging markets are the idiosyncrasies of daily life, from language and working patterns, to holidays and religious observances. Awareness of these factors, and a local presence on the ground in individual countries, can help avoid mishaps.

Avoiding Pitfalls

The fundamental facets of any approach to sourcing comparators in emerging markets belong to the stages prior to contact: it is all in the preliminary planning and sensible strategising.

Sourcing comparators for a clinical trial is neither a tactical nor purely a procurement issue. A strategic approach is one that is organised early on and customised to the particular market – preferably when a protocol is in development – to provide for maximum flexibility and multiple choices, in a bid to minimise risks and/or enable preparations for adequate actions to mitigate them. The ultimate goal is to manage the supply chain from day one, all the way through to the trial’s conclusion.

The task of selecting the right business partner should centre on each candidate’s track record of operating within emerging markets. It is vital that only pre-qualified suppliers and logistic providers – vetted through a rigorous qualification process – are up for consideration. The apt partner should offer a fully owned, integrated global approach to supply chain management – including sourcing, blinding, packaging, labelling and distribution – with a proven focus on quality and compliance. Consulting a trusted and knowledgeable partner, with experience of working in emerging regions, can pay dividends in the long-run, paving the way for future time and cost savings. Whenever possible, it is strongly advisable that your business partner heads straight to the source. By sourcing direct from the manufacturer, costs and the risk of counterfeit products are greatly reduced; it is the best way to guarantee reliable quality and quantity.

References

1. Pharma IQ, The Future of Clinical Trial Supply – Trends and Challenges Report, presented at Clinical Trial Supply Europe, Survey, 2015
2. Helmanis A, China to Require Registration of All Clinical Trials, Bioequivalence Studies, Regulatory Affairs Professional Society, 19 September 2013
3. US National Institutes of Health, 2015. Visit: www.clinicaltrials.gov
4. Blackstone E, Fuhr Jr J, Pociask S, The Health and Economic Effects of Counterfeit Drugs, American Health and Drug Benefits, 2014
5. WHO, 2012. Visit: www.who.int/ mediacentre/factsheets/fs275/en
6. Fisher Clinical Services, China: Land of Opportunities & Challenges for Clinical Research, Webinar, 2014


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Khaled El-Gendy joined Fisher Clinical Services in 2014 and serves as Associate Director – Head Comparator for the company. Khaled is a true believer in endto- end business models. He heads the comparator commercial team, designing and implementing tailored strategies pinpointing the needs of individual customers while developing and maintaining excellent relationships with suppliers. Prior to joining the organisation, Khaled spent 14 years at Roche, both in Finland and the company’s Basel headquarters, where he led global sales of clinical trial supplies to third parties.
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