The European Medicines Agency (EMA) has requested a label update to provide clearer guidance on the safe use of the anticoagulant Pradaxa (dabigatran).

The review has confirmed the drug’s positive benefit-risk balance as a stroke prevention treatment for certain patients, but stated the need for clearer notes on the medicine’s risks and what to do in case of bleeding.

The Boehringer Ingelheim drug is recommended for patients with non-valvular atrial fibrillation or following hip or knee replacement.

Because all blood-thinning drugs can cause bleeding, the EMA has maintained close post-market surveillance of this product.

The EMA’s scientific advisory committee, the CHMP, found that the incidence of fatal bleedings with Pradaxa in post-marketing data was significantly lower than in the clinical trials that led to the drug’s authorisation in 2008.

In November 2011, a safety review concluded that the drug should be used with caution, and at lower doses, with patients who were elderly or had moderate renal impairment.

Pradaxa “remains an important alternative to other blood-thinning agents,” the EMA said.

However, the guidance for doctors and patients should be strengthened to include details of the risks, when the drug must not be used, and how to manage patients if bleeding occurs.

In particular, patients taking Pradaxa should seek urgent medical attention of they fall or suffer any injury.

The European Commission is expected to confirm this opinion.

As the era of blockbuster drugs draws to an end, the pharmaceutical industry is looking to fresh markets and new models of drug development while facing legislative changes as well as economic threats. Sarah Hanson looks at what lies ahead for the industry in 2012.

2012 looks set to be the year when pharmaceutical companies face their scariest outlook: peering over the brink of a patent cliff. Major pharmaceutical companies are realising that they can no longer rely on a broken business model that is dependent on blockbuster drugs, and are looking for alternative ways to maintain profits and cover the loss of revenues due to patent expiry. This throws up a host of commercial, legal and regulatory challenges.

Entering new markets
Major structural shifts are taking place in R&D and how intellectual property is financed, meaning that the life sciences sector is providing a rare bright spot in the pervading economic gloom. Over the last decade, there has been almost US$700bn worth of deals in the pharmaceutical sector, which remains one of the prime industries in terms of M&A activity. Now we are likely to be at the start of a fresh cycle of M&A activity in the industry, with a particular focus on emerging markets (BRIC, South-East Europe and Turkey) where the portfolios of many pharma companies remain weak.

Japan has enjoyed a particularly busy year in terms of pharmaceutical M&A: across all sectors, cross-border acquisitions by Japanese companies nearly tripled relative to 2010. Liquidity among Japanese pharma companies remains strong, as does demand for prescription medicines from an ageing population, enabling Japanese companies to enter into deals at a time of intense competition for intellectual property in the industry. In 2011 Takeda, the largest Japanese pharmaceutical company, completed its €9.6bn (debt-free, cash-free) acquisition of Swiss drug company Nycomed. On the back of this transformative deal, we expect the industry to undertake more M&A activity in Japan in 2012. Factors such as the economic climate, demography and the state of R&D pipelines should see more Asian acquisitions of European patented drugs.

Emerging markets also continue to receive significant life science private equity (PE) investment, with China and India gaining the most. Historically, the risk involved in R&D has led PE firms to avoid large pharma companies and the biopharma industry in general. However, recently some small deals have linked PE and venture capital with biotechnology, and we are seeing investment in a number of diverse projects in different life science areas. This growing trend is already playing out in Europe – according to the European Private Equity and Venture Capital Association, the total investment in life sciences in Europe increased from €3.4bn in 2009 to €5.7bn in 2010, while the total venture investment in life sciences accounted for 30% of the total investment in Europe in 2010. Such funding is likely to increase as the cash-rich life sciences sector is seen to be ’recession proof’.

A helping hand for R&D
Pharmaceutical companies looking to weather the storm of patent expiry on key products are also looking to diversify their pipelines and develop replacement products. With most companies struggling to make a return on high R&D costs pumped into prospective pipelines, additional support is vital.

In the UK, the Government hopes its new Patent Box legislation will give a welcome boost to research and development. When it comes into force in April 2013, the Patent Box will reduce UK corporation tax on patent profits to 10%, encouraging R&D activity and providing incentives for companies to retain intellectual property in the UK. This will make the UK competitive with other European countries such as Ireland, Switzerland and Hungary, which have had similar systems in place for years. While the existing system of R&D tax credits has given some relief for R&D expenditure, there has until now been no similar incentive for businesses to retain their IP in the UK once it has been created.

Legislation such as Supplementary Protection Certificates (SPCs) will also play a significant role in assisting companies facing the expiry of major patent portfolios and provide more protection for companies investing heavily in R&D. EU patent offices have long been able to grant SPCs where there has been a large gap for a company between filing a patent application and getting authorisation to market a drug. However, legal issues surround how SPCs apply to medicines that contain more than one active ingredient. In a landmark case in November 2011, the Court of Justice of the EU said that there is no reason why an SPC may not be granted for a single active ingredient that is specified in a patent where the marketing authorisation also contains other active ingredients. This (and other recent cases regarding SPCs) is likely to have further ramifications in battles between generic and pharmaceutical companies into 2012.

New legislation: help or hindrance?
New legislation coming into force will also have an impact on the pharma industry in the year ahead. Whether the expected IP and regulatory legislation will help or hinder pharmaceutical companies in this challenging climate remains to be seen.

A number of significant regulatory issues are being debated in Europe. A Directive is being developed to improve the EU pharmacovigilance system, simplify regulatory decision-making, provide a legal basis for more proactive pharmacovigilance by both regulatory authorities and the industry, and involve patients more closely in reporting adverse drug reactions. Though it was adopted in 2010, compliance is not compulsory until 2012. The legislation will bring about the most profound change to the legal framework since 1995, when the EMA was set up. The European Commission, EMA and Member States have been carrying out work to implement the legislation, but companies still lack clarity on many of the new obligations. It is likely that the new requirements will be introduced in phases beyond the original July 2012 implementation deadline.

At a time when social networking continues to grow and become part of the daily routine of many working lives, pharmacovigilance is particularly important. The pharma industry must recognise that social networking and reporting are taking on a rapidly-increasing significance in the marketing, discussion and exchange of information concerning drugs. There are pharmacovigilance obligations at all stages of the life cycle of a medicine and the process of drug monitoring; the pharmacovigilance system will need to take account of this, not least because the increasing use of social media also poses interesting questions around geographical legal jurisdiction.

Discussions continue about the introduction of a Directive that would require substantial changes to the regulation of clinical trials. In March 2010, the Chancellor of the Exchequer announced that the Government would review the UK’s implementation of the Clinical Trials Directive in order to reduce perceived gold-plating and to increase the proportionality of the system. The MHRA has stated that it intends to wait for the outcome of the European negotiations before reviewing and amending the UK legislation.
2012 may also herald significant changes in the way drugs are marketed. EFPIA in particular will be under the spotlight this year as the implications of amendments to the advertising of medicines become apparent. Currently, the advertisement for a medicine must be in line with the product’s Summary of Product Characteristics (SmPC). Hence off-label promotion is not allowed. EFPIA has approved an amended Code of Practice on the promotion of prescription-only medicines to, and interactions with, healthcare professionals.

The changes to the Code make allowance, for example, for the provision of a limited number of samples to healthcare professionals for a limited time (Art. 16).  Previously, following EU Directive 2001/83/CE, the provision of samples was not allowed (due to concern over inducement); but in accordance with national and/or EU laws and regulations, a limited number of medical samples may now be supplied on an exceptional basis and for a limited period. A reasonable interpretation of this provision is that each health professional should receive, per year, not more than four medical samples of a particular medicine that he/she is qualified to prescribe for two years after he/she first requests samples of that particular medicine.

A landmark year
Last year saw significant developments for the pharma industry – and for lawyers – which look set to continue through 2012. With deals such as Takeda’s acquisition of Nycomed in 2011, we expect the trend of commercial and economic power shifting eastward to continue. Increased diversification, coupled with regulatory hurdles, will set a challenge for the pharma industry. Whether companies will survive and thrive on this challenge remains to be seen as the year unfolds, but the structural upheaval felt as a result of life beyond the patent cliff is already being witnessed.

Sarah Hanson is a partner at CMS Cameron McKenna: the UK branch of CMS, a leading European provider of legal and tax advice.

Takeda Pharmaceutical will acquire Brazilian pharmaceutical company Multilab Industria for $246m in cash, plus up to $20m in future milestone payments.

The acquisition shows the Japanese company’s growing interest in high-growth emerging markets.

Last year Takeda bought Swiss company Nycomed for $13.7bn, boosting its access to European and emerging markets.

Earlier this year it purchased US company URL for $800m.

Multilab is a mid-sized pharmaceutical company selling branded generics and OTC drugs, with an annual revenue in 2011 of $69m.

Among the products Takeda will gain is Brazil’s leading OTC cold and flu medication, Multigrip.

The acquisition, expected to close by the end of September, will place Takeda among Brazil’s top 10 pharma companies.

“This acquisition significantly reinforces Takeda’s position in Brazil, which is the world’s sixth largest economy,” said Jostein Davidsen, Corporate Officer, Head of Emerging Markets Commercial Operations at Takeda.

“Takeda has ambitious plans for growth in emerging markets. Brazil is our second largest emerging market after Russia/CIS and the acquisition of Multilab is a clear signal of our intention to become a significant player both in Brazil and other high-growth markets.”

Mylan has launched a generic version of Roche’s Bonviva tablets for the treatment of osteoporosis.

The Ibandronic Acid Film Coated Tablets have been released on the day the patent for Bonviva expired.

Didier Barret, Mylan EMEA President, said the manufacturer is “excited” to add the tablets to its portfolio of more than 350 products in the UK.

The treatment is used in postmenopausal women with osteoporosis who are at an increased risk of fracture.

The drug had sales of around £7.5 million in the UK for the year ending March 2012, according to IMS Health.

Mylan, the first company to launch a generic Ibandronic Acid formulation in the UK, recently launched the product in Spain after Bonviva’s protection expired there.

The UK pharmaceutical market is expected to experience slight growth over the next five years, a report predicts.

Research from IBISWorld found that until 2017-2018 the industry is predicted to post annual revenue growth of approximately 1.8%.

Arna Richardson, IBISWorld industry analyst, said the UK pharmaceutical market is “particularly important” to the national and global economy.

The report found the UK is the eighth-largest pharmaceutical market in the world. It also plays a vital part in the UK’s economy being the third-largest contributor to economic growth.

IBISWorld forecast that revenue will be around £18.9 billion in 2012-2013 – a 2.7% increase on the year before.

However, the combination of intensifying global forces and growing internal pressures due to the fallout from the NHS reforms will be translated into further pressure over the next five years and stunt growth.

Pharmaceutical companies will also have to contend with a wide assortment of issues, the report warns, as they adapt to the changing economic and operating environments in the UK.

The Welsh Government has decided not to adopt a Cancer Drugs Fund (CDF), but rather to rely on existing mechanisms to ensure patient access to cancer therapies.

Health Minister Lesley Griffiths said the fund, currently used in England to ensure patient access to non-approved medicines, was at odds with an “evidence-based” approach.

He also claimed that early diagnosis, surgery and radiotherapy were all higher priorities for cancer patients.

Speaking to the All Wales Medicines Strategy Group, Griffiths said: “A Cancer Drugs Fund would not be in the best interests of people in Wales. We already have robust mechanisms in place to ensure access to non-approved medicines is consistent for patients in exceptional circumstances.”

More contentiously, Griffiths claimed: “There is no evidence a Cancer Drugs Fund improves the quality of life or survival rates.” It would undermine the Group’s attempts “to deliver evidence-based advice on new treatments,” he argued.

“The available evidence does show survival is more closely linked to early diagnosis while surgery and radiotherapy are more likely to influence survival, and it is on these issues we should focus.”

The CDF allocates £200m per year to the NHS for 2012 and 2013 to ensure individual patient access to certain non-approved drugs prior to the introduction of value-based pricing at the end of 2013.

Details of the proposed configuration and member practices for 212 Clinical Commissioning Groups (CCG) have been published for the first time by the NHS Commissioning Board Authority.

The outline shows shadow CCGs now cover the whole of England, and their progression will gather pace as each organisation moves towards authorisation.

Dame Barbara Hakin, National Director of Commissioning Development at the NHS Commissioning Board Authority, said it was a “real landmark moment” in the development of CCGs.

The 212 commissioning groups range in size from 68,000 registered patients up to 901,000.

A number will need to be renamed under regulations which state CCGs must include ‘NHS’, the geographical area and ‘CCG’ in their title.

CCGs will now be authorised in four separate waves by the NHS Commissioning Board Authority – 35 in wave 1; 70 in wave 2; 67 in wave 3; and finally 40 in the fourth wave before April next year.

“We should not underestimate the hard work that has taken place to get us where we are and the huge progress that has been made across the country,” said Dame Barbara.

“We have proposed CCGs covering the whole of England. We have 212 groups of practices who have chosen to come together to shape and commission services to deliver better care, better experience, better outcomes and improved safety for their local populations.

“There is still a great deal of work to do as the proposed CCGs move closer to authorisation, but we should take a moment to celebrate this fantastic achievement.”