Adeline Siew is the editor of Pharmaceutical Technology Europe. Adeline Siew joined the editorial team of Pharmaceutical Technology and BioPharm International in 2012. She has a pharmacy degree from the University of Strathclyde and a PhD in Pharmaceutics (Drug Delivery) from the School of Pharmacy, University of London, where she also did her post doctorate research. She previously worked as an editor at IMS Health and BioMed Central before joining Advanstar’s Pharm Sciences group.

Adeline Siew

	A team of scientists recently reported on the first study of interactions between the antiretroviral drug, amprenavir, and the HIV-1 protease enzyme. The findings provide the first true picture of how the protease inhibitor blocks viral replication. More importantly, the study reveal how drug design can be improved to enhance performance, combat resistance and reduce dosage of antiretroviral medications to treat HIV.

	The study was carried out using neutrons at the Institut Laue-Langevin in Grenoble, France, with results reported in the 

. A joint X-ray/neutron structure of the HIV-1 protease enzyme in complex with amprenavir was determined. According to Professor Irene Weber from the Department of Chemistry and Biology, Georgia State University, the neutron crystal structure provides important new insights into the chemistry of how drugs bind HIV protease.

	The HIV-1 protease enzyme plays a key role in the lifecycle of a virus and is one of the most-studied enzymes. It breaks polypeptide chains to create proteins used for replication and production of new infectious virus particles. Scientists have been using X-rays to investigate how to target and block the protease’s action in spreading the virus. X-ray analysis, however, has limitations because it cannot detect the hydrogen bonds between the enzyme and the inhibitor, which is the antiretroviral drug. Hydrogen atoms are virtually invisible to X-ray analysis and scientists are often left to speculate how this binding takes place.

	Scientists from Georgia State University, Purdue University and Oak Ridge National Laboratory in the USA and Harwell Oxford in Great Britain found a solution to this problem through the use of neutrons. Neutrons are highly sensitive to lighter elements and the team were able to identify the positions of every hydrogen atom involved in the enzyme-inhibitor complex for the first time and see which were involved in bonding.

	The neutron studies revealed a different picture to that inferred from X-ray studies, which had overplayed the importance of many of the hydrogen bonds. The team found only two really strong hydrogen bonds between the drug and the HIV enzyme. This discovery now presents drug designers with a set of new potential sites for the improvement of the drug’s surface chemistry to significantly strengthen the binding and hence increase drug efficacy and reduce dosage requirements.

	The findings may also help address drug resistance, which is one of the biggest issues in combating HIV infection. Virus can evolve over time with binding between enzyme and inhibitor becoming weaker. One solution is to improve the binding of the inhibitor with the main-chain atoms of the virus’ protease rather that to target the side chains.

	This research has changed the landscape of drug design of protease inhibitors. Advances in antiretroviral therapeutics were once thought to be limited by the strong hydrogen bond interactions with the main-chain atoms of the HIV-1 protease enzyme. However, this study has shown that it is possible to create new avenues for HIV medications that are much less affected by virus evolution and resistance.

	“This study perfectly illustrates the benefits of neutrons in drug design due to their unique sensitivity to hydrogen atoms. Until recently high-resolution neutron studies of large biological systems were restricted due to the size of crystals that needed to be grown and the length of time it took for the results to be collected. However, significant technical developments, led by pioneering work here at the ILL, have greatly extended the range of experiments that can be performed providing the pharma industry with a powerful new tool to improve the performance of their products,” commented Dr Matthew Blakeley from Institut Laue-Langevin in a 

	Dr Andrey Kovalevsky from Oak Ridge National Laboratory said in the same 

, “X-ray crystallography has been playing a crucial role in the structure-guided drug design for over two decades.  It provides us with a picture of how a drug molecule binds to its macromolecular target, which is usually achieved through non-covalent interactions between these two molecules.  The majority of such weak intermolecular interactions involve hydrogen atoms that normally remain invisible in X-ray structures.  If one knows where hydrogen atoms are located it gives a researcher a much better idea about the nature and strength of the interactions.  By applying neutron crystallography we have effectively increased the clarity of this picture, because hydrogen atoms become visible in the neutron structures.  It is fair to say that by using neutrons we are now able to see every atom in a protein/drug complex, all the way to the smallest atom in nature.  We are confident that by combining the two crystallographic techniques it will be possible to significantly improve the method of structure-guided drug design, which will provide patients with newer more effective medicines to not only battle HIV infection, but for other diseases as well.”

Articles

A team of scientists recently reported on the first study of interactions between the antiretroviral drug, amprenavir, and the HIV-1 protease enzyme.

Neutron Studies Reveal New Areas for Improvement in Drug Design of HIV Inhibitors

Craig Stobie from Domino Printing Sciences shares on how to prepare for FMD and other emerging legislation.

	The Falsified Medicines Directive (FMD) has finally been transposed into UK legislation. The FMD came into force on 20 August 2013. “It is now time for pharmaceutical manufacturers to walk the talk,” said Craig Stobie, global life sciences sector manager at Domino Printing Sciences.

	Compliance with the directive, aimed at safeguarding patients by preventing the infiltration of falsified medicines into the legal supply chain, has always been a race against time, noted Stobie, but now, UK manufacturers must stop playing the waiting game and start working with suppliers. However, according to Stobie, there are no solid examples for manufacturers to learn from given that there are only a few pilot projects that have achieved the full extent of the FMD. “Hence, building on trusted relationships with suppliers and industry experts will enable manufacturers to make confident decisions on how best to comply,” said Stobie.

	While it is tempting for companies to push investments costs into the next financial year, Stobie pointed out that it is key for manufacturers to realise that implementing serialisation is not a straightforward engineering job. “In some respects, it is similar to a regular installation, but in others, it’s vastly different.” For example, getting a serialisation-ready line back to ‘business as usual’ standards has proved to be a challenge in pilots, with high levels of rejects and low line speeds cited as key problems that take time to overcome.

	However, it’s not all bad, said Stobie. “Item level serialisation as a result of the FMD, if done well, will raise overall equipment effectiveness levels. Moreover, in addition to improving consumer safety, it can potentially increase patient engagement, leading to improved adherence and patient experience.”

	Stobie provided some insights on how to prepare for FMD and other emerging legislation. The first step is to get senior colleagues involved. Secondly, senior stakeholder engagement is essential because serialisation will impact most if not all business functions during implementation, with a dip in efficiency across all departments at real risk. “Getting your business leaders to understand this will go a long way to getting teams working together to make compliance a company goal,” said Stobie. Thirdly, companies should invest in training. “Make time to train engineers and operators in optimising lines and don’t be afraid to champion the idea of a pilot line for staff to work on,” Stobie added. Last but not least, companies must not be reluctant in sharing best practices. The directive is making an industry-wide impact and it will help to take a collaborative approach with other companies.

	Adopted in 2011 to prevent falsified medicines from reaching the open market within the European Economic area, the EU Falsified Medicines Directive (FMD 2011/62/EU) will no doubt change the landscape of the European pharmaceutical business model. The scope of the Directive places new obligations on all branches of the industry from manufacturers and generics producers to contract packers, re-packers and importers, amongst which is the unique identification of products at unit of sale level. Domino established a European Group in 2011 to help manufacturers comply with the Directive. The Group consolidates Domino’s expertise in pharmaceutical legislative compliance solutions and comprises specialists in disciplines such as legislative standards, validation of automated manufacturing good practice, code formats and serialisation.

Falsified Medicines Directive Enforced in the UK

Guest blog written by Adrian Tombling, partner and patent attorney at Withers & Rogers LLP.

	The US Supreme Court ruling in the so-called ‘Myriad case’ regarding the patentability of human genes will undermine global biotech investment but all is not lost. Judge Thomas, in 

Association for Molecular Pathology v. Myriad Genetics

, effectively tightened the rules on the patentability of human genes, finding that all naturally occurring gene sequences, even when isolated in the laboratory, are not patentable. In future, only non-naturally occurring gene sequences (e.g., sequences that have been modified or entirely created in the laboratory), will be patentable, and therefore, attract investment from biotech companies.

	Myriad currently produces diagnostic tests used to detect mutations of two gene sequences-BRCA1 and BRCA2, which have been linked to the development of breast and ovarian cancer. The ruling will invalidate some, if not all, of the patents that exist for these tests and could allow rivals to bring similar products to market. Furthermore, literally thousands of patents granted for naturally occurring gene sequences, such as BRCA1 and BRCA2, by the US Patent and Trade Mark Office (USPTO) since 1982 have been rendered invalid by this decision.

	Not only did the decision come as a disappointment but it will also undermine biotech investment in the US and around the world. Patents exist to protect the commercial viability of certain areas of research and without them, the research will simply not happen in future.

	While Myriad will be disappointed by this decision, the company can at least take solace from the fact that the patents on their diagnostic gene sequence tests are due to expire in 2014 and 2015, and hence, so they didn’t have long left to run. This decision will mainly impact pioneering areas of gene-related research linked to gene therapy, genetically modified crops and disease diagnosis wherein gene markers are detected.

	However, all is not lost. While the patentability of naturally occurring gene sequences will not be possible, biotech companies will still be able to obtain patent protection for gene sequences that have been modified or created in the laboratory. Furthermore, as most naturally occurring genes have already been sequenced and identified (e.g., the human genome was sequenced in 2003), the opportunities to identify new and commercially relevant, naturally occurring gene sequences are considerably smaller than in the 1990s.

	Investors and researchers must not be put off by the US Supreme Court decision relating to Myriad Genetics because in reality, little has changed from a research and commercial perspective. Although it is no longer possible to obtain patent protection in the US for human gene sequences, even when they have been isolated, it is still possible to achieve commercially valuable patent protection for genetic tests and other diagnostic and therapeutic inventions.

	In the immediate aftermath of the ruling in 

, there was, in some areas, confusion about what it would mean for biotech businesses. Now that the dust has settled, it is clear that the judge made an important distinction in determining that human gene sequences were not eligible for patent protection, whereas complementary DNA or cDNA, which is synthesized in a laboratory, could still be patented. Other elements required for performing genetic tests also remain patentable in the US. This means that the ruling is far less obstructive to biotech research than some may have initially thought.

	Since the ruling, Myriad Genetics has taken legal action against two rivals-Ambry Genetics Corp and Gene by Gene Ltd-for bringing new screening tests to market that allegedly infringe their patented BRCA-1 and BRCA-2 tests, which are used to detect a genetic propensity to breast and ovarian cancer. Myriad claims that its genetic tests are still protected by 515 of the 520 patents, which it had originally secured in the US. While Ambry has opted to countersue, Myriad is convinced that the ring of patent protection secured for its BRCA-1 and BRCA-2 screening tests is still valid and robust enough to withstand competitor challenges. In the meantime, investor confidence appears to be siding with Myriad Genetics.

	Interestingly, despite the share price for Myriad Genetics falling after the US Supreme Court ruling, it has steadily climbed since then, indicating that smart investors are not concerned by the ruling. The company has also recently forecast full-year results ahead of market estimates, which suggests they are not overly troubled by the ruling either.

	Any dip in investor confidence could undermine valuable research in this area and without good reason but the fact is that such screening tests can still achieve commercially valuable patent protection in the US. Therefore it makes sense for the industry to continue to develop them so they can continue to play their part in disease prevention and intervention in the future.

Myriad Ruling Will Undermine Global Biotech investment But All Is Not Lost

Guest blog written by Dr Nicholas Jones, partner and patent attorney at Withers & Rogers LLP.

	While it may not happen often, clinical trials can sometimes be halted by patent disputes, leading to costly delays in bringing new drugs to market. At last, the UK Government has decided to do something about this in a bid to make UK patent law more consistent with that in some other parts of the world.

	By the time clinical trials get underway, pharmaceutical companies will have already invested large sums of money in research and development activities, just to get to this point. The final stage required to obtain market approval is often a large, double-blind trial involving the use of a comparator drug, where the efficacy of the new drug is pitched against an existing one that is already in use. At this stage, when the new drug comes head to head with a current treatment, and when publicity surrounding the new drug reaches another level altogether, the risk of being sued for patent infringement may be greatest.

	If a patent-infringement action arises, for example because the new drug is alleged to fall within the scope of another company’s patent, the patent holder could seek to slap a temporary injunction on the new drug, ultimately seeking to block its passage to market. Sometimes the patent holder will be the manufacturer of the comparator, but not always. If the infringement action was successful, then significant costs and delay would be incurred and the financial implications could be devastating for the company that has invested so much time and money in getting so far. If the injunction was upheld, the only realistic course of action would be to wait until the other company’s patent protection expires before restarting the trial and attempting to bring the new product to market again, which would of course eat into its profit potential in the meantime.

	At a lower and earlier level in drug research and development, scientists are often unaware of the risks involved in carrying out experiments that involve the use of third party drugs, or drugs covered by third party patents. It is rare for a pharmaceutical company to initiate this kind of legal action. But it does happen.

	Most pharmaceutical and chemical companies will recall the case of ‘rapamycin’, an antifungal and immunosuppressant drug, which was owned by American Home Products (now part of Pfizer). Novartis developed an analogue of rapamycin and sought to carry out clinical trials of its analogue. American Home Products sued Novartis for alleged patent infringement prior to the analogue’s market entry and the case reached appeal stage in the UK before being rejected.

	In a slightly different setting, field trials conducted by Stauffer Chemical prior to the introduction of its version of the herbicide, glyphosate, were blocked in 1985 by an infringement action based on a patent belonging to Monsanto. Such trials, aimed at demonstrating product efficacy to a regulatory body, were considered not to benefit from the ‘experimental use’ exemption to patent infringement.

	Seeking to remove this risk, Science Minister David Willetts, is proposing to introduce an amendment to the UK Patents Act 1977, which will exempt clinical and field trials of innovative drugs from patent infringement actions. Backed by an existing EU Directive, which was applied in a restricted manner in the UK a few years ago, this broader exemption already applies in a number of EU member states, such as Germany, Italy and France. There are plans to implement it in the broader form in the UK in October 2013.

	Most intellectual property experts believe that current UK patent law in this area is perhaps out of step. An EU Directive known as the ‘Bolar provision’ was passed in 2008 and was implemented into national law in each member state. This Directive provides that trials necessary to get approval of a medicine should be exempt from patent infringement actions. Under the narrowest interpretation of the Directive, this could mean that only clinical trials conducted to support market approval of a ‘generic’ product would be exempt from infringement, and this interpretation was adopted in the UK.

	In terms of the planned amendment to the legislation, research scientists in the pharmaceutical and chemical sectors will be hoping that the extent of the exemption is made as clear as possible. They may also be hoping that the amendment will allow patented drugs to be used more freely in the laboratory, for example when setting controls to measure against. This could be a very positive move that would benefit smaller research institutions in the drug discovery arena as well as those involved in early stage research.

	Patent laws in other parts of the world pose less risk to pharmaceutical research and development activity than those that currently apply in the UK. In Germany, for example, the EU Bolar provision was implemented in the broader form from day one.

	Whatever the position internationally, the fact is that pharma companies and scientists undertaking drug research work in the UK may currently be doing so at some level of infringement risk. Urgent action is needed to address this issue to protect the commercial interests of companies that are investing time and money in the development of new medicines. This will also ensure that research scientists and companies involved in clinical trials in the UK can operate on a level playing field with those in other parts of the world.

Dr Nicholas Jones is a partner and patent attorney at 

, specialising in pharmaceutical research and development. He is a member of the Royal Pharmaceutical Society of Great Britain and the Royal Society of Chemistry. 

While it may not happen often, clinical trials can sometimes be halted by patent disputes, leading to costly delays in bringing new drugs to market. At last, the UK Government has decided to do something about this in a bid to make UK patent law more consistent with that in some other parts of the world.

Drug Development: To Sue or Not to sue?

	It is well known that the pharmaceutical industry spends billions each year on promoting their products, especially to healthcare professionals. In the US, a significant amount is also spent on direct advertising to consumers. In a report by the FDA on 

Keeping Drug Advertising Honest and Balanced

Office of Prescription Drug Promotion (OPDP)

, shares on how the agency “protects consumers from false and misleading ads for prescription drugs that appear on TV, radio, online and in print publications.”

	In the US and New Zealand, direct-to-consumer advertising is allowed because of the First Amendment, which provides for freedom of speech, including commercial speech by pharmaceutical companies. Abrams however points out that the FDA has been charged by law to ensure accurate and balanced advertising so that consumers are provided with helpful information about the medical conditions and the drugs to treat them.

	According to Abrams, drug companies are required to submit to the OPDP their advertisements and other promotional materials at the time they make them public. “We receive anywhere from 6,000 – 8,000 pieces of advertising and promotional submissions each month. The materials are assigned to one of our 32 reviewers, who specialize in specific drug categories, such as asthma medicines or cardiac treatments. Many reviewers are healthcare professionals with diverse backgrounds in academia, industry, hospitals and pharmacies. They use a risk-based approach that allows them to prioritize their work to quickly identify promotional materials with the most potential for negative impact on public health,” says Abrams.

	In cases of misleading or false promotion (e.g., an advertisement claiming that a product is more effective or safer than has been demonstrated), the OPDP will issue enforcement letters to the company and legal actions can be taken through the Justice Department if such form advertising is not discontinued. “We also pay careful attention to balance, making sure the risks are displayed prominently so that they can be read, heard and understood easily,” Abrams adds.

	When asked if social media has complicated the job, Abrams says it has due to the increased volume of materials and speed of delivery afforded by the Internet. He gave an example where the OPDP had in the past acted against a company that developed and posted a video testimonial featuring a well-known TV celebrity promoting its drug on YouTube. A warning letter was issued, noting the promotional testimonial violated the regulations by overstating the benefits of the products without mentioning its risks.

	“The area of prescription drug promotion is such a dynamic one,” says Abrams in his concluding remarks. “The number of vehicles and ways that companies promote their products has increased significantly, as well as the amount of promotion. The office at FDA has had to grow with it.”

	For those who are unaware, the FDA has a 

, administered by the OPDP and designed to educate healthcare providers about the role they can play in helping to ensure that prescription drug advertising and promotion is truthful and not misleading. A video on “

” by the FDA is available in Medscape’s website.

It is well known that the pharmaceutical industry spends billions each year on promoting their products, especially to healthcare professionals.

Advertising of Prescription Drugs – Keeping it Honest and Balanced

	The issue of patients not receiving essential medicines because they cannot afford them is becoming a serious problem in the EU as the region battles through its economic crisis. In a briefing by the European Public Health Alliance (EPHA) on 

Access to Medicines in Europe in Times of Austerity

, it was highlighted that the three factors that will determine whether or not a patient gets his/her medicine are “

 in terms of developing new methods of assuring best possible health outcomes.”

	S&D Spanish Member of the European Parliament (MEP) Alejandro Cercas commented in a recent 

 that European governments are using the financial crisis as an excuse to cut public spending and as a result, “decades of social justice are being swept away in a matter of a few years” with citizens and residents feeling the negative effects of such austerity policies in European healthcare systems.

	“It is unacceptable that millions can’t afford the best lifesaving treatment in the EU. More fiscal solidarity has not led to more general solidarity. We are putting the EU at risk,” said Cercas. “What also raises eyebrows is the sense of arbitrarily that comes with the cuts - lifesaving medicines should have never made it into any cut list. Healthcare systems should be at the very bottom of the austerity list, not as a default option,” Cercas added.

	Monika KosiÅska, Secretary General of EPHA, pointed out that failure to consider the health consequences of austerity policies means that medicines are becoming less affordable and increasingly hard for people to access. “In particular, it has hit communities who are already affected by the crisis and the cuts and are struggling to put food on the table, let alone to pay for the medicines they need,”

	The situation in Spain has been described as a fiscal discipline in disguise by Joan Rovira from the Department of Economic Theory at University of Barcelona. The Spanish government is moving from a universal health system to a model where coverage is linked to employment, which “recklessly excludes disadvantaged groups, like undocumented immigrants, from receiving timely and adequate healthcare,” said Rovira. “As a result, the growing incidence of infectious diseases, like AIDS, will no doubt lead to increased health care costs.”

	The European Parliament is becoming a battlefield between public interests and big pharma companies, according to MEP Antonyia Parvanova (ALDE, Bulgaria).  As key directives relating to public health are being debated in the Parliament, it is important that policy makers remember to put the people’s interest first ahead of industry’s profits, said Parvanova.

	An extended version of EPHA’s press release on the seminar discussing Europe’s access to medicines can be found 

 with additional quotes from participants.

The issue of patients not receiving essential medicines because they cannot afford them is becoming a serious problem in the EU as the region battles through its economic crisis.