Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

The European Medicines Agency (EMA) has detailed plans for granting public access to information concerning the potential side effects of medicines. Members of the public will be able to access data in the EudraVigilance database—EMA’s central repository for reports of suspected adverse reactions related to authorized medicines in the European Economic Area, as well as those being studied in clinical trials.

, EMA will begin producing monthly reports by the end of this year that summarize information held in the database for all medicines authorized centrally. By the end of 2012, this will be extended to searchable reports for all medicines, and, subject to available funding, by 2015 EMA will further improve the search and data–output functions, and give the pharmaceutical industry access to tools that enable the detection and analysis of signals of adverse reactions. 

In addition, EMA said it will consider providing access to data for research purposes, but this will be on a case-by-case basis. Information on the potential side effects of veterinary medicines will also be available.

The access policy was developed as part of EMA’s ongoing plan to increase levels of transparency, for which it has been criticized on several occasions. In 

, for instance, the European Ombudsman intervened when EMA refused to grant access to documents regarding the suspected side effects of an antiacne drug. Earlier this year, an 

 that described the difficulties that authors experienced when trying to obtain access to unpublished trial reports from EMA concerning certain antiobesity drugs.

According to EMA, the new access policy has “been developed to contribute to public health protection, to facilitate the implementation of the European transparency initiatives and to comply with EU personal data protection legislation.”

Articles

Members of the public will soon be able to access data in the EudraVigilance database-EMA's central repository for reports of suspected adverse reactions related to authorized medicines in the European Economic Area.

EMA Plans Public Access to Side-Effects Data

An FDA panel has voted unanimously to withdraw approval for Roche’s Avastin for use in the treatment of metastatic breast cancer because there is not enough data to support the conclusion that the benefits outweigh the risks. The fate of Avastin in this indication now lies in the hands of FDA Commissioner Margaret Hamburg, who will make the final decision after the period for public comments closes at the end of July. Roche will also have the opportunity to submit its final summary on the matter.

"We are very disappointed by the committee's recommendation and hope the Commissioner does not decide to remove this important medicine for women with an incurable disease who already have too few treatment options," said Hal Barron, chief medical officer and head of global product development at Roche, in a 

. "We remain ready to collaborate with FDA to find a solution that is in the best interest of patients who need Avastin."Despite the proceedings, the US Centers for Medicare and Medicaid Services (CMS) have 

 said that Medicare will continue to pay for Avastin.

"The FDA decision, when it comes, does not affect CMS," Don McLeod, a spokesman for CMS, told Reuters. "The drug will still be on the market, doctors will still be prescribing it, and we will continue to pay for it.”

Whatever FDA decides, Roche’s statement added that the proceedings will have no impact on Avastin's approved uses for other cancer types in the US, or the use of Avastin for metastatic breast cancer in other countries.

Both FDA and the European Medicines Agency (EMA) scrutinized the risk–benefit profile of Avastin in 2010. In December 2010, EMA 

 that Avastin in combination with paclitaxel remained a "valuable" treatment option for women with breast cancer, but not with other combinations.

 a broader European Union label that enables the drug to be used in combination with Roche’s Xeloda as a first-line treatment when other chemotherapies are not considered appropriate.

FDA, on the other hand, had a different opinion on the matter. In December 2010, FDA 

 that the breast cancer indication be removed from the Avastin label because the drug had not been shown to be "safe and effective for that use." Roche appealed the ruling and refused FDA’s recommendation to voluntarily withdraw Avastin’s breast cancer indication—the first company to ever do so, according to a report from 

The deadline for public comments is July 28, 2011. The final decision will be made after this date.

An FDA panel has voted unanimously to withdraw approval for Roche's Avastin for use in the treatment of metastatic breast cancer because there is not enough data to support that the benefits outweigh the risks.

FDA Withdraws Approval for Roche's Avastin

Particle-characterization data is central to the development, manufacture, and quality control of pharmaceutical products. The characteristics of a pharmaceutical's composite particles can affect the product in many ways, including by influencing drug efficacy and stability, as well as how the product behaves during processing. When considering the importance of particle characterization, the International Conference on Harmonization's (ICH) Q6A guideline on specifications (1) is a useful starting point because it identifies potentially important particle variables, including polymorphic form, enantiomeric purity, and particle size and distribution. The guideline also provides a decision tree to help determine when related testing is required.  

Historically, industry has paid greater attention to control of particle size and distribution, which, according to ICH Q6A, can significantly affect the dissolution rates, bioavailability, and stability of drug substances in both solid and suspension products. Today, particle characteristics are attracting even greater focus as industry strives to increase manufacturing efficiencies. This drive has been largely influenced by the growing emphasis on quality by design (QbD), which encourages pharmaceutical companies to use an information- and risk-based approach to optimize product development and manufacture. Using particle characterization to understand how a product behaves during processing supports this initiative.  

IMAGE: INFLUX PRODUCTIONS, PHOTODISK, GETTY IMAGES 

This article takes a brief look at what factors have driven innovations in particle-characterization techniques and how technology may advance in this area in the coming years. 

Two of the earliest particle-sizing techniques were manual microscopy and sieving. These methods are still used today, but both have drawbacks. For instance, microscopy is slow and manually intensive, while sieving is unsuitable for fine or cohesive materials. As such, industry has sought more advanced particle-sizing techniques.  

One such approach that is gaining popularity is laser diffraction. "Although laser diffraction methods have been used for the last 30 years, continuous development has resulted in much more accurate and reproducible measurements between manufacturers," explains Graham Rideal, founder of and a senior scientist at Whitehouse Scientific, which specializes in particle-sizing methods.  

Paul Kippax, product group manager at Malvern Instruments, a producer of analytical equipment, agrees that laser diffraction is an important technology, particularly because its measurement range (0.1 to 3000 μ) covers the vast majority of particle-sizing applications used by industry. In addition, laser diffraction is capable of high-speed size distribution sampling (typically less than 20 s, according to Kippax), is nondestructive, and is suitable for automation. "Today's laboratory laser diffraction analyzers have been automated to the point of push-button operation, with sample loading being the only remaining routine manual task," says Kippax.  

Imaging and microscopy are not being left behind, however. Some recent advances have been made with these analytical techniques. "The continuous and concomitant development of imaging technology and high-speed computers has transformed the humble microscope from a predominantly qualitative instrument into one of the most potent quantitative tools available today," explains Rideal. "This development has extended the definition of a particle from that of a simple equivalent spherical diameter into a comprehensive shape analysis where length, width, and perimeter can be measured at tremendous speeds."  

Indeed, during the past few years, industry has placed a growing emphasis on particle characteristics other than size, such as shape, surface charge, and roughness. "Particle sizing is just one element of particle characterization," says Rideal. "Other disciplines in this sector include particle shape, flow properties, both in the dry state and as suspensions (rheology), morphology—including crystal structure, and porosity. Particle sizing alone is therefore not always the sole answer to efficacy.... A combination of physical properties is invariably investigated in arriving at the final solution." 

According to Kippax, particle shape, in particular, has become an important parameter for both processing and final product quality. "In direct compression tableting, for example, shape is known to have an impact on blend uniformity, the consistency of powder flow through the press, compressibility, and the mechanical strength of the finished tablet," he says. "On the imaging front, many are also already looking beyond shape to composition." 

Particle characterisation is used in many areas of the pharma industry, including excipient characterization and other quality control applications. Additionally, particle charcterization has a large role to play in the development of inhaled pharmaceuticals (see 

). The industry’s drive for improved manufacturing efficiencies has also increased the uptake of particle characterization technologies during process development. Particle characterization data help manufacturers to better understand their product, and provide the opportunity for process optimization according to the product’s characteristics. In isolation, however, particle characterization data do not always provide sufficient information to achieve this. In this case, techniques that characterize the powder, rather than the constituent particles, can play an important role. Over the past few years, there have been a number of advances in the area of powder characterization have helped manufacturers better understand their processes, ultimately leading to more efficient manufacturing (see 

Understanding particle characteristics can benefit process development in several ways. The latest technologies, such as the on-line laser-diffraction systems noted above, enable processes to be monitored in real time during development work, which provides better control and facilitates scale up. "The sector's interest in on-line, real-time measurement has risen sharply as it works toward greater manufacturing efficiency," says Kippax. "Real-time monitoring accelerates the reliable identification of 'cause and effect' during process development and has a valuable role to play in the transition to smarter operation." 

Real-time monitoring, however, is not yet available in all areas of particle characterization. Tim Freeman, director of operations at Freeman Technology, which specializes in powder characterization, adds, "I would perhaps highlight particle shape analysis—automated imaging—as a prime example of a technique with proven applicability, that would be a desirable addition to the real-time selection for pharma, but has yet to make this transition." 

Another way that particle characterization can benefit process development is through simulation, which involves using characterization data to construct mathematical models that predict process performance. These models, if robust, can be used to conduct virtual experiments. 

"The big attraction of process simulation is that it allows virtual experimentation, which is cheaper and quicker than the laboratory or pilot scale equivalent," explains Kippax. "The drawback is the effort required to develop a reliable model." Despite this, however, Kippax added that he expects process simulation to become more widely used within in the industry in the coming years because of the potential it has for aiding scale up and troubleshooting. 

Particle characterization has come a long way from its early days, but there is always room for more progress.  "The next major development in particle sizing is likely to be in measuring in three dimensions," says Rideal. "Computer technology will be a driving force where the current impressive computer graphics from the film industry will be incorporated into particle sizing. There is also a move to borrow technology from the medical world, so expect to see X-ray CAT scans and MRI instruments appearing in the particle-metrology laboratory."  

Meanwhile, Kippax is hopeful that there will be more advances in laser diffraction. "One goal is to make the performance gains already made more universally accessible. Greater embedded support during method development and throughout the measurement process, for example, would ensure that even inexperienced users could fully exploit the technology." 

With such improvements on the horizon, industry's main challenge may not stem from technology, but rather from the skill of the operator using it. "Just because an instrument costs in excess of $100000 does not mean that the results are any better than using a sieve costing £100," says Rideal. "The old adage of 'rubbish in, rubbish out' has never been so relevant."  

Specifications: Test Procedures and Acceptance Criteria for New Drug Products: Chemical Substances

Pharma's drive for manufacturing efficiency is bolstering particle-characterization technologies.

The Power of Particle Characterization

Data has highlighted the pharma industry’s high rate of Phase III drug terminations and significantly reduced research and development (R&D) spending. According with 

, 2008–2010 saw more than double the number of Phase III terminations compared to 2005–2007, while pharmaceutical R&D spend, in general, hit a three-year low in 2010. The information has been published in the 2011 edition of the Pharmaceutical R&D Factbook, compiled by Thomson Reuters’ CMR International unit. A 

 also added that the clinical trials dropout rate is at “unsustainable levels.”

More than 50 Phase III trials were terminated in 2010 and the number of drugs entering Phase III also fell by 55%. It’s not just the final hurdle that drugs are failing at either; the number of drugs entering Phase I and Phase II trials also fell by 47% and 53% respectively in 2010 compared with previous years.  Overall, spending on pharmaceutical R&D in 2010 was estimated at $68 billion, compared with $70 billion in both 2008 and 2009. One of the only therapeutic areas seeing an increase in the number of potential new drugs is anticancer.

“For the first time, drug companies are reducing costs in their R&D [organizations] and I believe we will see that trend continue,” Hans Poulsen, head of life sciences consulting at 

The release added that the decrease in R&D expenditure reflects the growing disillusionment with poor returns on pharmaceutical R&D, and stated, “Disappointing research productivity is arguably the biggest single factor behind the declining valuations of the sector over the past decade.”

According to the Factbook, more than 110 drugs will lose patent exclusivity in the US, including 14 blockbuster products. Many companies have adopted strategies geared towards in-licensing or acquiring compounds, but self-originated drugs have a 20% higher chance of making it to market.

“High failure rates continue to be of great concern to the industry and this is compounded by the decrease in NMEs,” Phil Miller, product director at 

, said in a press release. “The strategy of Big Pharma to in-license more drugs for development does not appear to be paying off at present. An earlier focus on clearing out weak drug candidates will be instrumental to successfully progressing drugs to market.”

Industry analysts have highlighted the pharma industry's high rate of Phase III drug terminations and significantly reduced R&D spending.

Pharma R&D Concerns

The Association of the British Pharmaceutical Industry (ABPI) has published a guidance that suggests best practices for managing adverse events and other pharmacovigilance data from the internet and social media tools. 

According to the ABPI, today’s array of blogs, tweets, online communities and other digital information represent a plethora of potentially important safety data that could compliment traditional pharmacovigilance methodologies. However, such information is not currently being accessed, analysed or even considered relevant by many stakeholders, partly because present legislation does not support marketing authorisation holders in “fulfilling their obligation to collect and analyse all safety data they become aware of”, according to the ABPI. 

“The ABPI Pharmacovigilance Expert Network has become increasingly concerned that the complex regulatory requirements for pharmacovigilance, brought in to protect patients at a time of information scarcity, are now acting as a barrier to the use of this information as an important additional resource to protect public health,” explained a white paper issued by the ABPI entitled 

Pharmacovigilance and the Internet: A Call for Change

Guidance notes on the management of adverse events and product complaints from pharmaceutical company sponsored websites

 were put together as a compilation based on current legislative requirements, and have also been shared with the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). The notes set out a number of points  and activities for consideration, including “listening in” on social media sites, engaging in one-way communication to share messages, engaging with the public via interactive communication. Although the notes emphasise the regulatory and legal considerations in these areas, they also explain that social media is a valuable tool for communicating externally with customers. 

According to the ABPI, eight in ten internet users search for health information online. Research from the UK’s Imperial College also added that 70% of UK patients use the internet to search for health information, with a third deciding not to visit their general practitioner afterwards. Not all of the sites visited are sponsored by pharma companies; in particular, many internets users visit online healthcare discussion communities or blogs, but pharma tends to shy away from these ‘non-pharmaceutical sponsored websites’. Such websites pose a number of challenges, but can also provide valuable information. The notes do not discuss the use of non-pharmaceutical sponsored websites, but the subject is examined in the ABPI white paper.

“Pharmacovigilance data from non-pharmaceutical company sponsored sites should not be ignored, but it is unique and must be treated differently. A new regulatory strategy must be found that will enable the use of this data pragmatically, focusing on the key outcomes of improving medicine safety and away from rigid regulatory reporting requirements,” said ABPI.

The ABPI proposes that companies should have no routine obligation to collect and follow-up on individual adverse events that arise from non-pharmaceutical company sponsored websites. “Data from this channel is best treated as an adjunct to conventional sources,” said the ABPI. “Marketing authorisation holders and regulators should therefore work harmoniously to adopt a more scientific approach to aggregate analysis of this data to help generate or confirm potential signals.”

Although the information disseminated by the ABPI does not represent official regulatory guidance, the agency is hopeful that its work will ultimately lead to improved protection for patients. In a 

, Dr Esteban Herrero-Martinez, ABPI Regulatory Manager, said: “Timing is crucial however, we have new pharmacovigilance, or drug safety, legislation that was approved in Europe in December 2010, and the implementing guidance for this legislation is currently being drafted. We have an opportunity now to influence the drafting of this implementing guidance to improve the current situation.”

The Association of the British Pharmaceutical Industry (ABPI) has published a guidance that suggests best practices for managing adverse events and other pharmacovigilance data from the internet and social media tools.

ABPI Releases Social Media Guidance

Novartis has commenced construction of a new manufacturing plant in Russia that represents the company’s most significant investment in that country to date. The facility will produce innovative and generic products and will create 350 jobs in Saint Petersburg.

The facility is expected to be completed in 2014 and will be located in the Novoorlovskaya Special Economic Zone, according to a company 

. Once completed and approved, the plant is expected to produce approximately 1.5 billion units per year.

“Novartis’ decision to launch drug production in Saint Petersburg is an outstanding example of a successful collaboration between Russia and foreign investors in the high-technology and innovation sphere, creating new job opportunities for local talent,” Valentina Matvienko, governor of Saint Petersburg, said in the press release. “We're looking forward to help Novartis in solving one of the key challenges on the government agenda—modernization of healthcare.”

Novartis and its predecessors have been active in Russia since the 1860s, and the company currently employs 2000 workers across the country. The new facility is part of the company’s $500-million, five-year investment into the Russian healthcare infrastructure, which was 

 in December 2010 when Novartis signed a memorandum of understanding with the city of Saint Petersburg. This partnership will address the core areas of local manufacturing, research and development collaborations, and public-health development in Russia. Novartis added that these activities may include collaborations with universities and academia, as well as with emerging Russian private business in various areas of medical science.

The groundbreaking ceremony at the new site took place earlier this week and was attended by E. Nabiullina, the Russian Federation’s minister of economic development, Matvienko, and Joseph Jimenez, CEO of Novartis, as well as other Novartis collaborators and key representatives from the Russian government and the Swiss embassy.

Novartis has commenced construction of a new manufacturing plant in Russia that represents the company's most significant investment in the country to date.