Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended Sanofi's six-in-one pediatric vaccine for marketing authorization. The hexavalent vaccine (DTaP-IPV-Hib-HepB vaccine) was developed by Sanofi Pasteur, the vaccines division of Sanofi. Once approved, the vaccine will be commercialized under two brands names: Hexyon in Western Europe and Hexacima in Eastern Europe. The vaccine will also be available in international markets under the trade name Hexaxim. 

Hexyon /Hexacima will be indicated for primary and booster vaccination of infants from six weeks of age in accordance with official recommendations. It is the only fully liquid, ready-to-use, six-in-one vaccine in Europe to protect infants against diphtheria, tetanus, pertussis (whooping cough), Hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b. 

"Availability of Hexyon/Hexacima ready-to-use, six-in-one pediatric vaccine will raise the standard of care of vaccination for millions of children. It reduces the number of vaccination visits for infants and it is more convenient for parents to complete the recommended vaccination schedule and thus better protect their children against six major childhood diseases," said Olivier Charmeil, president and CEO of Sanofi Pasteur in a 

. "Upon licensure, we intend to introduce Hexyon/Hexacima vaccine in countries that are looking for improved and effective solutions for public immunization programs." 

The formulation does not require reconstitution prior to administration, which makes it convenient for healthcare professionals. It is a fully liquid, ready-to-use vaccine, available in vial and pre-filled syringe presentations. Another key benefit is that the combination of six vaccines into one reduces the number of injections, hence improving comfort and vaccination compliance for infants. Moreover, the use of acP (acellular pertussis) antigens and IPV (inactivated poliovirus vaccine) improves safety and reduces reactogenicity compared with wcP (whole cell pertussis)-containing vaccines and OPV (oral polio vaccine). 

The CHMP’s positive opinion is supported by clinical data from multicenter trials involving approximately 5000 infants. Results from Phase III studies comparing Sanofi’s vaccine to licensed combination vaccines demonstrated that Hexyon/Hexacima is safe and induces a robust immune response against all six targeted diseases. 

Articles

The EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended Sanofi's six-in-one pediatric vaccine for marketing authorization.

Sanofi's Six-In-One Pediatric Vaccine Recommended for European Approval

Merck’s investigational integrin inhibitor cilengitide did not meet its primary endpoint in the CENTRIC Phase III trial evaluating if the agent could prolong overall survival when added to the current standard chemoradiotherapy regimen (temozolomide and radiotherapy). The randomized, controlled, multicenter, open-label trial, conducted in partnership with the European Organisation for Research and Treatment of Cancer (EORTC), assessed the safety and efficacy of cilengitide treatment in more than 500 patients with newly diagnosed glioblastoma and methylated-methylguanine-DNA methyltransferase (MGMT) gene promoter status from 23 countries worldwide. The results of the trial will be presented at the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting and submitted for publication in a peer-reviewed journal. 

Patient safety in the CENTRIC trial was monitored frequently by an independent data monitoring committee. There were no new or unexpected safety concerns reported. In prior clinical studies, the most frequently reported adverse events attributed to cilengitide were nausea and fatigue. 

 “These results illustrate how challenging this disease remains, and that thorough clinical investigations like in this study are crucial before adopting new treatment strategies,” said the lead investigator and president of the EORTC Professor Roger Stupp in a 

. “Nevertheless, the unique collaboration between academia and industry was key in establishing molecular tumor characterization towards personalized medicine. And it allows for investigation of mechanisms of disease, and identifying novel targets and combinations for the future. We remain committed to addressing the needs of patients suffering from this rare disease and will continue to investigate other treatment options.” 

In the same statement, Dr. Annalisa Jenkins, head of global drug development and medical for Merck, commented, "The results of CENTRIC are disappointing, especially for people who are fighting this devastating and difficult to treat cancer. Over the coming months, we intend to analyze the data sets and ensure appropriate public disclosure of key information that will serve future scientific research related to targeted therapies in oncology. For a complete picture, we will also evaluate the results of the currently ongoing Phase II CORE trial, which included only patients with an unmethylated MGMT gene promoter status. We remain committed to advancing our pipeline and developing new treatment options in oncology for patients with high medical need.” 

Merck is developing cilengitide as an anticancer therapy. The agent is thought to target certain integrins over-expressed or aberrantly expressed in many cancers that are involved in tumor cell growth and the formation of new tumor-related blood vessels in the tumor microenvironment. Cilengitide is currently being evaluated for the treatment of glioblastoma in a Phase III trial (CENTRIC) and in a Phase II trial (CORE). An additional Phase I/II trial is ongoing in patients with non-small cell lung cancer (NSCLC). Further trials are being conducted by the US National Cancer Institute (NCI). 

Merck's investigational integrin inhibitor cilengitide did not meet its primary endpoint in the CENTRIC Phase III trial evaluating if the agent could prolong overall survival when added to the current standard chemoradiotherapy regimen (temozolomide and radiotherapy).

Merck's Cilengitide Fails to Meet Primary Endpoint in Phase III Trial

Merck has agreed in principle to pay $688 million to settle two federal securities class-action lawsuits involving the company's anticholesterol drugs Vytorin and Zocor, thereby avoiding trial. The suits are pending in the US District Court for the District of New Jersey against Merck, Schering-Plough and certain of their current and former officers and directors. 

The lawsuits followed after shareholders, who purchased certain securities issued between December 2006 and March 2008, claimed that they lost money because Merck and Schering-Plough, delayed publication of data from the Enhance trial, which evaluated the combination drug Vytorin (ezetimibe plus simvastatin) compared with Zocor (simvastatin). The study was completed in 2006 but Merck took almost two years to publish the results, leading to accusations that the company was trying to conceal unfavourable data. Results from the trial indicated that Vytorin was no better in preventing atherosclerosis than the cheaper statin Zocor, despite being able to reduce cholesterol levels. The lawsuits claimed that Merck and Schering-Plough knew that the trial had failed but did not disclose this information to investors for a year. When the results were released in January 2008, the company’s share prices plummeted. 

Under the proposed agreement, which was reached after almost five years of protracted litigation, Merck will pay $215 million to resolve the securities class action against all of the Merck defendants and $473 million to resolve the securities class action against all of the Schering-Plough defendants. Both settlements still require court approval. In connection with the settlement, Merck recorded a pre-tax and after-tax charge of $493 million, which reflects anticipated insurance recoveries. 

Merck still believes that both companies acted responsibly in connection with the Enhance study. The agreement contains no admission of liability or wrongdoing. Bruce Kuhlik, executive vice president and general counsel of Merck, said in a 

, "This agreement avoids the uncertainties of a jury trial and will resolve all of the remaining litigation in connection with the Enhance study. We believe it is in the best interests of the company and its shareholders to put this matter behind us, and to continue our focus on scientific innovations that improve health worldwide." 

Merck acquired Schering-Plough in 2009. Before the merger, the companies collaborated on the development of Vytorin, which came to market in 2004 and generated more than $1.7 billion in sales last year. 

Merck has agreed in principle to pay $688 million to settle two federal securities class-action lawsuits involving the company's anticholesterol drugs Vytorin and Zocor, thereby avoiding trial.

Merck Pays $688 Million to Resolve Vytorin Lawsuits

Biotest Pharmaceuticals Corporation announced that Bivigam [immune globulin intravenous (human), 10% liquid] is now available in the pharmaceutical distribution channel for use by physicians, pharmacists and hospitals throughout the US. Bivigam is a sugar-free, glycine stabilized intravenous immune globulin that has been approved by the FDA in December 2012 for the treatment of patients with primary humoral immunodeficiency (PI). The product is available in 50 mL (5 grams) and 100 mL (10 grams) tamper-evident vials. 

This is the first new intravenous immune globulin (IVIG) approved in the US, with a validated assay for measuring potential thrombogenic activity. Thrombin generation tests are used to detect procoagulant activity. 

Biotest has developed and validated the thrombin generation assay (TGA) test in close cooperation with the FDA to help reduce the risk of thromboembolic events that PI patients experienced with alternative products in the past. Each lot of Bivigam will be screened before release to ensure that the product fulfills the stringent release criteria pertaining to the threshold levels of Factor XIa. Increased Factor XIa has been identified as one of the risk factors associated with thromboembolic events following immune globulin intravenous therapy. 

Biotest has made significant investments in its infrastructure and ability to efficiently manufacture and deliver the product to best serve the US market and patient population. The company has invested more than $50 million to enhance the capacity of its protein purification facility in Boca Raton, Florida. 

 “The FDA approval and first commercial sales of Bivigam are key corporate milestones for Biotest. The expansion and enhancement of our manufacturing capabilities have positioned us strongly to meet current and future patient and market demand,” Jordan Siegel, CEO of Biotest, said in a 

. “We are committed to supporting PI patients with Bivigam to ensure their uncompromised living.” 

Full prescribing information and more information about the product, the indication and additional services can be found at 

Biotest Pharmaceuticals Corporation announced that Bivigam [immune globulin intravenous (human), 10% liquid] is now available in the pharmaceutical distribution channel for use by physicians, pharmacists and hospitals throughout the US. Bivigam is a sugar-free, glycine stabilized intravenous immune globulin that has been approved by the FDA in December 2012 for the treatment of patients with primary humoral immunodeficiency (PI).

First Commercially Available Intravenous Immune Globulin with a Thrombin Generation Assay Test

 that it has reached an agreement in principle with the US government to resolve the previously disclosed civil investigation into its sales and marketing practices in the US relating to the company’s attention deficit hyperactivity disorder (ADHD) drugs, Adderall XR and Vyvanse as well as the ADHD patch Daytrana. The agreement also addresses sales and marketing practices relating to Lialda and Pentasa (both for the treatment of ulcerative colitis), pursuant to a subsequent voluntary disclosure made by Shire. 

Shire has provided full cooperation to the US government throughout the process of reaching this agreement. The company will pay out $57.5 million from its fourth quarter earnings in 2012 to cover costs of the agreement and interest. The agreement is subject to change until the matter has been fully resolved. Shire and the US government are in discussions on establishing a final resolution to the investigation. 

The investigation, led by the US attorney’s office for the Eastern District of Pennsylvania, was disclosed by Shire in 2009 when the company was asked for documents relating to the sales and marketing of Adderall XR, Vyvanse and Daytrana. 

Shire announced that it has reached an agreement in principle with the US government to resolve the previously disclosed civil investigation into its sales and marketing practices in the US relating to the company's attention deficit hyperactivity disorder (ADHD) drugs, Adderall XR and Vyvanse as well as the ADHD patch Daytrana.

Shire to Resolve Federal Investigation and Pay $57.5 Million

Protecting patients from counterfeit medicines is a pressing issue facing governments and the pharmaceutical industry. According to a review published in March 2012 in the International Journal of Clinical Practice, the global sales of counterfeit medicines were estimated at more than $75 billion, having doubled between 2005 and 2010 (1). The rapid globalization of the pharmaceutical industry, an increasingly complex supply chain on a raw material and ingredient level, and more difficult-to-control sales channels, such as the Internet, have contributed to the challenge on how to better secure the pharmaceutical supply chain. According to the World Health Organization (WHO), one out of two pharmaceutical products purchased through the Internet is a counterfeit (2). 

The EU Falsified Medicines Directive (FMD) that came into effect in January 2013 was designed to enhance the security of the pharmaceutical supply chain through a range of measures, including the use of anticounterfeiting technologies that enable identification, authentication, and traceability of medicines. “The key to increasing supply-chain security to better protect patients is the identification of each unit of packaging,” says Craig Stobie, global life-science sector manager of Domino Printing Science. “Counterfeiting thrives on the fact that items are indistinguishable from one another. Introducing a unique identity to every traded package allows you to confirm the package’s identity, provenance, history, movements, and distribution touch points; however, this only works if the identity is visible and readable throughout the lifespan of the packaging.” Anticounterfeiting technologies are categorized into overt and covert security features, forensic techniques as well as serialization and track-and-trace technologies. 

Overt (visible) features, such as holograms, optically variable devices, color-shifting security inks and films, security graphics, and sequential product numbering, enable end users to verify the authenticity of a pack. For them to be effective, however, public education and awareness are needed, which can be a challenge, particularly in developing markets. Moreover, there is the possibility of overt features being mimicked, reused, or refilled by counterfeits. 

Covert (invisible) features, on the other hand, are designed to enable the brand owner to identify counterfeit products. Examples include invisible printing on primary or secondary packaging using special inks that can only be seen under ultraviolet (UV) or infrared (IR) light, digital watermarks that can only be decoded using special software programs, and laser coding to produce recognizable artifacts that are difficult to copy. Although valuable as investigative tools, covert features can still be copied by counterfeiters, especially those that are simpler. 

Companies, such as Domino Printing Sciences, SICPA, and Payne Security, provide a range of overt and covert ink-based solutions, and when coupled with serialization, such strategies are not viable for counterfeiters to copy. 

Forensic markers, a subset of covert technologies, rely on chemical and biological parameters and require laboratory testing or dedicated field test kits to scientifically prove authenticity. For instance, chemical taggants can only be detected by highly specific reagent systems and not by common analytical methods while biological taggants are incorporated into formulations and coatings at such low levels in the parts-per-million range or lower, that they are undetectable by conventional analysis and require specific “lock-and-key” reagent kits to authenticate. Microtaggants are microscopic coded information applied on or in the packaging, such as alphanumeric data depicted on small flakes or threads, or fragments of multicolored multilayered laminates with a signature color combination. Microtrace offers taggant technologies that can be uniquely encoded in liquids or on solid materials, and like fingerprints, these microtaggants are virtually impossible to duplicate. 

Another forensic marker is isotope ratios, which can provide a natural fingerprint because they are highly characteristic of the identity of a compound and can be accurately determined by laser fluorescence or nuclear magnetic resonance techniques. While forensic technologies are advantageous in that they offer high security against counterfeiting, these licensed technologies are usually limited, costly, difficult to implement, and therefore, unlikely to be available to government authorities or the public. 

As one of the most important anticounterfeiting strategies emerging in recent guidelines and legislations, serialization and track-and-trace technologies, such as two-dimensional (2D) data matrix codes and radio-frequency identity (RFID) tagging, enable products to be tracked through the supply chain, thereby providing traceability of an item. Track and trace involve assigning each product with a unique identifying code during manufacture, which remains with the product through the supply chain until consumption by the patient. It contains details of product name and strength, batch/lot numbers, and expiry date. Although track-and-trace labels can be copied or falsified by counterfeiters, security is further enhanced by the inclusion of distinct and random serialization, or nonsequential numbering, attributed to the individual package. The unique identifying code with its assigned serialization number is activated, validated, and entered into a central database that can be used to identify any duplicates, invalid serials, recalled or expired products, and products appearing in the wrong market. In 2014, a new EU serialization law will be introduced as part of the FMD to harmonize the coding of pharmaceutical products on an international level and manufacturers will be required to implement serialization systems. 

Counterfeit medicines continue to be on the rise and “drug companies must maintain good reputations and act to protect their revenues,” observed Peter Williamson, pharmaceutical analyst at the business-information firm Visiongain, in an Oct. 29, 2012, press release. With a wide range of technology solutions available, manufacturers can use a combination of different technologies to form a multilayer approach for the best possible patient protection. For example, by combining tamper-evident features, serialization, and authentication technologies, manufacturers can create several layers of security for their pharmaceutical products. “The key to supply-chain security lies in the successful introduction of industry-wide standards worldwide,” Williamson said. “Cooperation and cohesion between regulatory authorities and manufactures must improve. Also, increasing public awareness will help fight against drug counterfeiters.” 

1. G. Jackson, S. Patel, and S. Khan, Int. J. Clin. Pract. 66 (3) 241–250 (2012).

2. WHO, “Medicines: Spurious/Falsely-labelled/ Falsified/Counterfeit (SFFC) Medicines,” WHO website, accessed Jan. 15, 2013. 

Protecting patients from counterfeit medicines is a pressing issue facing governments and the pharmaceutical industry.