Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

 from FDA informing the company that promotional materials as well as an associated webpage for Copaxone (glatiramer acetate injection) solution for subcutaneous injection were found to be false and misleading. Copaxone is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). FDA found that the materials overstated the efficacy, presented unsubstantiated claims, broadened the indication for Copaxone, and omitted and minimized important risk information associated with the drug.

FDA objected to wording in the promotional materials indicating that Copaxone’s safety record extended for 15–20 years, while the clinical-trials data in the FDA submission are only three years in duration. According to FDA, the open-label extension trials upon which the company based its claims are not sufficient to support those claims.

The promotional materials also included case studies from patients purportedly showing dramatic improvement in mobility and quality of life after taking Copaxone. According to the Warning Letter, the patient narratives misleadingly broaden the indication and overstate the efficacy of Copaxone by implying that Copaxone reverses patients’ disability and enables them to lead an active lifestyle, return to work, accomplish great athletic feats, and “live the life they’ve dreamed.” FDA says that while the patient narratives may be true reflections of those individual’s experiences, Copaxone is not indicated for slowing, preventing, or reversing physical disability associated with MS.

FDA also found that risk information was minimized or omitted in the promotional materials. In addition, the materials implied that Copaxone was safer than other treatments because it was not associated with risks associated with other drugs, when, in fact, those risks were associated with Copaxone. In the letter, FDA says it is not aware of adequate and well-controlled head-to-head clinical trials demonstrating that Copaxone is safer, more effective than, or otherwise superior to, other RRMS therapies.

The Office of Prescription Drug Promotion requested that Teva discontinue dissemination of violative materials and submit a plan to disseminate truthful, nonmisleading, and complete corrective messages about the issues discussed in the letter to those who received the violative promotional materials.

Articles

Teva Pharmaceuticals received a Warning Letter from FDA informing them that promotional materials as well as an associated webpage for Copaxone (glatiramer acetate injection) solution for subcutaneous injection were found to be false and misleading.

FDA Warns Teva Pharmaceuticals About Improper Promotional Materials

	A critical drug that has experienced shortages is Genzyme’s, Fabrazyme (agalsidase beta), the only enzyme replacement therapy approved in the US for Fabry disease. The drug was originally produced at the company’s Allston, Massachusetts plant. The Allston plant was plagued with quality problems, which resulted in a consent decree, temporary closure of the plant in 2010, and rejection of some lots of Fabrazyme for quality reasons. In January of 2012, FDA granted approval for Genzyme to start producing Fabrazyme at its Framingham, Massachusetts plant, bringing to an end a shortage that left patients without an adequate supply of medication for nearly two years.

	While Fabrazyme was in such short supply, some US patients were allowed limited access to Replagal (agalsidase alfa), a biologic produced by Shire Pharmaceuticals and approved in Europe for the treatment of Fabry disease. During the Fabrazyme shortage, FDA encouraged Shire to seek US approval of Replagal, which would have meant that there would have been a readily available alternative treatment for Fabry patients.

	Shire announced on Mar. 14, 2012 that it was withdrawing its Biological License Agreement (BLA) for Replagal. In its 

, Shire says, “Recent interactions with the FDA have led the Company to believe that the agency will require additional controlled trials for approval. No concerns over the product’s safety profile were raised by the FDA. Shire has concluded that the likely additional studies would cause a significant delay, and an approval of REPLAGAL for US patients would only be possible in the distant future. Shire has therefore decided to withdraw its BLA.”

	Apparently, Shire decided that a speedy approval was not forthcoming, and decided to take its ball and go home. Perhaps it did the calculation, and decided that the market share it might pick up in the US didn’t justify the cost of the additional trials. Whatever the reason, the ones affected are the patients, who are still depending on a single supplier to keep them healthy.

A critical drug that has experienced shortages is Genzyme’s, Fabrazyme (agalsidase beta), the only enzyme replacement therapy approved in the US for Fabry disease.

Crisis Averted, But No Long-Term Fix

On Mar. 7, 2012, GE Healthcare announced an agreement to acquire Xcellerex, a supplier of manufacturing technologies for the biopharmaceutical industry, for an undisclosed amount.

, the acquisition will allow GE Healthcare to expand its offering of products and services for the manufacture of biopharmaceutical products such as recombinant proteins, antibodies, and vaccines. Xcellerex develops and produces turn-key biomanufacturing systems and production-scale bioreactors based around single-use components, including single-use bioreactor systems that are complementary to GE Healthcare’s products and range of media for cell culture. The companies believe that the strong strategic fit between the two companies, combined with expanded capabilities in product development and marketing, will offer significant customer benefits.

Nigel Darby, vice-president of BioTechnologies, and chief technology officer of GE Healthcare Life Sciences says in the release, “GE and Xcellerex share the vision that an integrated approach, where we can help customers optimize every stage of their manufacturing process, has the potential to increase production flexibility and to deliver higher yields of finished product while reducing time to market. With the global focus on spiraling health costs and the need for sustainable healthcare, these are critical issues for the industry.”

Guy Broadbent, president and CEO of Xcellerex, adds, “The integration of Xcellerex’s products with GE Healthcare’s complementary capabilities in upstream and downstream bioprocessing will help bring great benefits to our customers.”

GE Healthcare to Acquire Xcellerex

	This week, the Drug, Chemicals, and Associated Technologies Association (DCAT) is holding its annual week-long meeting in New York City. The meeting covers topics including the business and regulatory environment, manufacturing practices, and supply chain logistics of the pharmaceutical industry. Wednesday Mar. 14, 2012 featured a session devoted to biologics, in which the first two speakers spoke at length on the topic of biosimilars, and highlighted important differences between follow-on biologics and generic small molecules.

	The first speaker, Neil Mahoney, President & CEO of Global Pharma Alliance examined the business environment for the development of biosimilars. His talk was a cautionary one for those looking to enter this arena. Several factors make it more difficult to turn a profit making biological follow-ons than it has been for generic small molecules. The first challenge is the very high cost of development compared with a generic: According to data presented by Mahoney, the average biologic follow-on will take $100-$200 million to develop, compared with $2-3 million for a small molecule generic. The second challenge is market share. While we’re all aware of the phenomenon of the patent cliff for small molecules, where generics can capture most of the market share within a few months of being introduced, the market penetration of biosimilars in Europe has not been nearly as profound, with some products capturing only a few percent of the intended market. Tiny market share combined with large start-up costs can result in no profitability for the developer.

	The second speaker, Steven Kozlowski, MD, Director, Office of Biotechnology Products at the Center for Drug Evaluation and Research at FDA spoke at length on the new biosimilar draft guidance. The biggest focus of his talk was the importance of a thorough and detailed characterization of a candidate biosimilar to assure FDA that the biologic product is similar enough to the originator biologic to be called biosimilar. It’s almost a given that two different production systems, starting with the same construct, will produce slightly different proteins. The key for a biosimilar approval will not be just to demonstrate similarity: it will be to exhaustively identify any differences between the follow-on molecule and the originator, and demonstrate to FDA that these small differences are unlikely to affect the products efficacy or safety.

	From these two talks, one begins to get a sense of how similar a biosimilar is to a generic. Clearly, quite different.

This week, the Drug, Chemicals, and Associated Technologies Association (DCAT) is holding its annual week-long meeting in New York City.

Biosimilars—It’s the Differences That Really Matter

Boehringer Ingelheim (BI) has announced in a 

 the expansion of its biopharmaceutical manufacturing capabilities at its plants in Biberach, Germany and in Vienna, Austria.

The expansion will include cell-culture and microbial-fermentation capacity and support cell-line and process-development services for BI’s contract manufacturing business. BI has invested approximately EUR 17 million ($26.8 million) to expand cGMP cell banking, process science, cell-line development, and quality laboratories at the two sites.

BI expects to use the expanded resources for services that include monoclonal antibody development, product development using BI’s proprietary high-expression systems, and proprietary plasmid DNA platform. In addition, the facilities will support collaborations with Pfenex on 

 bacterial expression technology and with VTU Technology on 

In the company release, Dr. Dorothee Ambrosius, senior vice-president of Biopharmaceuticals Global Process Science, says, “This is another milestone within our contract manufacturing strategy securing technology leadership and towards increased flexibility and customer orientation.”

Boehringer Ingelheim (BI) has announced the expansion of its biopharmaceutical manufacturing capabilities at its plants in Biberach, Germany and in Vienna, Austria. The expansion will include cell-culture and microbial-fermentation capacity, and support cell-line and process-development services for BI's contract manufacturing business.

BI Expands Biomanufacturing Capacity in Europe

	A short time ago, I wrote about the Transforming the Regulatory Environment to Accelerate Access to Treatments Act, (TREAT), legislation proposing to modify the regulatory environment to speed the approval of drugs intended to treat life-threatening conditions for which there are no effective therapies. This week brings us the Faster Access to Specialized Treatments (FAST) Act, introduced by Rep. Clifford Stearns (R-FL) and Rep. Ed Towns (D-NY) to the House Committee on Energy and Commerce on Mar. 5, 2012. 

 proposes to amend section 506 of the Federal Food, Drug, and Cosmetic Act to expedite approval of drugs for serious or life-threatening diseases or conditions. Rep. Stearns explains in a 

, “This measure codifies much of the Accelerated Approval regulations into statute and modernizes the program to reflect the amount of medical and scientific innovation that has occurred in the past 20 years.” The aim of the legislation is to encourage FDA to make full use of the accelerated approval pathway to speed the approval of life-saving drugs.

	FAST enjoys the support of The National Organization for Rare Disorders (NORD) and of the biotech industry group, BIO. Jim Greenwood, president of BIO, said in a 

, “Like the Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) Act, S. 2113, which was introduced by Senator Kay Hagan (D-NC), the FAST Act will update the Accelerated Approval process at the FDA so that it works in a transparent, predictable way for all therapies intended to treat debilitating conditions for which there is an unmet medical need. Making this change will better enable biotechnology companies to bring new, safe and effective treatments and cures to patients in need at the earliest point in time.”

	Time is of the essence for those with rare diseases or with other conditions for which there are no effective therapies. Certainly, FDA should do its part to get therapies to market in the shortest time possible, and the introduction of two similar bills in such a short time span underscores the public’s impatience with the drug development process. However, human physiology is complex, drug development is hard, and FDA always has to balance speed with safety. Will urging FDA to go faster bring the desired results?

A short time ago, I wrote about the Transforming the Regulatory Environment to Accelerate Access to Treatments Act, (TREAT).