Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

According to the latest figures from IMS Health, Inc., Japan's pharmaceutical market is expected to grow 1–2% this year compared to global industry growth expectations of 5–6%. Despite the lower forecast, Japan is still the largest market in the Asia-Pacific region and the second largest individual market in the world after the US. But China and India are catching up. According to IMS Health's 2006 world market report, Japan's pharmaceutical sales declined by 0.4% between 2005 and 2006 to $64 billion, whereas China's sales grew 12.3% to $13.4 billion, and India's grew 17.5% to $7.3 billion during the same time period. 

    One reason Japan's industry may not be growing as quickly compared to other parts of the world may be the country's regulatory system. It takes an average of four years to get a new drug approved compared to the average 18 months it takes in the United States and Europe. As a result, far fewer drugs are available in Japan and those that are available worldwide take much longer to hit the Japanese market.  

But the Japanese aren't just sitting back and watching their numbers slide. Just last year, the country's Pharmaceuticals and Medical Devices Agency set out to hire 240 new drug reviewers over a period of three years to help bring its drug approval process more in line with US and European timeframes. Also in 2007, Japan launched a five-year action plan (2007–2011) and "new vision" for its pharmaceutical industry. After a series of dialogues between government, industry, and academia, a group of representatives agreed to focus on innovation and international competitiveness, according to progress reports from Japan's Pharmaceutical Manufacturers Association (JPMA), a 75-member organization. Among the action plan goals are the creation of a New Drug Research Promotion Council, financial aid for medical institutions to carry out clinical research, greater industry-government collaboration, and personnel development geared toward drug discovery. 

    Japan's expenditures for research and development (R&D) in 2004, the latest data available according to the Japanese Ministry of Internal Affairs and Communications, totaled $907.7 billion as compared to $642.2 billion approximately a decade earlier. The largest Japanese companies (Takeda, Astellas, Eisai, Daiichi and Sankyo, Chugai, Shionogi, Tanabe, and Taisho), reports JPMA, spent an average of 14.2% of their sales on R&D in 2004 as compared to 11.1% in 1999. 

    With even more resources, collaboration, and attention being paid to the R&D side of Japan's pharmaceutical market, it looks as though the country intends to catch up to the US, or at least make sure it stays ahead of its Asian-Pacific neighbors. 

Articles

According to the latest figures from IMS Health, Inc., Japan's pharmaceutical market is expected to grow 1–2% this year compared to global industry growth expectations of 5–6%.

Market Watch: Japan

US Food and Drug Administration leaders issued another cry for help last week. Center for Drug Evaluation and Research Director Janet Woodcock testified before the Senate Health, Education, Labor and Pensions (HELP) committee at an April 24 hearing, “Restoring FDA’s Ability to Keep America’s Families Safe.”

She pointed out, just as her colleague John Jenkins  at the Office of new Drugs 

, that FDA desperately needs more inspectors, more overseas locations, and more modern IT systems to carry out its ever-demanding global agenda.

Addressing the heparin contamination issue specifically, Woodcock explained how complicated even one drug application might be in today’s industry. Some applications to import generic drugs, she said, may cite 15 different facilities involved in the drug’s manufacture and distribution. One goal FDA has in mind to manage these complex supply chains is to institute an IT system that includes an inventory of every establishment importing products into the US, said Woodcock.

In addition to more in-depth databases, Woodcock suggested that the agency needs more authority to pursue violators in the pharmaceutical supply chain. “The FDA or any other regulator cannot test quality into products, and we cannot inspect quality into products. The FDA must have the tools to hold all these parties accountable,” she said. 

The Government Accountability Office (GAO) estimated that it would take roughly $70 million per year for FDA to inspect all overseas facilities every two years, $16 million to $17 million of which would be required for sites based in China where contaminated heparin has been traced. 

Although FDA clearly needs more funding, Woodcock did not give the Senate committee a specific price tag for the above projects. She did take the opportunity, however, to point out that industry must be held responsible for its products. “All parties throughout the supply chain-from the production of the API and the ingredients, through brokers, through distributors, through importers, to finished product manufacturers-must be held responsible… for assuring the quality and integrity of the products they produce,” she said.

Gerald Migliaccio, vice-president of quality at Pfizer (New York), pointed out some reasons behind current challenges in the supply chain. “Traditionally, pharmaceutical companies in the US have sourced active ingredients and drug products from within the US, from Europe, Japan, and other developed countries. Our suppliers and contractors in these countries operate within sophisticated regulatory environments with highly competent inspectorates. Most operate to internationally recognized standards established by the International Council on Harmonization (ICH). Therefore, they generally have effective quality systems that provide a high degree of confidence in the overall supply chain. Companies in emerging markets are operating in a developing regulatory environment with a novice inspectorate. Many have rudimentary quality systems or none at all.”

Migliaccio pointed out that education, evaluation, and enforcement are key to improving today’s supply-chain challenges, especially with regard to imported ingredients and drug products. “Before a US pharmaceutical firm can consider sourcing from these suppliers, it is imperative that the firm work with the suppliers to upgrade their quality systems and standards.” Pfizer has been carrying out its own model for such practices, including having a dedicated quality-assurance unit to evaluate and provide oversight to contract manufacturers.

William K. Kubbard, former associate commissioner for policy and planning at FDA, also expressed to the Senate HELP committee that FDA is operating under a budget and standards that were developed decades ago. He presented seven action items that could help:

1)  An immediate infusion of new appropriations for FDA’s drug oversight activities
 2)  A requirement for GMP inspections of foreign drug-manufacturing facilities, with an immediate focus on drugs made in countries without a history of safe drug production and internal regulation
 3)  Creation of a Foreign Inspectorate for FDA that is dedicated to inspecting foreign manufacturing facilities
 4)  A requirement that all foreign drug producers register annually with FDA  
 5)  Appropriations and a specific Congressional mandate to improve FDA’s IT systems
 6)  A vigorous mechanism for testing drugs for ingredients or contaminants that are not approved for that compound
 7)  Clear authority for FDA to inspect sites in foreign countries. 

US Food and Drug Administration leaders issued another cry for help last week. Center for Drug Evaluation and Research Director Janet Woodcock testified before the Senate Health, Education, Labor and Pensions (HELP) committee at an April 24 hearing, "Restoring FDA's Ability to Keep America's Families Safe."

FDA Needs Help to Monitor Drugs, but Industry is Equally Accountable

-The US Food and Drug Administration issued a final guidance last week regarding investigational new drug applications for human gene therapy. Although gene therapy is still in the developmental stages, there is much hope for gene-based treatment and products. Because the therapy involves replacing a patient's faulty genetic material with normal genetic material,there is concern about safety in making sure replacement cells continue to function as they should. The guidance, therefore, focuses on the type of information that scientists need to consider and include in their documentation when studying these drugs and submitting them for FDA approval. 

Based on a draft guidance that was issued in November 2004 (69 

Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

, provides information on what to include in an original IND. The document also applies to combination products that contain a human gene therapy biological product in combination with a drug or device as part of the final product. 

There are some differences in the final guidance. For example, companies must list the reagents they use to manufacture gene-based products for investigational uses (e.g., fetal bovine serum, trypsin, digestion enzymes growth factors, cytokines, and monoclonal antibodies) as they can affect the safety, potency, and purity of the final product, says the guidance. In addition, any excipients used in the therapy-including information about the excipient's source and concentration-must be included in the IND. If the final product is to be frozen for shipping, manufacturers also need to provide data on product stability during transport.

The final guidance provides detail on testing as well, including testing sterility for short-shelf-life products and microbiological testing. The document brings in quality-by-design, noting that testing should be done throughout the manufacturing process, including on the manufacture of cell banks, to ensure the quality and consistency of the product. 

The full guidance is available for review and comment 

The US Food and Drug Administration issued a final guidance last week regarding investigational new drug applications for human gene therapy.

Gene Therapy CMC Guidance Released

Senator Chuck Grassley (R-IA) sent a letter to Amgen (Thousand Oaks, CA) last week asking the company to account for the high rebates it has given to certain physician groups who bought its "Aranesp" medicine. This particular anti-anemia drug  treats kidney and cancer patients.

“Some oncology practices in some states are receiving unusually high rebates for purchasing Aranesp,” wrote Grassley. “These trends underscore the need for greater transparency in the financial relationships between drug makers and doctors. Patients deserve to know what’s going on as they make decisions about their health and safety based on the advice of their doctors.”

 According to Grassley’s letter, Amgen paid nearly $800 million in rebates to more than 6000 facilities in 2006, including to group practices, hospital inpatient and outpatient departments, home health agencies, and skilled nursing facilities. 

 Grassley obtained the information about Amgen’s discounts from an earlier inquiry. He has been 

  greater access by the US Food and Drug Administration to study results for anti-anemia drugs. An FDA advisory committee, in fact, recommended limiting the use of these drugs among cancer patients in March because of safety concerns. Specifically, the panel recommended that anti-anemia drugs no longer be taken by patients with breast cancer or head and neck cancer until more information about the drugs’ effect is known. In some cases, the drugs may make patients’ situations worse, it has been reported. This recommendation also affects Johnson & Johnson’s anti-anemia drug, "Procrit."  

Amgen has not yet commented on Grassley’s letter. The Senator has actively followed  the pharmaceutical industry and its regulation during the past year, specifically regarding imported products. See related articles below:

Senator Questions FDA's Foreign Inspections

Senator Chuck Grassley (R-IA) sent a letter to Amgen (Thousand Oaks, CA) last week asking the company to account for the high rebates it has given to certain physician groups who bought Aranesp.

Grassley Questions Amgen's Doctor Discounts

Filing risk and mitigation strategies is now a requirement for manufacturers of new drugs and biologics. As part of the Food and Drug Administration Amendments Act passed last fall, manufacturers may be asked to submit a risk evaluation and mitigation strategy (REMS) to FDA when a drug is first marketed, or later if FDA becomes aware of new safety data about the drug. In a 

  published last week, FDA identified several drugs and biologic products for which companies will be required to submit such safety plans by Sept. 21, 2008.

 The purpose behind REMS is to ensure that drugs are prescribed  and used properly. For example, said FDA in a Mar. 27 release, certain drugs “may be safe and effective for patients, but if taken while pregnant can harm the fetus or cause miscarriage.” The agency has approved drugs and biologics with REMS before, but the implementation of the Amendments Act gives FDA explicit authority to require the safety plans and to take action against companies who do not comply. The new authority will be applied to drugs approved after Mar. 25, 2008, as well as for already marketed drugs for which new risks are identified after Mar 25, 2008.

 “These safety plans allow patients to have continued access to certain medicines for which there are safety concerns that can be managed through appropriate use,” said Jane Axelrad, associate director for policy at FDA’s Center for Drug Evaluation and Research, in the release. 

 FDA  asked for comments about whether other drugs or biologics should be added to the list for REMS requirements. The current list is located 

Filing risk and mitigation strategies is now a requirement for manufacturers of new drugs and biologics.

Risk-Evaluation Plans Now Required

-US Representatives Anna G. Eshoo (D-CA) and Joe Barton (R-TX) introduced legislation this month week to create a regulatory pathway for biosimilars, or follow-on biologics. The so-called Pathway for Biosimilars Act would allow the US Food and Drug Administration to determine “whether the biosimilar is interchangeable with the reference product, and gives the FDA the flexibility to determine what clinical testing-if any-is required for approval,” according to a release from Rep. Eschoo. In addition, the act would provide 12 years of data exclusivity and establish a process for resolution of patent disputes prior to the time the biosimilar enters the market.

 Although the Hatch–Waxman Act established a pathway for conventional follow-on drugs to be approved by FDA in 1984, the act does not apply to biologics. The challenges are considered to be greater with biologics in terms of documenting comparability and safety of large molecules, but scientists now feel they have the technology to do so. (Read more about the 

In addition, because many biotechnology patents are starting to expire, many feel that now is the time to provide the pathway for biosimilars to reach the market. An additional goal behind the Pathway for Biosimilars Act is to “promote competition and lower prices, and protect patient safety, drug efficacy, and sound science,” said Rep. Eshoo in the release. “The most exciting developments in modern medical science are occurring in the field of biotechnology, and this legislation will ensure that the amazing cures and treatments biotech delivers today will continue and more patients will have access to these revolutionary therapies.”

There is concern over the Congressional proposal, however. The Generic Pharmaceutical Association (GPhA), for example, feels the act provides a pathway “to the wrong destination for patients in need of safe and affordable biogenerics,” according to a statement from GPhA President and CEO Kathleen Jaeger. “This new bill, at best, is a disappointing distraction that does nothing to advance legislation. At worst, it’s a step backwards that puts brand company profits before patient needs. For a pathway to work, it must ensure patient access. Unfortunately, this new proposal creates a pathway filled with needless roadblocks to access.”

 Jaeger and others are concerned that the data exclusivity period, coupled with standard patent protection time, is too long and will hamper further innovation. “It will be decades before patients have access to affordable biogeneric medicines,” she explained, proposing that industry and Congress work together to create a pathway that will balance innovation and consumer access as did the Hatch-Waxman Act 25 years ago.

Biotechnology Industry Organization (BIO) President and CEO Jim Greenwood is in support of Rep. Eschoo and Barton’s proposal, but cautions industry on the use of biosimilars. “While this provision improves upon previous legislative proposals, we continue to believe that patients should not be given follow-on biologics unless expressly prescribed by a physician,” he wrote in a BIO press release.

US Representatives Anna G. Eshoo (D-CA) and Joe Barton (R-TX) introduced legislation this month week to create a regulatory pathway for biosimilars, or follow-on biologics.