Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

Representatives from FDA, the Generic Pharmaceutical Association, the European Fine Chemicals Group, and a task force from the Society of Chemical Manufacturers and Affiliates are nearing completion of draft legislation for the Generic Drug User Fee Act. The draft legislative language, once enacted, will provide authority for FDA to collect a fee, define the types of applications and facilities that will be subject to fees, and identify mechanisms by which FDA will notify industry of fee amounts, among other things. Some elements, such as an inflation adjuster, from the Prescription Drug User Fee Act (PDUFA), are included and the overall statutory structure is similar to PDUFA.

 from the Aug. 31, 2011 negotiation session, “The Generic Drug User Fee program is designed to keep individual fee amounts as low as possible to supplement appropriated funding to ensure that consumers continue to receive the significant benefits offered by generic drugs which provided more than $824 billion dollars in savings to the nation’s health care system in the last decade alone. The additional resources called for under the agreement, an inflation adjusted $299 million annually for each of the five years of the program, will provide FDA with the ability to perform critical program functions that could not otherwise occur.”

The program contains goals for application reviews and plant inspections. By year five of the program, FDA aims to review 90% of complete electronic abbreviated new drug applications within 10 months after the date of submission, and to review 90% of backlogged applications by the end of fiscal year (FY) 2017. FDA will conduct risk-adjusted biennial cGMP surveillance inspections of generic finished dosage form (FDF) and generic active pharmaceutical ingredient (API) manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms by FY 2017. 

Fees will be derived from both applications and facilities in a 30:70 split. Fees will be split across industry segments (FDF and API) in an 80:20 split.

The final meeting between FDA and industry representatives will be held on Sept. 7, 2011, after which the plan will be submitted for formal ratification.

2012 Prescription Drug User Fees Announced

Experts Ponder Ways to Fill Pharma Pipeline

Articles

Representatives from FDA, the Generic Pharmaceutical Association, the European Fine Chemicals Group, and a task force from the Society of Chemical Manufacturers and Affiliates are nearing completion of draft legislation for the Generic Drug User Fee Act.

Generic Drug User Fee Agreement Nears Completion

, triple the number recorded in 2005. Most of the drugs that experienced shortages (132 of the 178 that occurred in 2010) were sterile injectables, including cancer medications and anesthetics. Nearly all of those drugs are considered medically necessary, meaning they are used to treat or prevent a serious disease or medical condition, and there is no other source or alternative drug available. The human toll of the drug shortages was highlighted in a recent New York Times 

, in which patients undergoing cancer treatment were interviewed who were denied or were unsure of the supply of potentially life-saving medications.

According to FDA, there were numerous reasons for the shortages. Valerie Jensen, associate director of CDER’s Drug Shortage Program, 

, “Several different factors are contributing to the current shortage of sterile injectables and other drugs. Some firms decided to discontinue making their products for business reasons, others had problems with their raw materials suppliers, some had quality and manufacturing problems, and some were hit with an increased demand.”

Generic drugs made up a large proportion of the drugs in short supply, particularly older sterile injectables. The Pharmaceutical Research and Manufacturers of America (PhRMA) issued a statement in response, acknowledging the importance that generics play in the global drug supply, and urging its members to cooperate with regulatory agencies to avoid such shortages. Vice-president of PhRMA, Karl Uhlendorf, said in the 

, “Drug shortages of any kind are a complex problem that requires broad-based solutions from all stakeholders-including innovative biopharmaceutical research companies and generic manufacturers, whose products accounted for nearly 80% of prescriptions filled last year. Regardless of the cause, in order to provide patients with uninterrupted access to medicines, it is important for all of us who provide life-saving medications to work collaboratively to minimize unexpected disruptions in the supply of vital medicines. PhRMA member companies accomplish that by our commitment to maintaining good manufacturing practices and working closely and collaboratively with the FDA, supply chain partners and providers when unexpected-and rare-shortages occur.”

Such shortages can have important public health consequences. For instance, the World Health Organization was forced to delist three vaccines manufactured by Panacea Biotec because of quality issues. 

, “Specifically, deficiencies in the quality management system found at the Lalru site relate to the manufacture of the haemophilus influenzae type b (Hib) and hepatitis B bulks used for the formulation of the DTwP-Hep B-Hib, DTwP-Hep B, and hepatitis B vaccines.” Moreover, 

 healthcare professionals to expect shortages because it has banned the import of several drugs manufactured at Boehringer-Ingelheim’s contract manufacturing plant Ben Venue, again, because of quality issues.

Safety Concerns and Shortages Challenge Pharma

Senator to Draft Legislation to Mitigate Drug Shortages

Drug Shortages Rise, but No Requirement to Report Them

In 2010, FDA recorded nearly 180 drug shortages, triple the number recorded in 2005. Most of the drugs that experienced shortages were sterile injectables, including cancer medications and anesthetics.

Drug Shortages Loom Large

 with the Securities and Exchange Commission (SEC) for the quarter ending July 2011, Pfizer indicated that it has voluntarily provided the SEC and the Department of Justice (DOJ) with information concerning potentially improper payments made by Pfizer and Wyeth in connection with sales activities that took place outside of the United States.

Pfizer also says in the filing that it is in discussion with the DOJ and the SEC regarding a resolution of these matters. Pfizer also disclosed that other potentially improper payments are the subject of investigation by government authorities in other countries, including a tax investigation being conducted in Germany related to a wholly owned subsidiary of Pfizer.

If SEC finds that the improper payments constituted bribery, it could be costly for Pfizer. Earlier this month, Johnson & Johnson (J&J) agreed to pay $70 million to settle 

 brought by the SEC. J&J was charged with bribing public doctors in Greece, Poland, and Romania, as well as paying kickbacks in Iraq to obtain contracts under the Oil for Food Program.

US Steps Up Scrutiny of Foreign Transactions

Physician Payments Sunshine Act Reintroduced for 2009

In its latest filing with SEC for the quarter ending July 2011, Pfizer indicated that it has voluntarily provided the SEC and DOJ with information concerning potentially improper payments made by Pfizer and Wyeth in connection with sales activities that took place outside of the United States.

Pfizer Discloses Potentially Improper Payments

 in the Aug. 4, 2011, issue of The New England Journal of Medicine that describes their current thinking about a pathway for the regulatory approval of biosimilars. The agency’s approach reflects its examination of EMA guidelines, as well as the nature of biological drugs.

The authors began the article by acknowledging the innate complexity of biologics. “Given the complex nature of biologics, it’s unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed,” said the authors. “Instead, FDA scientists will need to integrate various types of information to provide an overall assessment that a biologic is biosimilar to an approved reference product.” FDA has studied the EMA guidelines and is drawing on that agency’s experience with an abbreviated approval pathway for proteins that are regulated as drugs. FDA favors a complex, “totality of information” framework, in which structural, chemical, and clinical data are evaluated for each product. The agency hopes to characterize some products well enough to produce a “fingerprint” by which they can be recognized with a high degree of certainty.

FDA is familiar with risk-based approaches to approvals and will be using them in its evaluation of biosimilars. Each product’s complexity, formulation, stability, and the usefulness of the available biochemical and functional characterizations will be evaluated for risk. The agency also will consider the mechanistic understanding of the clinical effect of a biologic and the level of clinical information available. Manufacturing processes will be examined for the potential to introduce variants or impurities that could affect risk.

Because of the complexity of large-molecule drugs, FDA expects that an extensive product review will be required to determine how much additional data are needed to approve a biosimilar. FDA is currently considering how review-related interactions might be structured and how they will affect the user-fee program that Congress mandated for biosimilars.

The article makes it clear that FDA has no simple way to answer the critical question of how similar a biosimilar must be to the branded product. Each generic small-molecule drug must meet well-defined criteria, but no formula exists for biosimilars. As more products are approved as biosimilars, the process may gain predictability. But for now, the answer is “We’ll know it when we see it.”

In 2009, Congress passed the Biologics Price Competition and Innovation Act, authorizing an abbreviated approval pathway for biologics that are biosimilar to already-approved products. Since that time, manufacturers have been waiting for guidance from FDA about the details of the approval process.

Last year, we also published a special feature on biosimilars, which can be accessed 

Finally, don't forget to take part in our biosimilars poll 

Since the passage of the BPCI Act in 2009, manufacturers have been waiting for guidance from FDA on what that approval process will look like.

For Biosimilars, No “One Size Fits All”

In late July, FDA announced the 2012 user fees collected under the Prescription Drug User Fee Act (PDUFA) of 2007. The act stipulates that one-third of the PDUFA fee revenues FDA collects each year will be generated from each of three categories: applications for approval of drug and biological products, establishments where the products are made, and drug and biological products. In some instances, the fees can be waived, reduced, or refunded, as spelled out in an FDA 

The fees are calculated using the fee base revenue amount for fiscal year (FY) 2008 published in the 

 of Oct. 12, 2007 (72 FR 58103) adjusted for the FY 2009, FY 2010, FY 2011, and FY 2012 drug-safety increases, for inflation, for workload, for excess collections through FY 2011, and for a final-year adjustment. 

For applications requiring clinical data, the FY 2011 fees were $1,542,000. FY 2012 fees will be $1,841,500, a 19.42% increase.

For applications that do not require clinical data, the FY 2011 fees were $771,000. FY 2012 fees will be $920,750, a 19.42% increase.

For supplements requiring clinical data, the FY 2011 fees were $771,000. FY 2012 fees will be $920,750, a 19.42% increase.

Establishment fees for FY 2011  were $497,200. FY 2012 fees will be $520,100, a 4.6% increase.

Product fees for FY 2011 were $86.520. FY 2012 fees will be $98,970, a 14.3% increase.

These fees are effective on Oct. 1, 2011, and will remain in effect through Sept. 30, 2012.

FDA Issues Draft Guidance on User-Fee Waivers, Reductions, and Refunds

FDA Holds Public Meeting on Prescription Drug User Fee Act

FDA announced in late July the 2012 user fees collected under the Prescription Drug User Fee Act of 2007.

The age of globalized industry should result in fewer barriers between countries, but it is rarely that straightforward in practice. At the India–US Strategic Dialogue held in New Dehli on July 19, 2011, India’s junior science minister Ashwani Kumar complained to US presidential science adviser John Holdren that a new US visa policy is hampering the ability of Indian scientists to travel to the United States, according to a 

 by ScienceInsider. Kumar asked that the procedure be streamlined. Indian scientists, even top aides to the government, are now required to renew their visa annually, but they previously could obtain a multiple-entry visa every 5 to 10 years. This change makes it difficult for Indian scientists to attend conferences in the US or engage in any other frequent, short-duration travel without attending to yearly paperwork. “I understand the visa issue is a problem and a challenge, and we hope to improve it,” said Holdren, according to ScienceInsider.

The United Kingdom has also been busy erecting barriers to foreign scientists. On July 20, 2011, the UK border agency created a 

, called Tier 1 “exceptional talent.” The category is limited to 1000 visas, and each applicant must be vetted by a member of a nationally recognized expert body to ensure that he or she is an expert in their field and an exceptional talent. The Royal Society can nominate 300 scientists for the visas, and the Royal Academy of Engineering can nominate 200. The visas will allow individuals to work in the UK for an initial period of three years and four months, with a possible extension of two years and a permanent settlement option. The visas do not apply to early-career scientists, such as postdoctoral scientists.

Although the Royal Society agreed to work with the border agency on this initiative, it is not happy in its role as gatekeeper for immigrant scientists. 

Paul Nurse, president of the Royal Society, told ScienceInsider

 that the organization does not believe that the number of scientifically talented individuals permitted to work in the United Kingdom should be restricted. He also said that the society would be monitoring the effectiveness of the program, and if it proved to be a real barrier for qualified scientists’ entry into the UK, that they would inform the border agency. “We’re very concerned this will be bureaucratic and laborious and that will put people off even on short-term visits, so we’re looking at it with significant concerns,” says Nurse. “I don’t know any research scientist who has any support for this scheme. It only seems to be making difficulties.”

The age of globalized industry should result in fewer barriers between countries, but in practice it is rarely that straightforward, according to a report by ScienceInsider.