Department of Justice files consent decree of permanent injunction against Ranbaxy

January 25, 2012. The Department of Justice, on behalf of the U.S. Food and Drug Administration, has filed a consent decree of permanent injunction against generic drug manufacturer Ranbaxy in the U.S. District Court of Maryland. The consent decree was filed against Ranbaxy Laboratories, Ltd., an Indian corporation and its subsidiary Ranbaxy Inc., headquartered in Princeton, N.J. Ranbaxy Labs.’ Dale Adkisson, senior vice president, head of global quality and Arun Sawhney, chief executive officer and managing director, and Ranbaxy, Inc.’s Venkatachalam Krishnan, regional director Americas, were also named as defendants. The consent decree will address outstanding current good manufacturing practice (CGMP) and data integrity issues at Ranbaxy’s Paonta Sahib, Batamandi and Dewas, India facilities as well as CGMP issues at Ranbaxy Inc.'s wholly owned subsidiary Ohm Laboratories facility located in Gloversville, N.Y. 

Ranbaxy’s Paonta Sahib, Batamandi, and Dewas, India facilities have been on FDA import alert since 2008 and Ranbaxy has closed its  Gloversville facility. The public should not be concerned that any drugs from those facilities are currently in the U.S. market. FDA recommends that patients not disrupt their drug therapy because this could jeopardize their health. Individuals who are concerned about their medications should talk with their health care professional.

The consent decree requires that Ranbaxy comply with detailed data integrity provisions before FDA will resume reviewing drug applications containing data or other information from the Paonta Sahib, Batamandi, and Dewas facilities.  Specifically, Ranbaxy must:

(1) hire a third party expert to conduct a thorough internal review at the facilities and audit applications containing data from the affected facilities;

(2) implement procedures and controls sufficient to ensure data integrity in the company’s drug applications; and

(3) withdraw any applications found to contain untrue statements of material fact and/or a pattern or practice of data irregularities that could affect approval of the application. 

In addition, the consent decree prevents Ranbaxy from manufacturing drugs for introduction to the U.S. market and for the President’s Emergency Plan for AIDS Relief (PEPFAR) Program at the Paonta Sahib, Batamandi, Dewas, and Gloversville facilities until drugs can be manufactured at such facilities in compliance with U.S. manufacturing quality standards. 

“Because this company continued to violate current good manufacturing practice regulations and falsify information on drug applications, the FDA took these actions in an effort to protect consumers,” said Dara Corrigan, FDA associate commissioner for regulatory affairs. “The FDA continues to be committed to protecting consumers from potentially unsafe products that may be offered on the market.”

Under this agreement, once Ranbaxy has achieved compliance with the data integrity requirements, a third party expert must conduct audits of the facilities to confirm that compliance is being maintained.  The company must authorize an individual to be responsible for all quality assurance and quality control activities to ensure that drugs have the required safety, identity, strength, quality, purity, and potency and are in compliance with the law and the decree.  In addition, they must establish an Office of Data Reliability to conduct pre-submission audits of all applications submitted from any facility after entry of the decree.

Ranbaxy has agreed to relinquish any 180-day marketing exclusivity that it might have for three pending generic drug applications, and the firm has further agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic drug applications if it fails to meet certain decree requirements by specified dates.

The consent decree contains liquidated damages provisions to cover many potential violations of the law and the decree. In addition to a provision requiring Ranbaxy to pay $15,000 in liquidated damages for each day defendants violate the law or the decree at the facilities covered by the decree and an additional sum of $15,000 for each overall violation of the law and the decree, the decree states that:  (1) if defendants distribute any drug from the facilities covered by the decree, Ranbaxy shall pay liquidated damages equal to two times the retail value of such drug, not to exceed 10 million dollars in any one calendar year; and (2) if defendants submit an untrue statement in connection with any application they file with FDA, Ranbaxy shall pay up to three million dollars in liquidated damages for each such statement, not to exceed 30 million dollars in any one calendar year. 

The decree also permits FDA to order additional Ranbaxy facilities to be covered by the decree if the agency discovers through an inspection that the facility is not operating in compliance with the law and/or has serious data integrity issues. 

The decree was filed on January 25, 2012, and is subject to court approval.x

FDA completes work on three drug user fee programs

FDA.For Immediate Release: Jan. 13, 2012. The U.S. Food and Drug Administration has completed its recommendations for three user fee programs that will help speed safe and effective drugs and lower-cost generic drug and biosimilar biological products to patients, FDA Commissioner Margaret A. Hamburg, M.D. said today. The recommendations were transmitted to Congress today by Health and Human Services Secretary Kathleen Sebelius.

The programs include the fifth authorization of the Prescription Drug User Fee Act (PDUFA), and new user fee programs for human generic drugs and biosimilar biological products. Work on the proposals was concluded before the agency’s mid-January deadline.

Under a user fee program, industry agrees to pay fees to help fund a portion of the FDA’s drug review activities while the FDA agrees to overall performance goals such as reviewing a certain percentage of applications within a particular time frame.

“These final recommendations offer a great example of what can be achieved when the FDA, industry and other stakeholders work together on the same goal,” Hamburg said. “At a time of greater budgetary constraint, user fees provide a critical way for leveraging appropriated dollars, ensuring that FDA has the resources needed to conduct reviews in a timely fashion.” 

Said Hamburg: “Human drug user fees have revolutionized the drug review process in the United States since they were adopted 20 years ago, allowing the FDA to speed the application review process without compromising the agency’s high standards.”

The proposed user fee programs for generic drugs and biosimilars are modeled on the successful PDUFA program “which has ensured a predictable, consistent, and streamlined premarket program for prescription drugs,” Hamburg said.  As a result of the continued investment of PDUFA resources, the United States now leads the world in first introduction of novel drugs.

PDUFA was created by Congress in 1992 and must be reauthorized every five years. The current program, known as PDUFA IV, will expire on Sept. 30, 2012, unless reauthorized by Congress. FDA’s recommendations for PDUFA V were developed in consultation both with drug industry representatives and with patient and consumer advocates.

Under the recommendations, fees paid by industry would support continued timely review of critical prescription drugs, as well as advance the development of drugs for rare diseases, provide for enhanced communication with small or emerging companies, increase the use of standardized electronic data to improve quality and efficiency, and foster the use of new clinical endpoints that improve drug development times and help address unmet medical needs.

The proposed new Generic Drug User Fee program would provide the FDA with needed funding at a time when generic drug applications are on the rise. Generic drug user fees would help ensure consumers timely access to safe, high-quality and effective generic drugs, which account for two-thirds of all prescriptions dispensed in the U.S.

The FDA receives 800 to 900 new generic-drug-related applications annually. These applications are increasingly complex and frequently involve products manufactured outside of the U.S. In exchange for fees on facilities and product applications, the proposal includes performance metrics such as review timeframes and a commitment to achieve parity between surveillance inspections of foreign and domestic establishments by the 2017 fiscal year. As a result, FDA expects that the proposal would effectively eliminate the review backlog and significantly reduce review times.

A biosimilar is a biological product that is highly similar to a U.S.-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. The proposed Biosimilar and Interchangeable Products User Fee program is intended for products approved under a new abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological product. The Affordable Care Act of 2010 contains a subtitle called the Biologics Price Competition and Innovation Act (BPCI) of 2009, which established this pathway.

Prior to it becoming law, competition in the biologic drug market was stifled. Enactment of BPCI will spark the development of a new segment of the industry, where companies will be able to develop alternative products. This will help spur innovation, improve consumer choice and drive down costs.

The recommended user fee program for biosimilars includes fees for products in development to generate revenue in the near-term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates.

For more information:

Prescription Drug User Fee Act

     

Prescription Drug User Fee Act: PDUFA V Reauthorization

 

PDUFA V Reauthorization Goal

 

PDUFA V Statutory Language

 

Generic Drug User Fees

 

Generic Drug User Fee Act Program Performance Goals and Procedures

 

Generic Drug User Fees Statutory Language

 

Biosimilar and Interchangeable Products User Fees

 

Biosimilar Biological Product Authorization Performance Goals and Procedures

 

Biosimilar Statutory Language   

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Multi-therapy Drugs: Opportunities for Generics & Biosimilars

Highly-detailed analysis, outlook & forecasts of 24 leading drugs which are indicated for a range of critical conditions.

Targeting multiple conditions is likely to increase a drug's potential target audience and result in large financial returns for the developing company. With annual sales counted in billions of dollars, these blockbuster drugs are undoubtedly attractive to companies developing generics and biosimilars.

The logic is simple: more indications result in a larger number of potential patients and, consequently, greater revenue opportunities. Obviously this logic only works if there is unmet clinical need and efficacy is demonstrated in each indication, so the number of drugs approved for multiple indications is relatively small. But where multiple indications are approved, annual sales can be counted in billions of dollars. The trend for developing products for multiple indications has been particularly evident in biological pharmaceuticals and has resulted in multi-billion dollar sales over a number of years. The commercial costs of developing biosimilars are great. Better, then to have the possibility of multiple revenue streams.

Assessing additional sales potential from a valuable product fit

The multi-therapy drugs included in this report realised total sales in excess of US$70 billion in 2010. It is, therefore, hardly surprising that many are being targeted by generic companies for the development of either traditional bioequivalent generics, or as targets for the next
wave of biosimilars.

The top selling multi-therapy drug in 2010 was Enbrel (etanercept), with sales reported separately by Amgen, Pfizer and Takeda amounting to a total of US$7,850 million. Remicade (infliximab) was a close second, with sales reported by Johnson & Johnson and Merck & Co totalling US$7,581 million in 2010. In third place was Abbott's Humira (adalimumab), with sales of US$6,738 million; while Roche reported global sales of Rituxan/MabThera (rituximab) worth US$6,094 million in 2010.

While the top five in terms of sales in 2010 were biologicals, a number of small molecule multi-therapy drugs have established a place among the market leaders and are worthy of attention as they will not face the same regulatory obstacles of biosimilars. These include AstraZeneca's Seroquel franchise, with revenue of US$5,302 million; Otsuka/Bristol-Myers Squibb's Abilify (aripiprazole) with sales reported by Otsuka amounting to US$4,266 million; and Novartis' Glivec/Gleevec (imatinib) with sales of US$4,265 million.

Generic and biosimilar opportunities: high risk, high reward?

With annual sales counted in billions of dollars, these blockbuster drugs are undoubtedly attractive to companies developing generics and biosimilars. Competition is often fierce for bioequivalent generics of the big sellers. Consequently, companies are likely to be vying for a relatively small slice of the market. Nonetheless, when branded sales are counted in billions of dollars, companies could still make a significant return even with generic price erosion.

The market for biosimilars is inherently different to the traditional generics market. Market acceptance remains a big challenge and the take up of biosimilars in Europe to date has been relatively slow. Not only will companies need to convince healthcare providers that biosimilar drugs are as good as the originator products, they will also have to compete with the originator companies who are less likely to exit the market than if faced with a flood of bioequivalent generics.

Biosimilar approval for multiple indications: extrapolation or additional trials?

One question that has yet to be fully answered with regard to multi-therapy drugs is whether biosimilar approval for one indication will automatically lead to approval for all indications associated with the reference product.

In the EU - so often the leading player in biosimilar regulation - the current position seems a little vague. In November 2010, the EMA discussed extrapolation in its draft guideline on similar medicinal products containing monoclonal antibodies (MAbs: EMA/CHMP/BMWP/403543/2010). The guideline suggested the possibility of extrapolation of clinical efficacy and safety data to other indications of the reference MAb, based on the overall evidence of biosimilarity. However, the reality is unlikely to be simple, particularly when the reference product is approved in unrelated indications.

The final guideline has yet to be published and a year later the subject of extrapolation remains a major topic of discussion. In the meantime, companies are hedging their bets and conducting comparative studies of their biosimilar MAbs in more than one indication.

Multi-therapy Drugs: Opportunities for Generics & Biosimilars