Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

As part of Ranbaxy's recently announced  consent decree, the company is required to set up a program whereby whistleblowers can come forward with information related to potential violations of the Food, Drug, and Cosmetic Act. According to the decree,  Ranbaxy must, within 75 days, establish a phone line and a system to receive and maintain submissions from individuals wishing to report suspected violations. The submissions are required to be confidential, there should be no retaliation, and a good-faith effort must be made to investigate any allegations.  

But what's good for Ranbaxy has been causing some discomfort for FDA.Whistleblowers from FDA's Center for Devices and Radiological Health have sued the agency over allegedly being harassed and dismissed after publicly questioning the agency's approval methods for devices. The suit brought by the whistleblowers alleges, among other things, that FDA improperly read private emails to support a case for dismissing the plaintiffs. This prompted a letter to FDA commissioner  Margaret A. Hamburg from Senator Charles Grassley (R–IA), in which he castigates the agency for perceived mistreatment of the whistleblowers, and includes a series of questions for the agency to answer to clarify its actions with respect to email monitoring. 

Among the questions to the agency, Grassley asks, "What steps have you taken to reassure employees that they have a right to direct communications with Congress?" The answer to that question is an important one. FDA should expect no less from itself with respect to whistleblower protection than it demands of others. 

Articles

FDA's treatment of whistleblowers lacks internal consistency.

FDA Encourages Whistleblowers, Just Not Its Own

 measures intended to reduce costs and increase efficiency to ensure the long-term success of its business model. The measures announced this week are part of a comprehensive transformation program that will be implemented in two phases. In the first two years, Merck plans to implement a new leadership organization, implement efficiency measures, and develop a long-term growth strategy. In the second phase, the company will explore new areas for growth. Cost savings from the first-phase efficiency measures are expected to fuel second-phase growth.

The announcement this week marks the beginning of the efficiency measures. At the beginning of 2012, Merck began the implementation of the new leadership organization, which defines the relationship of businesses, group functions, and country organizations. According to the press release, the objective of the new leadership organization is to streamline the organizational structure to be leaner, easier to navigate, and to speed up decision-making processes. The organizational realignment will continue in parallel to and support the efficiency program as well as the development of Merck’s long-term growth strategy.

The company expects the efficiency measures to result in workforce reductions across all businesses and regions, according to the release. The company deliberately did not release figures related to expected headcount reductions. In the release, Karl-Ludwig Kley, chairman of the executive board says, “We have a view on what needs to be achieved, but we will consult with the employee representatives on a country-by-country basis and we will consider any pragmatic proposals. We have specifically not published potential figures related to the efficiency program as we are committed to engaging constructively with the relevant stakeholders to achieve a mutually acceptable solution.”

Merck KGaA announced measures intended to reduce costs and increase efficiency to ensure the long-term success of its business model. The measures announced this week are part of a comprehensive transformation program that will be implemented in two phases.

Merck KGaA Announces Restructuring

Rare disease day is an annual awareness-raising event coordinated at the international level by 

, a non-governmental patient-driven alliance of patient organizations representing more than 502 rare diseases patient organizations in over 46 countries.  This year marks the fifth that EURORDIS has coordinated the event, which was marked by outreach activities in more than 40 countries that centered on the theme of solidarity.   EURORDIS organized a summit in Brussels, Belgium on Feb. 29, 2011, featuring speakers from European governments, rare disease research groups, and patient advocacy groups who highlighted both the progress and the remaining challenges around developing medicines for rare diseases and bringing them to market in Europe.

		In the US, Educational outreach to patient advocacy groups representing those with rare diseases was the focus of events held on Feb. 29 2012 at the NIH campus in Bethesda, MD and on Mar. 1, 2012 in Silver Spring, MD. Rare Disease Day was established to raise awareness with the public about rare diseases, the challenges encountered by those affected, the importance of research to develop diagnostics and treatments, and the impact of these diseases on patients’ lives.

		NIH’s event was organized by the NIH Office of Rare Diseases Research. The focus of the presentations was basic and translational research that can be used to identify the causes of rare diseases and develop cures. Presentations highlighted basic research from NIH scientists on the mechanisms of certain rare diseases. Additional presentations highlighted the potential application of stem cell therapies for rare diseases, and the role that molecular biology can play in identifying disease mechanisms.

 featured presentations by the Centers for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health, outlining the role that each agency plays in approving therapies for rare diseases. Presentations included an overview of the drug development and approval processes, and an explanation of accelerated review processes available for therapeutics intended to treat rare diseases. In addition, a presentation by the Office of Drug Shortages summarized the drug shortage problem and outlined the steps that FDA has been taking to alleviate shortages. This is of particular interest to patients with rare diseases because at least three drugs intended to treat rare diseases, Cerazyme, Fabrazyme, and doxil, are currently experiencing shortages.

		Patient advocacy groups are playing an increasingly important role in influencing the development of new therapies. These events offer an opportunity for government organizations to engage with the public about government’s role in the development of new drugs, and in turn to gain the perspective of the public about rare, but unmet medical needs.

Rare disease day is an annual awareness-raising event coordinated at the international level by EURORDIS, a non-governmental patient-driven alliance of patient organizations representing more than 502 rare diseases patient organizations in over 46 countries.

Spotlight on Rare Disease Day

On Feb. 21, 2011, FDA posted a copy of a 

 that was sent to the chairman of the executive board of Merck KGaA on Dec. 15, 2011, regarding cGMP violations identified at three of its European facilities: MS-Corsier-sur-Vevey, MS-Aubonne, and MS-Tiburtina. The letter was issued in response to inspections conducted between Jun. 27 and Jul. 1, 2011. Merck KGaA provided responses to the inspection reports in late June and July 2011 that FDA found to be insufficient. 

At the MS-Corsier-sur-Vevey plant, which manufactures APIs, FDA found that changes to a product, production process, quality controls, equipment, or facilities were not reported to FDA. The company indicated in its response letter to FDA that the changes had no effect on the finished API, but in the Warning Letter, FDA asks the company to provide the scientific rationale behind that assertion.

At the MS-Aubonne plant, a finished drug-manufacturing facility, FDA found several violations of cGMP. They found that the company had not:

Established or followed appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile

Established or followed appropriate written procedures for the handling of complaint records to determine if an investigation is required

Established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity

Submitted a Biological Product Deviation Report (BDPR) to FDA

Reported changes to a product, production process, quality controls, equipment, or facilities.

The MS-Tiburtina site is responsible for testing products destined for the United States. At the MS-Tiburtina, FDA found that Merck KGaA had not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed.

FDA notes in the Warning Letter that some of the cGMP violations listed in the letter impacted all three Merck KGaA facilities, and that “The lack of compliance with cGMPs may lead to production problems and adversely impact the availability of critical medically necessary products that meet required quality standards.”

On Feb. 21, 2011, FDA posted a copy of a Warning Letter that was sent to the chairman of the executive board of Merck KGaA on Dec. 15, 2011, regarding cGMP violations identified at three of its European facilities: MS-Corsier-sur-Vevey, MS-Aubonne, and MS-Tiburtina.

FDA Issues Warning Letters for Three Merck KGaA Plants

 a piece of legislation called the Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) Act. The bill is intended to accelerate the approval process for medicines targeted to conditions for which there are no effective treatments. The bill will be referred to the Senate Health, Education, Labor and Pensions (HELP) Committee that oversees healthcare issues.

		Specifically, the bill aims to accelerate approval for treatments that target an unmet medical need, that significantly enhance the standard of care, or are highly targeted therapies for distinct subpopulations. Hagan hopes that conditions for which there are currently no or limited therapeutic options will benefit from the same leg-up that was given to HIV/AIDS treatments in the 1990’s.

		According to the backgrounder, the bill contains specific recommendations for accelerating approval, including enhancing FDA access to external scientific and medical expertise, and including patient advocates and disease research organizations in Advisory Committee reviews. The bill also calls for establishing several new positions at FDA to ensure that the agency is up to date on the latest scientific and policy issues, including Chief Medical Policy Officers at the major branches of FDA to address emerging medical and scientific policy issues, and a Chief Innovation Director to ensure rapid development, testing, and review of new drugs and devices.

		It should be noted that FDA already has mechanisms for speeding up approval of drugs intended for unmet medical needs: fast track approval, accelerated approval, and priority review. The TREAT Act does not authorize any new funding for FDA, but proposes to reorganize FDA’s internal processes to ensure more consistency and clarity. While many sponsors complain that FDA is lacking in consistency and clarity, I’m curious to see how adding extra director-level positions will improve either.

Senator Kay R. Hagan (NC) introduced a piece of legislation called the Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) Act.

A TREAT for Patients

Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality

. The guidance was issued in response to a 2008 incident in which heparin sourced from China was adulterated with oversulfated chondroitin sulfate (OSCS), causing serious adverse reactions in patients.

The draft guidance is intended to alert manufacturers of APIs, pharmaceutical and medical-device manufacturers of finished products, repackers, and others to the potential risk of crude heparin contamination. In addition, it offers guidance for identifying and responding to adulterated crude heparin. FDA defines crude heparin as an unrefined mixture of heterogeneous polysaccharides including various impurities isolated from mammalian tissues that requires further purification and processing before clinical use.

According to the guidance, FDA considers the presence of OSCS or any nonporcine origin material, especially ruminant material (unless specifically approved as part of the drug application) in crude heparin, or any other form of heparin, to render that drug adulterated under section 501 of the Food, Drug and Cosmetics Act (21 92 U.S.C. 351).

The draft guidance contains recommendations for procedures to ensure that crude heparin does not contain OSCS or nonporcine origin material, including:

Testing and confirming the species of origin of crude heparin in each shipment

Testing for OSCS sulfate in each shipment

Knowing and identifying the actual manufacturer of crude heparin as well as any repackers or distributors who handle it before receipt and use

Employing the controls described in ICH Q7 to prevent the use of adulterated heparin, and fully and promptly investigating and resolving any deviations in quality

Rejecting and properly disposing of any adulterated crude heparin, as well as notifying FDA of the finding.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the 

 of the notice announcing the availability of the draft guidance.

Inside USP: Heparin Monographs Further Revised

FDA and Senate Call for Urgent Supply Chain Attention

FDA has released a draft guidance for API manufacturers in response to a 2008 incident in which heparin sourced from China was adulterated with oversulfated chondroitin sulfate, causing serious adverse reactions in patients.