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When I think of Jerusalem, iconic images of religious and historic sites come to mind. Last month, I had the pleasure of visiting Jerusalem. There I met with Chen Levin, Executive Director of BioJerusalem, and learned that Jerusalem is working to become the Bio-Pharmaceutical capital of Israel.

BioJerusalem, an initiative of the Jerusalem Development Authority, was founded in 2006 by Dr. Shirley Kutner to help fuel the economic development of Jerusalem by leveraging the vast Life Sciences resources available in the city. BioJerusalem is committed to growing Jerusalem into a thriving Life Sciences center of sustainable enterprises and solid investments, grounded on cutting edge innovation.

Dr. Kutner is now in the Philadelphia region, where we’ve had the opportunity to collaborate on a number of Life-Science committees and projects. She is currently leading the strategic planning for the creation of the Regional Health Innovation Partnership based on BioJerusalem’s model.

“If you are in the basic sciences and research, the names Hebrew University and Hadassah have a strong meaning for you. Over 50% of clinical research in Israel is performed at Hadassah & Shaare Zedek hospitals and 43% of the biomedical research is performed at the Hebrew University all based in Jerusalem,” commented Chen Levin. “Two blockbuster drugs, Exelon used to treat of Alzheimer’s and Doxil used to treat of cancer, originated from the Hebrew University of Jerusalem,” she added.

“If you look on the Industry side, over 150 pharmaceutical, biotech and medical device companies are already operating in Jerusalem,” Levin told me.

Teva Pharmaceuticals, which was founded in Jerusalem in 1901, operates 2 large manufacturing facilities in the city. In addition, Omrix Biopharmaceuticals, - which was acquired by Johnson & Johnson in 2008 for $438 million, BioLineRx, Medinol and Gamida Cell have operations in Jerusalem. The Life Science sector employs 32,000 people, which represents 12% of the Jerusalem’s workforce.

In 2005, the Israeli government allocated 280 million NIS (~ 93 million USD) to the Jerusalem Economic Development Program to be distributed over seven years, for the economic development of the city. As a result, a number of leading companies have expanded their presence in Jerusalem since 2005. Here are some examples:

• Teva Pharmaceutical has opened a new plant in Har Hotzvim with an investment of $80 million. Teva operates 2 plants in Jerusalem, which together employ ~1,000 people.
• Omrix Biopharmaceuticals constructed its main manufacturing site in Jerusalem. The company is building new facilities with an investment of approximately $20 million, which will employ 60 people.
• Rafa Laboratories has 5% of the Israeli pharmaceutical market, with annual sales of approximately $70 million. The company was founded in Jerusalem in 1937, and is building a new 10,000 square meter plant with an investment of ~ $38 million. The plant is expected to be finished in 2013 and will employ 300 people.
• Sigma Aldrich - Opened a new plant in Har Hotzvim in 2010, and is now planning another expansion. Sigma has 2 plants in Jerusalem which together employ 100 people.

To continue to support the momentum of the Life Science cluster in Jerusalem, the Israeli Government approved the Marom (Hebrew for uplift) Program in May 2011. The program offers financial incentives including:

• Grants for Life-Science companies 
• Creation of subsidizes laboratories facilities for start-up companies
• Grants for companies that supply R&D services to biotech companies
• Grants for encouraging doctors in hospitals to perform applied translational research

So why should Life Science companies establish a presence in Jerusalem?

“The main considerations for companies looking to establish a presence is the nature of the collaboration, the quality of the research and development taking place, and we have an edge in all of those areas here in Jerusalem. In addition we offer the most financial incentives in all of Israel. We’d like to see companies establish themselves in Jerusalem and take advantage of our leading edge research and development, whether they are Israeli companies, foreign companies or a collaboration.” said Levin.

This week, the U.S. Food and Drug Administration released its Strategic Plan for Regulatory Science. The plan calls for a sweeping modernization of the science used in developing and evaluating products critical to the nation’s health, economy, and security. According to FDA Commissioner Margaret A. Hamburg, “It positions us to foster innovation through better science without compromising our high safety standard,” M.D.

The Strategic Plan identifies eight priority areas of regulatory science where new or enhanced engagement is essential to the continued success of FDA’s public health and regulatory mission. These priority areas are:

1. Modernize Toxicology to Enhance Product Safety
2. Stimulate Innovation in Clinical Evaluations and Personalized Medicine to Improve Product Development and Patient Outcomes
3. Support New Approaches to Improve Product Manufacturing and Quality
4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies
5. Harness Diverse Data through Information Sciences to Improve Health Outcomes
6. Implement a New Prevention-Focused Food Safety System to Protect Public Health
7. Facilitate Development of Medical Countermeasures to Protect Against Threats to U.S. and Global Health and Security
8. Strengthen Social and Behavioral Science to Help Consumers and Professionals Make Informed Decisions about Regulated Products

In this article, I would like discuss priority #3, “Support New Approaches to Improve Product Manufacturing and Quality.” 

To support this priority, FDA will continue to promote what it calls “state-of-the-art manufacturing strategies,” Process Analytical Technology (PAT) and Quality-By-Design (QbD). The challenge for industry and regulators is that outsourcing may be hindering the application of PAT and QbD. In my Viewpoint article published in the current issue of Pharmaceutical Technology (you decide if it was a coincident), I discuss the issues and propose solutions and best practices to address them (See: Has Outsourcing Derailed PAT and QbD?).

As the pharmaceutical industry increases outsourcing, many brand owners have lost their ability to collect, act, and capitalize on critical quality attributes and process parameters. These data are critical to achieve PAT and QbD.

This lack of visibility supports the need for the implementation of data acquisition and analytic systems and processes that can provide On-Demand Visibility across a company’s supply chain. Such information would afford a sponsor company the opportunity to better and more tightly control ingredients, components, and products supplied by third parties. This control is crucial to help reduce the risk of nonconformances, CAPAs and recalls.

Technology is not the stumbling block. Today, mature technology is available to support the implementation of interconnected and interoperable systems that provide On-Demand Visibility across the supply network. This level of transparency would not only support PAT and QbD approaches across the global supply chain, but also would manage product safety, efficacy, and quality.

To support PAT and QbD approaches in a global and outsourced environment, companies must implement strategies to provide On-Demand Visibility across every stakeholder in their supply network.

Do you have On-Demand Visibility?

You are not alone. According to our research only 3% of industry executives said they have it.

Winston Churchill said that “Democracy is the worst form of government except all the others that have been tried.” Similar arguments have been made by most constituents in the Medical Device ecosystem about the 510(k) process. Seeking ways to improve the 510(k) process the FDA’s Center for Devices and Radiological Health (CDRH) commissioned the Institute of Medicine (IOM) to evaluate and provide recommendations for improving this process.

On July 29, 2011, the IOM released its long awaited report on FDA’s 510(k) clearance process. The IOM report concludes that “the current 510(k) process is flawed based on its legislative foundation. Rather than continuing to modify the 35-year-old 510(k) process, the IOM recommends that the “FDA’s finite resources would be better invested in developing an integrated premarket and postmarket regulatory framework that provides a reasonable assurance of safety and effectiveness throughout the Device Life Cycle.”

The response from both FDA and industry was swift and direct. Although all seem to agree that the 510(k) process needs to be improved neither the FDA nor industry stakeholders are willing to start from scratch to implement them.

Jeffrey Shuren, MD, Director of CDRH, noted that: “FDA believes that the 510(k) process should not be eliminated but we are open to additional proposals and approaches for continued improvement of our device review programs.”

Comments from industry groups were more forceful in their disapproval of the IOM report recommendation.  Medical Device Manufacturers Association (MDMA) President and CEO Mark Leahey stated in part “…we completely disagree that the 510(k) pathway is ‘flawed’ and that the FDA needs to eliminate it. While we are pleased that the IOM recognizes the crucial role medical devices have in health care, it is also important to remember that studies prove the 510(k) process has a strong track record on patient safety, and a complete overhaul of the system is simply not warranted.”

Stephen J. Ubl, president and CEO of the Advanced Medical Technology Association (AdvaMed) was more specific in his statement: “The report’s conclusions do not deserve serious consideration from the Congress or the Administration. It proposes abandoning efforts to address the serious problems with the administration of the current program by replacing it at some unknown date with an untried, unproven and unspecified new legal structure. This would be a disservice to patients and the public health.”

Where do we go from here?

Most constituents agree that improvements to the current 510(k) process are needed.
IOM’s recommendations for the “Ideal Medical-Device Regulatory System” are a worthy goal to strive for. The IOM committee defined the following six attributes of an Ideal Medical-Device Regulatory System (not presented in any priority order)

• The process should be based on sound science.
• The process should be clear, predictable, straightforward, and fair.
• The process should be self-sustaining and self-improving.
• The process should facilitate innovation that improves public health by making medical devices available in a timely manner and ensuring their safety and effectiveness throughout their Life Cycle.
• The process should use relevant and appropriate regulatory authorities and standards throughout the Life Cycle of devices to ensure safety and effectiveness.
• The process should be risk-based.

The IOM’s proposed “approach” for the Ideal Medical-Device Regulatory System sounds a lot like FDA’s Total Product Life Cycle approach. The Top priority in CDRH’s 2011 Strategy is the full implementation of a Total Product Life Cycle approach. To support this effort, The Agency plans to integrate premarket, postmarket, and compliance information and functions to take into consideration all of the relevant information available to the Center at any stage of a product’s Life Cycle to assure the safety, efficacy, and quality of medical devices. (See: Is Industry Ready To Meet FDA CDRH Top Strategic Priority)

FDA’s 5 year plan further asserts its commitment to a Life Cycle approach. To this end, FDA is working to take steps to facilitate the seamless incorporation of new scientific information available throughout the Total Product Life Cycle into regulatory decision making.

So rather than throwing out the baby with the bathwater, I would suggest that all constituents collaborate to improve the 510(k) process to:

• Provide reasonable assurance that marketed devices, throughout their Life Cycles, are safe and effective according to current standards for the clinical indication at the time of use. 
• Facilitate innovation by allowing prompt access of devices to the market.

By Daniel R. Matlis

Today, 80 percent of the active pharmaceutical ingredients and bulk chemicals used to make U.S. drugs originate outside of this country. Increased outsourcing of manufacturing, a complex and globalized supply chain, and criminal actors create the potential for counterfeit or substandard medicines to reach patients. “Compared with a decade ago, pharmaceutical supply lines stretch around the world and out to a complex web of suppliers. Regulators and industry must modernize supervision of the manufacturing process to ensure the drugs we consume are safe,” said Allan Coukell, director of medical programs at the Pew Health Group.

To examine today’s pharmaceutical supply chain and its risks, the Pew Health Group produced a white paper entitled After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs. The report takes a comprehensive look looks holistically at the production and distribution of drugs from the sourcing of raw materials to the pharmacy counter.

After Heparin is based on public information, including FDA documents, U.S. Government Accountability Office (GAO) reports, congressional testimony, peer-reviewed journals and interviews with more than 50 supply chain experts and stakeholders. The initial findings and recommendations were discussed during a two-day March convening in that included a diverse group of industry representatives, ranging from ingredient manufacturers to community pharmacists. (The Pew Health Group whitepaper references Axendia’s Report “Achieving Global Supply Chain Visibility, Control & Collaboration in Life Sciences.”)

“Today’s prescriptions are being produced under last century’s oversight,” said Allan Coukell, director of medical programs at the Pew Health Group. “As pharmaceutical manufacturing is increasingly globalized and outsourced, Congress must close serious gaps in FDA oversight. In particular, the agency must be able to order the recall of adulterated drugs — a power now lacking — and must have the ability to block medicines from entering the U.S. if they were made at a factory that refused an FDA inspection. At the same time, manufacturers should bear ultimate responsibility for drug safety. Congress should require companies purchasing pharmaceutical ingredients from overseas to ensure that their suppliers are manufacturing to the highest standards.”

The Pew Health Group White paper details a number of recommendations for industry and policy makers to remedy drug supply chain problems, including:

• Pharmaceutical companies must have comprehensive systems to ensure quality and safety. This means that companies must take responsibility for the entire supply chain by: improving oversight of contract manufacturers and suppliers; ensuring documentation and transparency of incoming drug ingredients; and developing rigorous testing standards. Drug makers must audit suppliers on-site and institute supplier quality agreements. Company management must be held accountable for implementing these systems.
• The security of drug distribution must be improved. Once manufacturing is complete, medicines may pass through many hands before reaching patients, providing opportunities for stolen or counterfeit products to enter the system. Insufficient tracking and transparency can prevent industry and regulators from identifying the source of stolen or counterfeit products. Congress should establish stronger national standards for the oversight of drug wholesalers and require the private sector to track and verify the authenticity of pharmaceuticals.
• FDA authority and enforcement gaps must be addressed. Despite globalization of manufacturing, U.S. government oversight is largely domestically focused. Overseas inspections by the agency must be significantly increased, along with expanded use of third-party sources of information to supplement FDA inspections. Congress should ensure that FDA can order the recall of an adulterated or substandard drug, similar to the agency’s authority for food and medical devices. In addition, the agency needs the authority to subpoena documents and witnesses and an improved set of enforcement tools, such as strengthened penalties for certain violations.

“The After Heparin white paper identifies links in the supply chain that government and business should strengthen” Coukell added.