Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The US Food and Drug Administration needs to enhance its oversight of drugs approved on the basis of surrogate endpoints, according to a September 

 from the Government Accountability Office (GAO) that was released this week. 

FDA established its accelerated approval process in 1992 to expedite drug approvals for products that treat serious or life-threatening illnesses. The agency approved 90 such applications between 1992 and Nov. 20, 2008. These approvals are based on the drug’s impact on a surrogate endpoint such as blood pressure rather than on direct clinical evidence such as the drug’s ability to prevent a stroke, according to the GAO report. The agency then relies on postmarketing studies to further assess the drug’s effectiveness, which is where problems seem to come into play, according to the GAO report. 

Specifially, GAO found that the agency’s ability to effectively monitor postmarketing studies is weak. Furthermore, the agency does not have clear procedures for using its authority to withdraw a drug from the market if a manufacturer fails to complete a postmarketing study or if such a study fails to confirm a drug’s clinical benefit. The GAO report states that FDA has never exercised its authority to withdraw a drug in such conditions even if a required postmarketing study, in one instance, was still not completed after 13 years.

GAO recommends that FDA clarify the conditions under which it would expedite the withdrawal of drugs under its accelerated approval process as a way to enhance the agency’s oversight.

FDA disagreed with the need for such clarification in its drug-withdrawal procedures, according to the GAO report.  Although the agency does have a plan to strengthen its oversight, “the agency has taken a passive approach to enforcing confirmatory study requirements,” says GAO.


Articles

The US Food and Drug Administration needs to enhance its oversight of drugs approved on the basis of surrogate endpoints, according to a September report from the Government Accountability Office (GAO) that was released this week.

GAO Report Calls Out FDA's Poor Oversight of Accelerated Drug Approvals

for industry and review staff titled, 'Labeling for Human Prescription Drug and Biological Products  Determining Established Pharmacologic Class for Use in the Highlights of Prescribing Information'. The good review practice guidance defines established pharmacologic class and helps to identify the most appropriate term for describing the established pharmacologic class for a drug or biological product for inclusion in the 

 section of Highlights of Prescribing Information (

A 2006 final rule requires that drug manufacturers include the following statement on labels for drug products that have an established pharmacologic class: "(Drug) is a (name of class) indicated for (indication(s))." 

"Knowing the established pharmacologic class can provide health care professionals with important information about what to expect from a drug and how it relates to other therapeutic options," says the guidance. The FDA also explains in the guidance that the agency is "in the process of using structured product labeling (SPL) to index certain types of prescribing information content for all drug products" and that because of its importance, pharmacologic class is being indexed in the first phase of this process. 

 can be based on one of the following three drug attributes: 

Mechanism of action (MOA)  that is, pharmacologic action at the receptor, membrane, or tissue level

Physiologic effect (PE)  that is, pharmacologic effect at the organ, system, or whole body level

The guidance further defines established pharmacologic classes, how to identify the most appropiate term for describing a class, and when to include a combination of classes on the drug product label.

The FDA issued a guidance for industry and review staff titled, 'Labeling for Human Prescription Drug and Biological Products &#151; Determining Established Pharmacologic Class for Use in the Highlights of Prescribing Information'.

FDA new guidance on drug labeling and pharmacologic classification

The US Food and Drug Administration issued a 

Labeling for Human Prescription Drug and Biological Products-Determining Established Pharmacologic Class for Use in the Highlights of Prescribing Information

. The good review practice guidance defines established pharmacologic class and helps to identify the most appropriate term for describing the established pharmacologic class for a drug or biological product for inclusion in the 

  A 2006 final rule requires that drug manufacturers include the following statement on labels for drug products that have an established pharmacologic class: “(Drug) is a (name of class) indicated for (indication(s)).” 

“Knowing the established pharmacologic class can provide health care professionals with important information about what to expect from a drug and how it relates to other therapeutic options,” says the guidance. FDA also explains in the guidance that the agency is “in the process of using structured product labeling (SPL) to index certain types of prescribing information content for all drug products” and that because of its importance, pharmacologic class is being indexed in the first phase of this process.

 can be based on one of the following three drug attributes:

  Mechanism of action (MOA)-that is, pharmacologic action at the receptor, membrane, or tissue level;

  Physiologic effect (PE)- that is, pharmacologic effect at the organ, system, or whole body level;

    The guidance further defines established pharmacologic classes, how to identify the most appropiate term for describing a class, and when to include a combination of classes on the drug product label.


The US Food and Drug Administration issued a guidance for industry and review staff titled, Labeling for Human Prescription Drug and Biological Products-Determining Established Pharmacologic Class for Use in the Highlights of Prescribing Information.

FDA Issues New Guidance on Drug Labeling and Pharmacologic Class

IMS Health delivered some good news last week with its updated pharmaceutical market 

. The market-research firm expects the global pharmaceutical market to grow 4–6% in 2010, reaching more than $825 billion. Looking ahead to 2013, industry can expect a 4–7% annual growth rate, reaching more than $975 billion. This forecast represents a 1% increase in IMS’s five-year global market estimates released 

“While our outlook for the global market is more positive than earlier in the year, the fundamental dynamics of the innovation cycle, funding pressures, and the broader macroeconomic environment will result in mid-single-digit growth over the next five years,” said Murray Aitken, senior vice-president of Healthcare Insight at IMS in an Oct 7, 2009 press release. “Notwithstanding the improved prospects in the US market, the drive by pharmaceutical manufacturers to adapt to the longer-term marketplace trends and evolving patient needs will continue undiminished.”

Recent near-term growth prospects in the US provided a major reason for the new, increased forecast. “Pharmacy chains are more tightly managing their inventory levels based on expectations of patient demand, which has led to greater purchasing volatility than in previous years,” says the IMS release. “This also has played a role in unusually high sales growth in the first quarter of 2009 relative to forecast expectations.”

Also driving global pharmaceutical market growth, says IMS, is “the changing mix of innovative and mature products, and the rising influence of healthcare access and funding on market demand.”

Other major points from the new IMS report include:

 The seven pharmerging countries (Brazil, Russia, India, China, Mexico, Russia, and Turkey) are expected to grow together 12–14% percent in 2010, and 13–16 % during the next five years, with China holding the lead. That said, growth has slowed in markets such as Russia, Mexico, and South Korea where there is “high out-of-pocket spending on pharmaceuticals and steep declines in macroeconomic activity.” And growth has been less affected in countries like Germany, Japan, and Spain were drugs are largely publicly funded. 

  US manufacturers have played a role in lessening the impact of the global economic downturn throughout the pharmaceutical industry with its “efforts to expand access to and awareness of patient assistance programs, as well as co-pay subsidies for patients in need.”

 The primary factor limiting global pharmaceutical market growth remains the “significant imbalance between new product introductions and patent losses.” 

Looking to 2010, IMS notes that its forecast could change again based on pending healthcare reform, the H1N1 pandemic, and the pace of recovery of the economic downturn.

IMS Health delivered some good news last week with its updated pharmaceutical market forecast.

IMS Raises Global Pharma Market Growth Forecast

Leaders from Brazil, Russia, India, and China, also known as the BRIC nations, met in Yekaterinburg, Russia, this past June at the first formal emerging economies summit. The group of nations is expected to surpass the current leading economies by 2050 (1), and the pharmaceutical industry is paying attention. IMS Health projects pharmaceutical sales in the so-called pharm-erging markets (the BRIC nations plus Mexico, South Korea, and Turkey) to grow collectively at 13–16% in 2009 and through 2013, according to April 2009 estimates. Meanwhile, the global pharmaceutical market is expected to grow by only 2.5–3.5% for 2009, and only 3–6% through 2013, with US pharmaceutical sales declining 1–2% this year. 

With so much promise in developing pharmaceutical markets, small and large companies as well as contract research and manufacturing organizations (CROs and CMOs) are seeking a piece of the warming pie. Although China and India remain hot spots for industry growth, Central and Eastern Europe (CEE), along with the neighboring Commonwealth of Independent States (CIS) (see sidebar, "The region"), constitute a region to contend with.    

After having lost ground during the past 20–30 years, European active pharmaceutical ingredient (API) producers, specifically in CEE, seem to be rebounding. It's well known that API manufacturers in Europe have been squeezed out by competition from China and India as a result of Europe's more prohibitive operating costs for the good-manufacturing-practice (GMP) compliant production of off-patent APIs (typically, 25% of site operating costs) and increased regulations, says Agnieszka Stawarska, a pharmaceutical market analyst at PMR. A market-research firm based in Poland, PMR issued a report on the CEE pharmaceutical market, "Pharmaceutical Contract Manufacturing and API Sourcing in Central and Eastern Europe," in January 2009. The number of companies throughout Europe that offer contract manufacturing services, including API production, is also quite low in comparison with the number of companies operating in China and India.  

But after a series of supply-chain breaches such as the contaminated heparin event and a high percentage of reported incidences of counterfeiting in China and India, global firms are taking more notice of the CEE region's advantages. For starters, "CMOs and API suppliers in Europe are located much closer to their clients in comparison with CMOs and API suppliers that come from China and India, which translates into lower transportation costs," explains Stawarska. Moreover, most companies in CEE are GMP-compliant, she says, whereas most companies in China are not. There are an estimated 5000 rogue API manufacturers in China, Stawarska explains, and about 3000 of them are not Chinese GMP-compliant.  

In comparison with Western Europe, production costs in the CEE region are still lower, and wages are between one-quarter and one-sixth of those in Western Europe. On the other hand, CEE companies do not have a long tradition of cooperation with companies from Western countries.   

Currently, "the most attractive countries in the CEE region for finding partners for contract manufacturing and API sourcing are the Czech Republic and Poland," says Stawarska. Home to the sites of the largest API manufacturers in the CEE region—Polpharma (Starogard Gdanski, Poland) and Zentiva (Prague), which was acquired by sanofi aventis (Paris) in September 2008, these two countries offer an abundance of qualified scientists and high levels of investment into the domestic pharmaceutical market. The Czech Republic and Poland even have more companies specializing in API production than Russia, which is surprising given Russia's size and market potential, says Stawarska.  

Neighboring Hungary, however, has been losing favor among international players because of its government's recent cost-cutting measures and their effect on the country's business environment, she says. So pharmaceutical firms based in Budapest such as Egis and Gedeon Richter, which have provided pharmaceutical production and drug-development services for decades, are losing some ground. 

Gedeon did, however, invest HUF 15 billion ($103.7 million) in a new manufacturing plant for biopharmaceutical products, including mammalian-cells and therapeutic proteins, in Debrecen, Hungary, in July 2008 (2). The plant, which will create 110 new jobs, is expected to be operational in 2012, starting with clinical trial materials and moving to commercial-scale production in 2014. 

Among BRIC nations, Russia holds #2 spot 

Russia's pharmaceutical sales grew by approximately 20% between 2006 and 2007 to $7.9 billion, according to IMS Health, beating out its BRIC competitor nations Brazil, which grew 9.7%, and India, which grew 13%, over the same period (3). Russia's pharmaceutical sector is also expected to grow by 2% in 2010 and could recover from the global recession faster than other markets, according IMS Health. There are a few reasons Russia may be ahead, according to David Campbell, senior principal at IMS Consulting.  

Historically, Russia's scientific sector has always been very strong and, because several companies identified the Russian market early on, the country has remained favorable for low-valued generic drugs, he says. The country is also considered a good bet for sourcing innovative pharmaceutical products and as a place of opportunity for imported pharmaceutical products.  

Domestically, there is a lot of out-of-pocket cost for individuals buying medications in Russia, but a significant portion of the population is reimbursed by a government agency or another insurance system. "As a whole, the Russian market does well from this perspective," says Campbell.  

Russia's overall economy also may explain why its pharmaceutical sector is likely to pick up faster than other markets, starting as soon as 2010. According to the Economist Intelligence Unit, says Campbell, oil prices may rise to $50–52 per barrel by the end of this year. In addition, Russian consumers are in a safer place financially than their counterparts in other countries because of low household debt and a small mortgage market, among other factors. A government stimulus package is cushioning the effects of the global recession, and finally, there is now a lower tax burden on some sectors.  

Unlike Brazil and India, Russia does not have major issues with distribution channels, access, or intellectual property, says Campbell. "These simple challenges have prevented [Brazil and India] from growing as rapidly as the Russian market," he says.   

China, on the other hand, has remained the BRIC leader (with growth of nearly 26% between 2006 and 2007) because of its large-volume market and its huge opportunities for innovative and generic products as the population turns away from Traditional Chinese Medicines and toward Western medicines, explains Campbell. In addition, China's infrastructure and distribution are more mature than in the other BRIC markets, and access is critical to market success, he says.  

Looking ahead, Russia's domestic pharmaceutical sector is transforming. "We're seeing two things happening," says Campbell. "First, Russian physicians are increasingly open to prescribing highly innovative products. Second, the proportion of patients that have a need and desire to access these high-value innovative medications that weren't traditionally available is growing." Overall, the population at large is starting to feel that cheaper products and preparations are not necessarily what they want.  

The government is also determined to change the way the pharmaceutical industry operates. With the recent currency devaluation, oil-price drops, and credit-crunch, the Russian government has spent most of 2009 working on pricing-control measures across the pharmaceutical sector, says Campbell. Specifically, they are changing various reimbursement lists to ensure that the government can meet the needs and expectations of the population. They also want to ensure that the country's life expectancy, which until recently was very poor (In 2007, life expectancy was age 66 in Russia and 80 in the European Union), continues to improve. "To do so, the government will have to invest in healthcare going forward," says Campbell.  

The government wants to increase local pharmaceutical manufacturing, but what that means exactly (e.g., APIs, finished products, packaging)—and how it will be managed (e.g., tax rebates) remains to be seen. "Several pharmaceutical companies are looking at this intently and are concerned about the implications going forward," says Campbell. "We may see more strategic partnerships between local players and multinationals or multi-nationals moving manufacturing capabilities into the country in response."  

 1.  A.E. Kramer, "Emerging Economies Meet in Russia," 

 2. Gedeon Richter Press Release, July 22, 2008, 

www.richter.hu/EN/Pages/pressrel080722.aspx

 3. A. Drakulich, "A Reality Check on Emerging Markets," 

For more on this topic, see the online exclusives "

The countries of Central and Eastern Europe and the Commonwealth of Independent States are closing in on global pharmaceutical competition.

The Emerging Markets of the East

The US Food and Drug Adminstration released its 

Pharmaceutical Quality for the 21st Century: A Risk-Based Approach 

report in 2004. Since that time, the concepts around quality by design (QbD) have been discussed in multiple meetings and regulatory guidances, including in three finalized guidelines by the International Conference on Harmonization (ICH) (1–3). Christine Moore, acting deputy director of the Office for New Drug Quality Assessment, and Joseph Famulare, deputy director of the Office of Compliance, both within FDA's Center for Drug Evaluation and Research (CDER), address some common industry questions about how to implement the manufacturing practice. 

manufacturing process seems to be the biggest challenge facing industry with regard to QbD implementation because this approach involves different instrumentation and additional testing. And yet, process analytical technology (PAT) can offer industry great advantages. Why do you think there is so much pushback from industry with this issue, and what might it take for industry to accept the changed approach that FDA is promoting? 

I see a few major concerns of companies in shifting toward implementing PAT. First is the unavailability of the equipment in current pharmaceutical plants and the data-management systems needed for tracking, control, and knowledge management. Also, many manufacturers are unfamiliar with the equipment and its operation, which could lead to a steep initial learning curve and new needs for maintenance on the manufacturing floor. The second hurdle I perceive is cultural. The traditional mindset of the pharmaceutical industry often has been to put a validated process in place and not look at it again unless it breaks. PAT systems can allow for a continuous window on the operation which will give you much greater and richer information so that the manufacturer can more easily detect process drifts and correct them before they become problems. I think as more companies implement QbD and PAT approaches, the regulatory and business benefits will become more evident. 

Pharmaceutical manufacturers also face QbD challenges with legacy products and scale-up. How does FDA intend to address these issues? 

Firms have different motivations for applying new technologies to legacy products, including finding ways to gain better process control and efficiency. Commercial data, in conjunction with additional development work, can lead to anything from better process controls to seeing the need to update the application with new specifications for the product, and may or may not include the implementation of a design space. ICH Q10 

(PQS) provides guidance in implementing these approaches during all phases of the product life cycle, including technology transfer and scale-up. 

FDA continues to train compliance and investigative staff in advanced technologies, risk-management, and quality systems. CDER compliance technical experts lead and participate in preapproval and postapproval inspections on occasions where their expertise is needed and in the foreign arena, which has proven very helpful in looking at many of these opportunities. CDER's Office of Compliance (OC) has been instrumental in coordinating joint inspections with international colleagues [e.g., the European Medicines Agency] that have new technologies working and is open to preoperational visits where new technologies are put into place. 

Some recent industry presentations have discussed the size of the design space and what's most effective. What's the regulatory perspective on the size of a design space and how close a company's process results come to the edges of the design space?  

The value of design space is not its size—or where the process lies within the design space—but the process understanding it represents based upon good development and knowledge obtained during the commercial process over the product's life cycle when the design space is changed. This allow for a firm's self-management of change to foster innovation and continual improvement. In the past, many processes remained fixed based upon limited knowledge at the time of development and were limited to fixed processes prescribed in applications. 

Design space will provide the opportunity to present a good understanding of the proposed process based on development and to innovate and improve the process. As described in ICH Q10, developing an effective control strategy based upon the most current product and process understanding should provide the opportunity for manufacturers to control variability and to produce a quality product minimizing deviations. In addition, FDA's draft process validation guidance addresses more clearly than ever before that validation is not a fixed activity but should be a life-cycle approach that can be adapted to work with or without design space and can be used with modern technologies that continually monitor or measure the process. 

As you mentioned, ICH Q10 focuses on a life-cycle approach by adopting a quality system. What are some ways that industry can best apply this approach? 

The life-cycle approach is at the heart of FDA's quality systems guidance published several years ago and has now been superseded internationally by ICH Q10 (see Figure 1). The challenge can be met by harnessing the data amassed in a commercial process to drive continual improvement.  

Table I: Quality-by-design (QbD) programs in progress at the US Food and Drug Administration.			

An important PQS element is the process-performance and product-quality monitoring system. That system will confirm whether predictions made in development have provided a good understanding of the process. QbD approaches to development will [also help a firm] to learn from the process in a knowledge management system (a PQS enabler).... The newer regulatory approaches derived from ICH Q8 

and Q10 will allow companies to drive continual improvement. Processes will not be fixed by commitments made in applications that may not reflect an adequate understanding of the manufacturing process because of limited knowledge. 

Why is it recommend that a company begin to think about QbD concepts at the end of Phase II? Is there ever an ending point for applying a quality-based approach (e.g., should it affect sales and marketing)? 

Paraphrasing Qbd, it means a systematic approach to development, which is worthwhile at any phase of development. The intensity of certain development studies may increase at the end of Phase II (e.g., in deciding to use a design of experiment more extensively, whether or not to develop a design space for a particular unit operation, and whether certain technologies such as PAT are being considered for the commercial process). There will also be considerations as to what types of process controls will be used and consideration of real-time release testing (RTRT). ICH Q10 illustrates consideration for each phase of the product life cycle and the OC's Division of Manufacturing and Product Quality (DMPQ) has looked at proposals at various phases, especially when new facilities or manufacturing technologies are being considered. They can be contacted 

subject matter experts listed on the website (

www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/default.html

A PQS should extend throughout all parts of a firm's operations from preclinical, clinical, and marketing. This is a challenge CDER has seen firms meet by creating an opportunity to have lower deviations, fewer complaints, and to make better linkages from clinical to quality. 

Now that the Chemistry, Manufacturing, and Controls (CMC) Pilot Program is winding down, will FDA be changing the way QbD-based applications for new drugs need to be submitted? 

Applications for QbD and traditional approaches are submitted in the same manner. From an administrative standpoint, it is helpful to us if the applicant mentions the QbD aspects or other unique features of the application in the cover letter. 

What were some of the major lessons learned by FDA as a result of the CMC pilot? 

We learned how to make science- and risk-based regulatory decisions based on QbD data and proposed manufacturing approaches. Importantly, we gained experience dealing with different types of flexible regulatory approaches such as design spaces, in-process testing, and RTRT. We found that having a reviewer on Prior Approval Inspections was synergistic in that it benefitted both the review and inspection. 

One of the major findings through the pilot was that quality risk-management and a pharmaceutical quality system are equally important to pharmaceutical development for the success of a QbD approach. As we get additional applications containing QbD approaches, we are continuing to refine our review practices, and are sorting out questions such as what detail of information should be in an application. We are further looking at how best to maintain our internal knowledge management and information-sharing across offices. 

FDA has received more QbD-based submissions (12 new drug applications [NDAs], 18 investigational new drug applications [INDs], and 3 supplemental NDAs as of May 2009) than it did under the CMC Pilot Program. Does industry seem to have a hold on what FDA is looking for when it comes to QbD-based submissions? 

The early applications under the CMC pilot had most of their development complete by the time the pilot was announced. The applications were more like hybrids, containing both traditional and QbD approaches. Some of the newer applications that we are seeing were wholly developed using QbD approaches. Every application is different and we are still learning and coalescing our review approaches. For example, we don't have much experience in changes to approved design spaces. 

How long do you expect before QbD and its related tools and concepts become a natural practice in drug manufacturing? 

Many of the approaches of QbD (e.g., continual improvement) are a change to the traditional approach of putting a validated process in place and not touching it. I think that the pharmaceutical community has already made huge strides in advancing QbD concepts. Five years ago, practically no one had heard of design space, and formalized quality risk-management was rarely done. Today, we see a growing number of manufacturers incorporating these concepts in their day-to-day development practice and manufacturing operation. 

One way to break down barriers to QbD implementation is to increase communication between industry and the regulatory authorities. Do you expect FDA to seek more interaction with firms during the review process or inspection process? 

We have already seen a greater level of interaction in many of the QbD applications, both within and outside of the pilot. As I often mention in my presentations, we encourage companies looking to implement QbD approaches to meet with us prior to their submission. Even though not all the details of the design space will be available yet, we find that an end-of-Phase-II meeting [as Mr. Famulare mentioned above] is a good time to start discussing the proposed approaches. Pre-NDA meetings are a good time to discuss more specifics of the content and format of a QbD application. For legacy products, a meeting can be requested to discuss proposed QbD approaches in a supplemental application. 

Does FDA expect to see more communication and interaction between, for example, research and development (R&D) departments and quality-control departments? 

Yes, these are really important links for successful implementation of a PQS approach within a company to relay not only information but knowledge from development to manufacturing with quality integrated throughout. This applies whether or not QbD approaches are used in product development and especially important to transmit commercial manufacturing information back to R&D. This will also provide for a more robust change-management system within a company to recognize when change can be made to foster continual improvement or in response to a corrective action/preventive action (CAPA). This is an important tenant of the ICH Q10 change-management system element. 

It is also important for the regulator to have systems to transfer knowledge between review and inspection. The OC is developing a system of knowledge transfer to facilitate this communication. 

There is an informal practice among industry to avoid providing FDA with too much detail out of fear that more information will lead to more questions, and perhaps more 483s. Can you address how the agency is trying to change this mindset? 

A discussion point in the FDA 2004 report on pharmaceutical quality was to focus on important, well-summarized information in the application, rather than voluminous raw data. I think quality risk-assessment is a good example of the additional important information in a QbD application. It is a change in mindset for companies to admit that they have risk. Of course, their processes have always had risk, and reviewers have always looked for the risks. Addressing these risks and their control in a formalized manner increases transparency and aids in understanding the firm's assurance of product quality. 

Is the agency planning to increase its practical workshops or speaking engagements to help clarify the questions that still exist around QbD concepts and quality systems? 

There are [still] questions about the regulatory implications [of ICH Q8, Q9, and Q10] and how to present some of these proposals to the agency and how investigators may look at these proposals. I believe that conferences, papers, and shared learning on good case studies will help answer some of these questions and relieve some of these concerns. Those regulators, including myself, and industry members involved in ICH quality initiatives realize that ICH Q8, Q9, and Q10 are forward-looking and that help is needed for implementation. Hence, the ICH Implementation Working Group (IWG), led by rappateur John Louis Robert, is looking to do that through papers and conferences beginning next year. Papers drafted will have input and guidance from I WG members. Any questions about manufacturing and various approaches to science- and risk-based approaches and CGMP interpretations can be directed to DMPQ. So far, we have looked at proposals for RTRT, PAT, and approaches to validation involving continuous manufacturing and verification. 

Officials from the US Food and Drug Administration discuss best practices for applying quality-by-design concepts. This article contains bonus online-exclusive material.