FDA Seeks Regulatory Flexibility

The US Food and Drug Administration has been encouraging manufacturers to expand applications to include discussions of how process knowledge and a full understanding of critical product parameters ensure drug quality. Adopting quality-by-design (QbD) approaches offers manufacturers important benefits and savings, as well as the potential for regulatory relief. FDA may waive the requirement to file supplements that describe postapproval manufacturing changes. The agency is also considering further reductions to the scope and frequency of plant inspections for companies that demonstrate risk management and modern manufacturing approaches.

Jill Wechsler

Although such initiatives are gaining more currency in industry, formally establishing regulatory relief has been more difficult. FDA officials are anxious to reduce the number of supplements manufacturers file with the agency but cannot decide exactly how. A proposal that manufacturers could negotiate a "regulatory agreement" with the Center for Drug Evaluation and Research (CDER) fell by the wayside because it seemed too much like a legal agreement that would oblige the agency to take certain actions.

Extending CMC pilot

Initiatives to provide regulatory flexibility are moving forward now because of wider industry adoption of QbD approaches. The Office of New Drug Quality Assessment (ONDQA) in CDER's Office of Pharmaceutical Science (OPS) initiated a chemistry, manufacturing, and controls (CMC) pilot program to assess the value of applications that contain more scientific information about product development and formulation than typical new drug applications do. ONDQA has reviewed and approved six pilot applications that demonstrate an understanding of critical quality attributes, process development, and design space. Several more applications await assessment.

The success of this program for drugs is encouraging regulators to extend it to biotechnology therapies. OPS's Office of Biotechnology Products (OBP) is inviting biotechnology manufacturers to submit QbD information, demonstrate process control, and define products' critical attributes. At the January WCBP conference on biotechnology regulation and analysis, in Washington, OPS Director Helen Winkle explained that this information looks like an expanded comparability protocol for biologics. And because relatively few new biologics license applications are filed each year, Winkle thinks the biotech QbD pilot will primarily examine manufacturing supplements.

OBP director Steven Kozlowski recognizes that defining product attributes and design space is more complex for biotechnology products. Compared with small-molecule drugs, finished biological products often have lower heterogeneity, and later manufacturing steps are more likely to change the product, he noted at a workshop last year. The manufacturer's challenge is to determine what data are relevant in defining critical product attributes. For innovative oncology products moving quickly through development and review, it may be very difficult to include QbD data in an initial market application.

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FDA is encouraging manufacturers to share information about the development of product-control strategies and process analytical technology to better define what constitutes a QbD-based submission and science-based risk assessment. Many manufacturers have adopted modern manufacturing methods, but have been afraid that providing information about such innovations would raise more questions, delay application approvals, and generate objections from field inspectors.

To dispel such concerns, FDA would like to hold a workshop with industry to evaluate science-based risk assessment and lessons learned from the pilot exercise. Winkle and her colleagues regard the CMC pilot as a means to help FDA understand the difficulties in defining critical attributes. Some filings have inadequate quality information; others have too much data. Fully evaluating the drug pilot, Winkle notes, would improve the program for biotechnology therapies.

Setting forth a plan

FDA is working on new strategies for linking QbD investments to regulatory relief. Instead of negotiating a firm regulatory agreement as part of bringing a new drug to market, CDER officials are talking about devising a CMC postmarketing plan (PMP) that provides a roadmap for FDA and manufacturers to manage postapproval changes. Companies would collect data on critical quality performance and design controls during product development. They would include this information in the market application, along with a list of anticipated changes in equipment, process, site, and other procedures. The PMP would distinguish between upcoming changes that are not expected to affect product quality, and thus not likely to require a supplement application, from significant changes such as site relocation, which would likely require a supplement.

Winkle hopes to implement the PMP program in the coming months, initially for drugs and later for biologics. The PMP concept has been described as an "individual SUPAC," which reflects some similarities to FDA's earlier Scale-Up and Post-Approval Changes initiative. SUPAC aimed to streamline reporting requirements for postapproval manufacturing changes based on dosage forms. Difficulties in establishing broad reporting policies for a wide spectrum of products, though, ultimately led to SUPAC's abandonment.

Cutting CBEs

FDA also wants to reduce manufacturing supplements across the board. At the January WCBP meeting, Winkle expressed hope that a much-anticipated new policy for eliminating many supplements would soon be published in the Federal Register. FDA held a public meeting in February 2007 to discuss options for revising CMC supplement regulations (see "Down with Supplements!" Pharmaceutical Technology, April 2007).

Agency officials discussed how new tools and approaches that let manufacturers assess and manage product risks and establish quality systems should permit modifications to policies that manage the postapproval manufacturing process. These developments could support changes in policies that inhibit manufacturing process improvements and, instead, encourage companies to adopt quality-systems approaches. FDA has prepared a guidance and a proposed new regulation to eliminate most changes-being-effected (CBE) supplements.

Manufacturers now must file supplements to inform the agency of most changes made to processes, equipment, packaging, and other elements that will alter the product. Significant changes require prior FDA approval. Innovations that are unlikely to compromise product safety or efficacy can be described in a CBE supplement and implemented without the agency's sanction. A company must wait 30 days after filing certain CBEs before it can make the change. But the CBE process still requires FDA to examine thousands of supplements every year. Filing a supplement also involves a good deal of work for the manufacturer.

If a change is important enough to warrant filing a supplement, says Winkle, it likely requires a prior-approval submission. Site relocations generally fit this category because they often involve installing new equipment and altering production processes, and a field inspection of the new facility is usually required.

Most routine changes, though, would be submitted in annual reports that manufacturers file with FDA. This approach would expand the role of FDA's field force in assessing on site the impact of a greater number of postapproval manufacturing changes described in companies' annual reports.

Manufacturing executives would like more similarity between the submitted annual report and their companies' internal annual product reviews, which are kept at the manufacturing site.

Facing new challenges

A reduction in supplements will help CDER deal with its expanding workload. But the broader goal is to encourage manufacturers to incorporate QbD and risk management approaches into production processes. Adopting these approaches will ensure drug quality throughout a product's life cycle. A flexible approach to managing change will encourage process improvement, which, in turn, will raise production yields and simplify manufacturing processes.

Although many pharmaceutical companies say they have been adopting QbD practices for several years, they still have many questions about QbD policies, about how much information to share with regulators, and about differences between FDA and European QbD policies.

One challenge for FDA, says Winkle, is to apply these QbD policies to legacy products that have no QbD data in their original applications. Some manufacturers may gather QbD information for legacy products to establish a CMC postmarketing plan and gain flexibility in managing change. Others will not want to invest resources in such an undertaking for older products.

So far, it has been up to each company to decide whether it will adopt QbD approaches and develop continuous quality-control operations. Proposals that mandate such activities will surely generate opposition on many fronts. FDA's challenge is to devise a strategy that offers regulatory relief to companies that adopt modern manufacturing practices without penalizing those that do not.

In addition, a regulatory change that even remotely appears to compromise drug safety will raise a red flag. In the current political climate, critics of industry and FDA could regard modified reporting rules for manufacturers as allowing production-system changes without appropriate oversight of safety effects.

A recent FDA proposal to clarify when manufacturers can file CBEs for labeling changes that reflect new safety information was blasted on Capitol Hill. Congressional leaders objected that the proposed rule would encourage pharmaceutical companies to hide drug-safety information and protect marketers of unsafe products from legal action. Though the point of reducing supplements is to help FDA handle its expanding workload and to encourage modern manufacturing practices, even the best intentions face intense scrutiny these days.

Streamlining adverse events

Skepticism about FDA regulatory actions may affect efforts to streamline the agency's complex and costly process for adverse event (AE) reporting. Current rules require manufacturers to submit reports that involve serious and unexpected events within 15 days. Less serious problems may be filed in quarterly reports. After a product has been marketed for three years, minor problems may be filed annually.

In the US, most AE data are fed into FDA's Adverse Event Reporting System (AERS). AERS holds about 4 million case reports, and this number is growing by about 300,000 reports each year. This spontaneous reporting system relies on patients and healthcare professionals to detect and inform manufacturers and regulatory authorities of problems related to medical products.

AERS is considered effective at detecting signals of rare, unexpected drug-safety problems such as new drug interactions and confusion about product names and labeling. But reports are often incomplete. In addition, the system does not address safety issues that involve heavy background noise (e.g., cardiac problems related to COX-2 inhibitors or diabetes drugs).

In reauthorizing the Prescription Drug User Fee program under the FDA Amendments Act of 2007, Congress approved additional funds to expand and improve the AERS system. The legislation also supports developing an active AE detection system linked to health-system and government healthcare databases.

As part of this effort to modernize drug-safety oversight, legislators instructed FDA to engage outside experts to assess the value of AERS. Experts will determine how long the current system takes to identify safety problems and the extent that passive or spontaneous reports from patients and health professionals lead to regulatory action.

FDA held a public workshop in January to gain input on how to assess the current AE reporting system, as well as its capabilities and shortcomings. Solomon Iyasu, of CDER's Office of Safety and Epidemiology (OSE), explained that AERS is valuable because it covers all FDA-regulated products. Moreover, the system reaches a large real-world patient population, including those who take drugs for off-label uses.

At the same time, many safety problems go undetected, and reports filed with AERS are often uninformative.

Despite these and other weaknesses, the healthcare community believes that spontaneous AE reporting should be retained and strengthened. Practitioners and patients say a new, active safety detection system should complement what already exists. OSE researchers found that safety issues occur throughout a drug's life cycle and that many serious issues emerge after drugs are on the market for more than 13 years.

How can regulators make AERS more effective and efficient? At the AE workshop, Ralph Edwards of the World Health Organization commented that the massive volume of reports in AERS "varies from utter nonsense to real gold." The challenge is to identify those "utterly ridiculous" reports and avoid using them to make regulatory decisions.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com