The following three rules of engagement are recommended to take place at an End of Phase II meeting, either face to face or by telephone. Each rule helps to ensure a successful negotiating strategy based on the actual discussions with the Agency. Note the fundamental position of the approach in every case:

1) Bring the discussion to the data presented on e.g., the process capability and robustness, acceptance criteria, effectiveness of the analytical capabilities etc.

2) Seek clear understanding of the FDA position

3) Seek agreement that the data package is adequate to support the approach while understanding that the FDA must review the actual NDA submission to come to a final determination

Coming Soon

Speaking for the Center for Biologics Evaluation and Research (CBER) Division of Manufacturing Product Quality (DMPQ) at the PDA Annual Meeting in San Antonio, Texas in April, David Doleski emphasized the importance of transparency around changes in a roundtable on regulatory expectations for BLA CMC filings.  In his portion of the presentation at the meeting, Doleski highlighted “desirable and undesirable” attributes in BLA submission trends in approvals, and examples of specific issues causing applications to be significantly delayed or even not
approved.

FDA is advising sponsors filing Biologic License Applications (BLAs) and supplements to clearly highlight any significant add-on items, that may not have been previously discussed and any changes to the application and their scope upfront to accelerate the agency review and approval process. This advice reveals the agency’s experience that both original and supplemental filers are not always giving a comprehensible picture up-front, which can lead to significant review delays or a Complete Response (CR) letter indicating that the application is not approvable in its current form.

I spoke at the conference, alongside David at the meeting. The reason I bring it up, from my experiences in other situations, inadequate information is being submitted to the FDA. Some of the information used to support process validation just for example during preapproval inspections is held at the manufacturing site for inspections and is never shared with the Agency. Few process details are described in submissions that clearly suggest critical variables and their relationship to clinical performance.

As a result, Agency reviewers often remain unsure about whether a subsequent change in a critical process parameter or end-product specification will adversely affect product performance. To address this uncertainty, a conservative regulatory approach has typically been adopted by regulators that often results in specifications and controls being based very narrowly on clinical trial lots. Such conservative approaches can lead to the approval of tests or restrictive acceptance criteria that may not be directly relevant to product performance, but that may increase the potential for product failures. In turn, providing too much information on aspects of existing facilities that have not changed – for example, through links to prior submissions – can also slow down the process as the reviewer must take time determining what has changed and what has not.

FDA is advising sponsors filing Biologic License Application (BLA) supplements to clearly draw attention to the significant areas or changes and to put emphasis on them in the cover letter to expedite the agency review and approval process. For additional information on requisite items and their location position in the BLA, feel free to contact me at:

enarke@dsinpharmatics.com

Coming Soon!

Perhaps the new (draft) ICH Q11 will be much like the storming of the Bastille which was more important as a rallying point and symbolic act of rebellion than a practical act of defiance.

Shortly after the storming of the Bastille, feudalism was abolished and the Declaration of the Rights of Man and of the Citizen proclaimed. What will ICH Q11 bring? Stay tuned Marie Antoinette!

Q11_Step_2

The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) have agreed to accept the first application under their pilot program for the parallel evaluation of marketing-authorization applications involving ‘quality by design’ (QbD). This should be interesting to watch.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/06/news_detail_001279.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1

coming soon

FDA has recently revised its process validation guidance stating: “Data gathered (during the Continued Process Verification stage) might suggest ways to improve and/or optimize the process by altering operating ranges and set-points, process controls, components, or in-process materials.” So the FDA is stating clearly that it expects manufacturers to study, learn, and improve their processes.

The more work that can be done up front in development, the bigger the impact on overall required design of experiment (DOE) studies, design space, and validation work. If something isn’t there, you don’t have to control it, you don’t have to do DOE studies around it, and you don’t have to validate it. The amount of work that research can do for you in those very early stages can save you a huge amount of time, effort, and money farther down the line. The development of the design space creates an understanding of what is critical and noncritical for your performance parameters and therefore allows you to focus on what is important when you execute validation. There is little point in spending a lot of time validating performance parameters that really don’t affect the quality of your product. A hypothesis is that development of design space would allow for wider validation acceptance criteria. If you don’t do QbD or DOE studies, you have to validate a process within the ranges of the experience you have during development. If you have made only three lots and you only varied between X and Y, there is not much choice for the regulatory authorities to give you much wider acceptance criteria since there are simply no data to use to understand what is going to happen to the process if you go outside those experience limits.

Classical process validation where you run straight down the middle at a set point does not validate anything regarding the acceptance criteria for the operating process parameters that have been set. Running confirmation runs at set points does not validate parameter limits. Confirmation runs are really more an experience of what it is like to run at full scale with your trained personnel following the SOPs and pushing the right buttons. With QbD in mind, you have to rethink the term validation and what it means; and specifically what design space does for what you are doing now. The validation of design space is essentially assuring that the risk assessments identifying CQAs, followed by DOEs, and understanding critical process parameters (CPPs) and then developing a control program are all “valid” processes. Process validation has moved back into process development and characterization, and confirmation runs are simply illustrating that at full scale the manufacturing process can run smoothly, without failures, on a regular basis. For more thoughts, drop me a mail at enarke@dsinpharmatics.com

COMING SOON!

By defining hurdles to registration, emerging companies benefit from early regulatory guidance.

There are no holidays or time off when it comes to complying with regulations. Companies need to be ready to meet the latest standards at all times. With that in mind, new FDA programs are sure to keep pharmaceutical companies of all sizes busy in the year ahead. Here’s how to get through.

The development of a global CMC regulatory strategy document should be on top of a company’s “to do list” in 2011. This document provides a blueprint for regulatory strategy to achieve a company’s objectives in developing, and ultimately supporting a drug. The strategy document should include information such as:

• Product’s indication, intended use, and target population
• Partners involved in the product (e.g., research or manufacturer organizations, consultants, submission outsourcing partners)
• Product registration strategy
• Order of application filings (e.g., which countries and when)
• Country specific requirements (e.g., local requirements)
• Submission timelines
• Short- and long-term regulatory objectives
• Manufacturing strategy.

Given their focus on discovering and rapidly building scientific evidence to support the safety and efficacy of their compounds, emerging pharma companies often direct their limited resources to near-term activities. In doing so, they are often unaware of or undervalue the importance of getting early CMC regulatory guidance on long-range development strategies.

In early development, emerging companies often view regulatory affairs as a function that is primarily necessary to ensure compliance. They recognize the need to manage operational activities such as preparing, submitting, and maintaining an IND, submitting information amendments, and coordinating other routine communications with the FDA. However, this approach potentially neglects a greater value-added contribution that these experts can provide: regulatory strategy.

There are no guidelines or regulations that explain how a CMC regulatory strategy should be compiled. However, several industry organizations have resources and conferences that outline what should be included for pharmaceuticals and biologics in a regulatory strategy.

While creation of a solid CMC regulatory strategy is a critical enabling factor in the efficient development of a product for both emerging and established companies, there is particular importance for emerging companies, since they typically have fewer available resources than larger companies. For smaller organizations, an external regulatory strategist can serve as a bridge between scientific and commercial disciplines, integrating their respective needs, forming a cohesive internal strategy, and developing an external communication approach for the health authorities.

In this way, the strategist can provide efficiencies to development teams, informing the sponsor of requirements and options while outlining a pathway and defining the hurdles to registration.

As pointed out, the key to gaining the greatest efficiencies, however, is to launch development of the regulatory strategy early in development, ideally before starting clinical trials. In that way, the regulatory expert is an integral part of the team for all the subsequent critical steps, including implementation and negotiation with health authorities.

The year 2011 will be challenging for pharmaceutical companies given the ever evolving requirements of the FDA. Although this fact should not come as a surprise to anyone in the industry, companies still need to be prepared and be able to move quickly so as not to compromise their businesses.