Media Coverage

Pharma Magazine
September/October, 2009

Staying On Track with Fast Track
By Gary A. Baker, Vice President, Quality Assurance and Regulatory Affairs, Ash Stevens Inc.

To download a PDF version, click here.

Introduction

For over a decade, the U.S. Food and Drug Administration (FDA) Fast Track program has been expediting the review of investigational drugs for patients with serious or life-threatening conditions and that demonstrate a potential to address an unmet medical need. Cutting average drug approval times from more than 18 months to less than a year, Fast Track can literally be a lifesaver for a patient with a life-threatening illness.

Although the program has innumerable benefits for both patients and sponsoring firms, drug sponsors are under increased scrutiny to ensure the safety of new drugs. A successful Fast Track drug application requires excellent project management, talented technical resources, experience with regulatory requirements and hard work.

Background

In 1992, the FDA implemented the Prescription Drug User Fee Act (PDUFA). The act requires that drug manufacturers submit payment with their applications. The fees support additional FDA staff to allow for faster review of the filings. The act also specified that certain new drugs that treat a serious disease and address an unmet medical need would be eligible for “Accelerated Approval” and “Priority Review.”

These aspects of PDUFA speak to the application review and approval process. But what happens before the application is submitted?

Features of Fast Track designation

In 1998, the FDA published its “Guidance for Industry: Fast Track Development Programs” to speed up the drug development process. Firms may request Fast Track status at any point from submission of the original Investigational New Drug Application (IND) to the approval time of the New Drug Application (NDA). Usually, firms make the request during clinical trials, after safety has been demonstrated and preliminary efficacy data show encouraging results. The FDA will determine whether to designate the drug for Fast Track within sixty days of the request. Typically, the Fast Track designation occurs during Phase 2 of clinical trials.

There are several features of Fast Track designation that, once granted, greatly accelerate the submission process. First and most important, the sponsor is encouraged to meet with the FDA several times throughout the drug development process to reach an agreement on the Agency’s expectations for NDA submission, and to make sure that all appropriate data has been collected. Another feature that expedites the process is the eligibility for Rolling Review, which means that a sponsor can submit individual sections of its NDA as they are completed, as opposed to waiting for the completion of the entire NDA. Fast Track designation also qualifies the drug for Accelerated Approval based on a surrogate endpoint.

Fast Track designation comes with a degree of flexibility. Often, firms can submit the Chemistry and Manufacturing Controls (CMC) section of the NDA before submitting the Clinical section. Further, the FDA may agree to accept sections without the full data or full reports that are required for non-Fast Track drugs. For example, the FDA may accept the section with limited stability data, contingent that the application will be amended with additional data as it becomes available. If the FDA agrees, this will significantly reduce the time between initiation of the stability study and submission by many months.

There are, however, risks involved with Fast Track submission. During the development process, much is learned about the drug and about its performance in the clinical setting. When time to submission is so dramatically reduced, some of the knowledge normally acquired during development is lost. Fewer manufacturing replicate batches may result in less manufacturing knowledge. Unpleasant surprises such as unanticipated impurities can arise with materials, processes or test methods. More dire consequences may result from less experience in the clinic. But for those with a life-threatening disease such as cancer, the potential benefits often outweigh the risks. There are many cases of people who were told that they had untreatable cancer and given only a handful of months to live, but went into remission after treatment with a new drug that had been Fast Tracked to approval.

I. Same work, less time

In one instance, a sponsoring firm reported that their submission timeline was compressed from 36 months to 12 months. Still, the same amount of work had to be done to satisfy regulatory requirements.

Although the submission and review process is accelerated, all of the work required for a “non-Fast Track” drug is still required for a Fast Track drug, and careful design of the project plan will make or break a sponsor’s application. While each project plan is specific to its drug, sponsors should know that they will need the following critical path items:

Processes must be developed, challenged and validated for both the drug substance and for the drug product.
Analytical methods must be developed and validated.
Reference standards have to be prepared and characterized.
It may be necessary to prepare impurities for use in analysis.
Specifications for all materials and components must be developed and justified.
Drug substance and drug product must be put on stability.
Microbiological concerns must be addressed.
If new facilities or equipment are installed, they must be qualified.
Equipment cleaning procedures and analytical methods must be developed and validated.
Manufacturing process hazards must be evaluated.
Operating personnel need to be trained.

II. Choosing the right contractors

In choosing the various contractors, there are several factors to consider: What is their experience with Fast Tracked applications? Do they have experience with materials of a similar chemical class to the new drug? Do they have experience with approval in international markets?

A contractor will leverage his or her experience and share his or her knowledge and expertise with the sponsor and make recommendations where appropriate. A responsible contractor will not take undue risks. If needed, the project will be provided with additional manpower to ensure approval. On the other side of the coin, a good sponsor will not ask their contractors to cut corners, take risks that put their employees or facilities in danger or break or bend any laws or regulations.

When evaluating contractors, sponsors should also consider the markets they will be entering in both the short and long term. The European regulatory agencies have different expectations than those in the U.S. A sponsor who expects that their product may eventually be marketed in Europe may wish to choose contractors who have such experience to help accelerate approval down the line. Even very early in the process, data can be collected that will be important in the E. U.

III. Understanding FDA regulations

The FDA's Guidance, “Fast Track Drug Development Programs,” specifies that the sponsor can have meetings before the IND submission, at the end of Phase 1, at the end of Phase 2 and right before the NDA submission. Sponsors may choose to have their contractors participate in these meetings. This is especially valuable if the contractor possesses expertise that the sponsor does not. Even with the best of communication between the sponsor and contractor, the contractor has a more complete and thorough knowledge of the processes and systems and will be able to answer questions about them.

After submission, all of the contractor and clinical sites are subject to Pre-Approval Inspections (PAI) from the FDA. It is wise for the sponsor to retain auditors to review work at manufacturing contractor sites and clinical sites to ensure that all are in compliance with regulations and protocols in the submissions.

If a drug is non-approvable, most often it is because it fails in the clinic. But another significant reason for non-approval is non-compliance with the filed procedures or protocols at the manufacturing or clinical sites. One contractor firm reported that they failed a PAI because the sponsor had made major changes to their filing but did not provide their contractor with current processing, sampling and testing procedures. Ultimately, the sponsor’s application was approved, but because of the delay, countless patients were not treated, and significant sales revenue was lost.

Before you host a PAI, you should have at least one lot of API completed under the Process Validation protocol. Inspections may be waived at the discretion of the FDA, and this decision is based in large part on the contractors' inspection profiles, when they were last inspected and if the material under review is similar to material from a prior inspection. While no contractor is immune to inspections, a good inspection history minimizes the chances that additional questions from the FDA will slow down the approval process. If issues are raised, however, they must be responded to promptly to minimize delays in approval.

One of the first documents that the FDA will want to review during the PAI is the Development Report. This document provides the basis for the intended commercial process and provides data from process challenges (“parametric studies”), which define the critical process parameters and define and justify the processing operating limits. A thorough, well-written development report will set the tone for the rest of the inspection. The contractor should also be prepared to present documentation for analytical methods validation, cleaning validation and equipment qualification. Any batch failures or discrepancies must be thoroughly investigated and corrective/preventative measures should be taken.

At the conclusion of the inspection, the Investigator may issue a citation (an FDA-483), which lists any areas of non-compliance identified. It is imperative that those who will be preparing the response--department heads, directors, vice presidents--understand the observations. While a formal response is not required, it is strongly recommended. Whenever possible, the issues should be addressed and closed (for example, procedural rewrites or additional training). In some instances, planned corrections should be described and commitments should be made as to when the remedial action will be complete. Any commitments must be met. Once a timeframe has been agreed upon with the FDA for a response, that deadline simply cannot be missed. If further data will need to be supplied to supplement the available data, it must be submitted or the sponsor risks the very real possibility of having their approval revoked.

During the NDA review, the FDA may issue chemistry questions to the sponsor. Here again, the contractor’s support is critical to the approval process. One of the more common questions will relate to the specifications and request that the limits be tightened. It is important that the contractor know their systems and processes thoroughly to know whether to tighten the limits or to explain why they are justified as submitted. If you can’t make the product to meet the new specifications, you must defend your existing specification. One approach is to indicate that the specification has been developed based on limited data and commit to review the specification after completion of additional lots. Other issues that may appear in the FDA chemistry questions may necessitate development and validation of new analytical methods. As with the PAI response, a formal response to the chemistry questions should be submitted as soon as possible. Depending on the nature of the questions, it may be appropriate to request a meeting with the reviewer to discuss options for remediation. If the issues are not too serious, the FDA may be willing to discuss matters in a teleconference. Again, the contractor’s assistance can be invaluable, particularly if they have experience responding to FDA questions.

IV. Anticipating FDA concerns

While there will always be some unexpected issues along the way, a successful Fast Track application will have anticipated as many potential problems as possible and will be prepared to mitigate them as they arise.

A good contractor will report good news to the sponsor quickly and bad news even faster. Any problems left unattended will only increase delays, or worse, sink approval altogether. Validation lots may not meet specifications, new impurities may be discovered and there may be a loss of quality when scaling up the process. Humidity, temperature, pressure and countless intangibles have a very real effect on processes and must be managed appropriately.

A major area of concern from regulatory authorities will be the specifications of the materials (API, drug product). The more you can anticipate questions on the specifications and have a prepared response, the faster you will be able to come to terms with the FDA and the faster you will be able to achieve approval. One cannot over prepare when it comes to identifying potential questions and building your responses and justifications.

The Fast Track approval process has accelerated the delivery of a number of vital drugs to the market to meet the needs of serious conditions. While the FDA works just as hard to help get these drugs to market, it is their responsibility to ensure that the public’s safety is not compromised. A successful Fast Track relies on the experience and expertise of the contractors to prepare for and work with the FDA to ensure a smooth process from PAI to approval.