Postapproval Maintenance

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Once a NDA/BLA is approved and the product can be made commercially available, the obligations of the sponsor and the FDA continue as long as that product is on the market. If there are no significant safety issues that arise after the product is on the market, the maintenance of that product by both the sponsor and FDA is usually a routine process. Annual reports are provided by the company to the regulatory authority. Because a clinical program of an investigational product can never fully identify all the possible safety issues with a product, one of the most critical postapproval responsibilities of the sponsor and the FDA is the monitoring of the reported safety profile of the product when it is in general use.

The sponsor's obligations to support a product postap-proval can be product-specific, in the form of postapproval commitments (studies), or general requirements that apply to all products (Fig 7.27). During the final phases of the approval process, the FDA may request a commitment from the sponsor to conduct certain studies after the product has been approved. Although the sponsor has some room to negotiate these postapproval commitments, with the approval of the product being held in the balance, most sponsors agree to conduct the studies proposed by the FDA. The specific commitments and time frames for completion are outlined in the approval letter. For every product that is approved, the sponsor is required to conduct safety surveillance, designed to capture and evaluate all reported adverse events, and submit these data to the agency. As the population exposed to the product is much greater once the product is available on the market and has broader demographics, concurrent disease, and concomitant medications, it is not unusual to see adverse events that were not observed in the clinical trials; or, the same adverse events may be observed but at a higher incidence or at a greater level of seriousness than observed during the clinical trials. Additionally, if the sponsor makes any major r Post-approval commitments (studies):

c Voluntary or required r Post-approval safety surveillance requirements r Changes to an approved application Fig. 7.27. Post-approval NDA/BLA activities changes to the product or to the package insert from what was initially submitted and approved, those changes need to be submitted and approved by the FDA.

As described earlier, during the final phases of the approval process, the FDA may require the sponsor to do additional work on the drug product after it has been approved. These postapproval commitments range from generation of additional safety and/or efficacy data to generation of additional data on the manufacture and control of the drug or biologic product (Fig. 7.28). During initial drug development, studies are conducted in a relatively small number of patients selected under strict inclusion and exclusion criteria with limited long-term safety data. Special patient populations, such as patients with concurrent diabetes or heart conditions, renal failure or hepatic failure, or pediatric and geriatric patients, may not have been specifically studied during the development program. Subpopulations within a general disease indication may need further exploration (e.g., at different disease stages or levels of severity). Due to the exclusivity provisions for studying products in a pediatric population, the sponsor may elect to do this work to obtain the 6-month market exclusivity that this work can afford. In addition, drug interaction information is likely limited at the time of product launch and may need to be further studied. Long-term safety studies may be required to determine whether there are unique safety issues associated with chronic exposure to the product. If the sponsor has agreed to postapproval commitments, then periodically they must advise FDA of the status of their work on these commitments. If the sponsor does not conduct the studies to satisfy these commitments in a timely fashion, the FDA may withdraw approval of the application.

Typically, the chemistry, manufacturing, and controls section of an approved NDA/BLA will require updating postap-proval. For some products, real-time stability data must be generated to support extended expiration dating. The time the product is on the market is additional time the sponsor can study the stability of the product and determine its maximum shelf-life. Typically, the sponsor can extend expiration dating of the product based on additional real-time data that meets a FDA-approved stability protocol and change the expiration r Clinical:

c. Safety data in additional patients

^ Long-term safety data c Special patient populations (i.e. renal failure, diabetes)

c Drug interactions studies c Pediatric trials and exclusivity c Geriatric studies date on the product without obtaining FDA approval. It is required that those data be submitted to the FDA at the appropriate time.

For many products, FDA allows the sponsor to scale up the production of the product by 10-fold to accommodate the commercial demand, as long as the impact on the quality of the product is not different at this larger scale. The first lots made on a scale larger than what was approved in the NDA/BLA must be placed on a stability program and the appropriate validation data collected and available for FDA review.

Postapproval safety surveillance is critical for further defining and refining of the safety profile of a drug (Fig. 7.29). Data generated from clinical trials are from a small, tightly controlled subset of the overall patient population, and clinical trials are usually not large enough to detect rare adverse events. Vigilance on the part of the FDA, the sponsor, and the public must be maintained to ensure new and more serious adverse events are identified and promptly incorporated into the package insert so that prescribers and patients are aware of the risks associated with the product. Also, the most common reason for withdrawal of a product from the market by FDA action or voluntarily by a company is a serious adverse event situation often unanticipated based on the NDA safety file, especially of a cardiovascular or liver nature.

Sponsors are required to evaluate and report adverse events from all sources, including those reported to them in both the United States and foreign countries, the published literature, and postmarketing studies. If an adverse event occurs that is "serious and life threatening," it must be submitted to FDA within 15 calendar days of the receipt of the report by the sponsor. Once the drug is approved, the sponsor must submit all adverse experience reports, not just those that are serious or life threatening, and an evaluation of these reports, to the FDA every 3 months for 3 years. After 3 years, unless otherwise specified, reports must be submitted annually for as long as the product remains on the market.

FDA may determine that a drug can be approved but that the safety profile needs to be carefully monitored in patients r Sponsor requirements r Registry / risk management r Med Watch: c. Voluntary reports from health care professionals o Types adverse events to report:

> Death

> Life-threatening hazard 5> Hospitalization

> Disability 5> Birth defects

Actions based on new safety issues: e Medical Alerts c Revised Labeling o Boxed Warnings o Product Withdrawals r Chemistry, Manufacturing, and Controls: c- Long-term stability c Manufacturing data at scale c Validation data

Fig. 7.28. Post-approval Commitments

Post-approval Safety Surveillance Requirements who receive the drug. This can be accomplished through a registry, where each patient receiving the drug is "registered" in a database and followed periodically to collect additional safety information. A patient registry can also be used for a subset of patients (e.g., to monitor for birth defects in patients who take the product during pregnancy).

Another mechanism to uncover new adverse events is MedWatch. This is a voluntary reporting system established by the FDA whereby the general public can report serious adverse events, although most of the reports are received from health care providers such as doctors, nurses, pharmacists and dentists. MedWatch reports should only be submitted for serious adverse reactions. Serious adverse events are defined with the following criteria: 1, death (if an adverse event from the drug resulted in a patient's death); 2, life-threatening (if a patient was at risk of death at the time of the adverse event); 3, hospitalization (the adverse event requires a patient to be hospitalized or an existing hospitalization to be prolonged); 4, disability (if an adverse reaction results in a persistent or significant disability/incapacity); and 5, birth defects (a congenital anomaly/birth defect).

Depending on the severity of the adverse event profile, FDA, in conjunction with the sponsor, has several avenues available to alert health care providers, patients, and the general public of potentially serious adverse events. Medical alerts can be issued in the form of "Dear Doctor" letters. These letters are sent to physicians advising them of the new serious adverse event. The package insert can be revised to add the event or strengthen a warning regarding an existing event. If FDA feels an event needs to be prominently displayed, they can require that it be outlined in a black box in the package insert, a so-called "black box warning," or an adverse event could lead to a new "contraindication." Lastly, although rare, a drug can be withdrawn from the market either voluntarily by the sponsor, or as a mandate from the FDA, if the nature of the adverse event significantly changes the balance of risks and benefits to the patient.

After BLA/NDA approval, a plethora of activities can occur that requires submission of additional information to the FDA (Fig. 7.30). These changes can occur as a result of further experience in manufacturing and testing, new clinical information, the need for risk mitigation, or the desire to grow the market. The more significant the implications of the change, the greater likelihood FDA will need to review and approve it prior to implementation. Chemistry, manufacturing, and controls changes that occur after approval include such things as adding a new supplier of drug substance, adding a new finished product manufacturer and or packager, adding new vial/bottle sizes, changing the batch size, or changing the labeled storage conditions. Clinical changes could include new indications for the use of the product, new safety information, or new pharmacokinetic data in special populations. New information that impacts the product's package insert needs to be submitted, as well as advertising copy updated to reflect the new information.

r Types of changes: o Chemistry and manufacturing o Clinical o Labeling c Advertising copy r Supplements to an approved application: o Prior approval supplements o Changes made at time supplement is filed o Annual Report changes

Fig. 7.30. Changes to an Approved Application

Major changes to an approved application require a supplement to the NDA (sNDA) or BLA describing the change and providing the necessary supporting documentation for FDA review and approval prior to implementation. Examples of these types of changes include broadening a drug substance or finished product specification, changing or adding a manufacturing facility where the facility is materially different from the approved facility, or any major change in labeling. These are called "Expedited Review Requested" supplements.

Clinical changes including new indications for the use of the product are major changes and require a supplemental NDA or BLA to be submitted. A new indication requires full phase 2 and 3 clinical studies for efficacy and safety. A new indication also may require preclinical work for safety and/or clinical pharmacokinetic studies. The registration strategy for Enbrel® (etanercept) included an original BLA submission for treatment of moderate to severe rheumatoid arthritis. After the initial BLA approval, supplements were submitted and approved for treatment of moderate to severe acute polyartic-ular-course juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis, and chronic moderate to severe plaque psoriasis.

Less significant changes are submitted in a "Changes Being Effected" supplement. These changes can be implemented after the sponsor has submitted the supplement and before FDA approval. Examples of these types of changes include adding a specification that will provide added control to the manufacture of the product, changing or adding a new manufacturing facility that is not materially different from the approved facility, or changes in the package insert that strengthen instructions about dosing, precautions, warnings, or adverse reactions.

Minor changes can be reported in the annual report to the NDA or BLA. The sponsor is required to submit this report near the anniversary date of the product's approval. These changes include minor changes to the package insert such as grammatical changes, deletion of an ingredient that serves only to add color to the product, or an extension in expiration dating based on real-time data that conforms to an FDA-approved stability protocol.

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