We estimate that it generally takes 10
to 15 years, or possibly longer, to discover, develop and bring to market a new pharmaceutical product in the United States. Several
years may be needed to complete each phase, including discovery, preclinical, Phase 1, 2 or 3, or marketing authorization.
In addition, under the Pediatric Research
Equity Act, or PREA, an NDA or supplement to an NDA must contain data to assess the safety and effectiveness of the drug for the
claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation
for which the product is safe and effective. Recently, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which
was signed into law on July 9, 2012, amended the FDCA. FDASIA requires that a sponsor who is planning to submit a marketing
application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing
regimen or new route of administration submit an initial Pediatric Study Plan, within sixty days of an end-of-phase 2 meeting or
as may be agreed between the sponsor and FDA. The initial Pediatric Study Plan must include an outline of the pediatric study or
studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical
approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments
or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information. FDA and
the sponsor must reach agreement on the Pediatric Study Plan. A sponsor can submit amendments to an agreed-upon initial Pediatric
Study Plan at any time if changes to the pediatric plan need to be considered based on data collected from nonclinical studies,
early phase clinical trials, and/or other clinical development programs.
The cost of preparing and submitting an
NDA is substantial. Under federal law, NDAs are subject to substantial application user fees and the sponsor of an approved NDA
is also subject to annual product and establishment user fees. Under the Prescription Drug User Fee Act, or PDUFA, as amended,
each NDA must be accompanied by a user fee. The FDA adjusts the PDUFA user fees on an annual basis. PDUFA VI eliminates fees for
supplements as well as for establishments, though applicants will be assessed annual prescription drug program fees for prescription
drug products, rather than the prescription drug product fee assessed under the previous iteration of PDUFA. According to the FDA’s
fee schedule for the 2019 FY, the user fee for each NDA application requiring clinical data is USD 2,588,478 and the annual program
fee is USD 309,915. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee
for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as
orphan drugs, unless the product also includes a non-orphan indication.
Once the NDA submission has been submitted,
the FDA has 60 days after submission of the NDA to conduct an initial review to determine whether it is sufficient to accept for
filing. Under the Prescription Drug User Fee Act, or PDUFA, the FDA sets a goal date by which it plans to complete its review.
This is typically 12 months from the date of submission of the NDA application. The review process is often extended by FDA requests
for additional information or clarification. Before approving an NDA, the FDA will inspect the facilities at which the product
is manufactured and will not approve the product unless the manufacturing facility complies with cGMPs and may also inspect clinical
study sites for integrity of data supporting safety and efficacy. The FDA may also convene an advisory committee of external experts
to provide input on certain review issues relating to risk, benefit and interpretation of clinical study data. The FDA is not bound
by the recommendations of an advisory committee, but generally follows such recommendations in making its decisions. The FDA may
delay approval of an NDA if applicable regulatory criteria are not satisfied and/or the FDA requires additional testing or information.
The FDA may require post-marketing testing and surveillance to monitor safety or efficacy of a product.
After the FDA evaluates the NDA and conducts
inspections of manufacturing facilities where the drug product and/or its API will be produced, it may issue an approval letter
or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information
for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application
is not ready for approval. A Complete Response Letter may require additional clinical data and/or an additional pivotal Phase 3
clinical study(ies), and/or other significant, expensive and time-consuming requirements related to clinical studies, pre-clinical
studies or manufacturing. Even if such additional information is submitted, the FDA may ultimately decide that the NDA does not
satisfy the criteria for approval. The FDA could also approve the NDA with a Risk Evaluation and Mitigation Strategy, or REMS,
plan to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such
as restricted distribution methods, patient registries and other risk minimization tools. The FDA also may condition approval on,
among other things, changes to proposed labeling, development of adequate controls and specifications, or a commitment to conduct
one or more post-market studies or clinical studies. Such post-market testing may include Phase 4 clinical studies and surveillance
to further assess and monitor the product’s safety and effectiveness after commercialization.