Dozens of products have been switched from prescription status to being available over-the-counter (OTC) without a prescription (Fig. 7.13). In order for a drug to be switched, the product must be used to treat or prevent symptoms in a disease where physician oversight is not necessary. The patient must also be able to self-diagnose the condition being treated. Sinus congestion, headache, pain, upset stomach, and itching are examples of symptoms a patient can recognize. Drugs that must be monitored carefully to assure efficacy or that have significant toxicities are not good candidates for OTC switch. A sponsor can petition FDA for an Rx to OTC switch or make a submission for OTC status. Petitions do not need to come from the sponsor but can be submitted by anyone. An insurance company petitioned FDA to switch Claritin® to over-the-counter status as a means to save money on reimbursement of prescription allergy medications. The family of ulcer medications (H-2 antagonists) has been approved for OTC use (e.g., Pepcid® and Zantac®) because of relative safety and the symptom changes will be discernable to patients, but the anticholesterol product Pravacol® was turned down in 2005 because of the lack of symptomology and the inability for patients to self-diagnose need and beneficial activity.
An optimal registration strategy is ideally developed by a multidisciplinary project team involving experts in basic research, pharmacology and toxicology, clinical development, statistics, marketing, manufacturing, regulatory affairs, and project management (Figs. 7.14 and 7.15). Typically, this project team is put in place when data are available from in vitro and animal studies suggesting the drug may be effective. If it is possible to develop multiple indications for the product, the indication that would lead to the most rapid approval and market launch is typically given the highest priority. The wording of the indication should be developed with input from the entire project team. The package insert from approved products with similar indications should be analyzed. A target package insert should be developed that compares desired claims/statements with those made in approved package inserts and products pending approval. This target package insert will serve as a guide to determine the types and design of studies for the preclinical, clinical, and chemistry and manufacturing development programs.
r Define potential indications r Develop targeted package insert r Evaluate database and regulatory requirements of approved products: f FDA drug approval packages f FDA Advisory Committee meetings, transcripts, video tapes o Freedom of Information searches
A review of competitors' drug development programs is extremely useful to determine which indication might be the lead indication for a drug candidate (Fig. 7.15). The FDA web site contains information regarding their review of competitors' applications, plus transcripts of advisory committees. The comments of FDA reviewers on a drug approval package become available after a drug product has been approved. Transcripts of FDA advisory committee hearings on competitors' products (if held) can usually be obtained.
It is also important to evaluate products currently in the pipeline that could be competitive with the one being developed. It is important that the evaluation of potential competitor products be evaluated for the science, the patent and market exclusivity situations. Preclinical and clinical data can be obtained at scientific conferences, as well as through internet/literature searches of periodicals, abstracts, and press releases. A wealth of information on a competitive product can be gleaned if that product is discussed at a public FDA advisory committee. Understanding why one product was approved, or another not approved, can provide valuable insights to aid in designing an optimal development and registration strategy.
The development plan must meet the regulatory requirements, which are legally binding. As an example, the Code of Federal Regulations designated 21 CFR 314 outlines application requirements for FDA approval to market a New Drug Application. The contents and format of the application, definitions of adequate and well-controlled studies, acceptance of foreign data and accelerated approval requirements are some of the many areas covered. Guidance documents, although not legally binding, provide far greater detail. As an example, the regulations are not specific as to the number of patient exposures required in an application for a product that is going to be chronically administered. There is a guidance document that outlines the number of patients overall that should be exposed to the drug, as well as the number of patients that needs to be followed for 6 months and for 1 year. Understanding this guidance will help ensure that the r Collect regulatory information on products not yet approved:
o FDA Advisory Committee meetings c Trade organizations, periodicals, abstracts, press releases r Evaluate regulatory pathways with optimal critical path/market potential: o FDA regulations c FDA guidances o Podium policy r Evaluate market exclusivity and patent extension opportunities r Evaluate competitor patent status Fig. 7.15. Develop Optimal Registration Strategy development program is designed to study an appropriate number of patients.
Patent status of a new product is important for regulatory strategies along several lines of registration planning. The sponsor's new product patent will offer certain opportunities for exclusivity, but potential patent extensions in the future (e.g., new indications or formulations) need to be factored into the strategy as well. Also, the strategy needs to take into account the patent situation with the competitor's products, too.
In 1984, the Drug Price Competition and Patent Term Restoration Act was passed (Fig. 7.16). This act of Congress allowed generic companies to obtain approval of their drug without repeating all the testing required to demonstrate safety and efficacy of the brand-name product. The effect was to lower the hurdle for the development of generic drugs and to make them available as soon as the pertinent patents on the brand-name drug have expired. To maintain a balance between the commercial rewards for generic and innovative companies, under the act, the brand-name product is granted up to 5 additional years of patent protection. This additional patent protection is to compensate for the amount of patent life used up during animal and human testing, as well as FDA review.
Several opportunities for market exclusivity exist. A period of market exclusivity is one in which a competitor cannot market the same product, giving the innovator a market without direct competition. As previously discussed, an orphan drug is protected from direct competition for 7 years. If a new chemical entity is approved, the drug receives at least 5 years' exclusivity, even if its patent expires within this 5-year window, protecting it from generic competition. Three years' exclusivity is granted for new indications for an already approved drug product. Congress and FDA are keenly aware of the lack of approved indications for use of drugs in a pedi-atric population. As an incentive to generate data to support use in children, FDA grants 6 months of market exclusivity for new indications in children.
The Patent and Trademark Office of the federal government has responsibility for issuing patents. The FDA has only r Patent term restoration: c Maximum five years of patent extension r Exclusivity periods: o Seven years for orphan drugs o Five years for innovator products o Three years for selected changes in an approved drug product c. Six months for pediatric studies r FDA has administrative role in patent extensions and exclusivity:
o FDA Approved Drug Products with Therapeutic Equivalence
Evaluations (Orange Book) c Tentative approvals granted
Fig. 7.16. Patent and Exclusivity Interests an administrative role to make information on patents and periods of market exclusivity readily available. Information regarding patent coverage, market exclusivity, and therapeutic equivalence for approved drugs and biologics appears in a booklet entitled "FDA Approved Drug Products and Therapeutic Equivalence." Because the publication has an orange cover, it has become commonly known in the industry as the Orange Book.
The FDA can grant a tentative approval to a generic version of a drug product that still has a remaining period of patent life or market exclusivity by the innovator. Generic companies are allowed to legally perform all the required development for a generic product approval, primarily bioequivalence and drug product formulation development, during the patent period of the innovator, resulting in accelerated market availability of generic products. A tentative approval is given when the FDA has completed its review and determined that all requirements for an approval have been met. A product with a tentative approval can be legally marketed as soon as the patent or period of exclusivity held by the innovator has expired.
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