One of the most dynamic areas in the pharmaceutical industry today is the prescription-to-OTC switch, commonly called the Rx-to-OTC switch. This is the process by which a drug that has previously been used only by prescription is converted to self-medication status. We have already considered the criteria for OTC use of medications and these criteria represent a sound guide to determining what drugs are suitable for switching. There are no hard and fast guidelines for determining which drugs may become suitable for OTC switch, but a consideration of self-diagnosability of the disease state to be treated, the general safety and tolerabil-ity of the drug, its ability to show efficacy in the hands of non-professionals, and a relative absence of problems with masking of symptoms all contribute to making a drug more OTC-able.
The first question that arises when considering the possibility of an OTC switch is, why has the drug not been available OTC before and what can be done to remove the obstruction? It is possible that a drug may simply not have had adequate prescription experience in the past. It takes time to accumulate a substantial use database of real-world experience. This is essential to make it possible to form a judgment about safety in prescription use and, therefore, projected safety in OTC use. What constitutes substantial use is always a relative matter. Typically, at least 3 years of data accumulation with a widely marketed drug is required to be able to feel some security in making judgments from the adverse reaction database accumulated. For small selling drugs, this can easily take 10 years or more. The fewer problems this database reveals, the better the drug will be as a switch candidate.
It is sometimes possible to accelerate the accumulation of data for a promising OTC candidate by specialized Phase IV studies. These studies accelerate the process of data collection by conducting what amounts to a survey amongst physicians using the drug on a prescription basis. Since the sole interest is the gathering of adverse reaction data, with special emphasis on rare and serious events, record forms are kept very minimal, often to a single page. The study design consists simply of a survey, done without control groups. Hundreds of physicians, or even thousands, must be contacted to participate in the survey by submitting brief record forms on patients they treat in their usual manner with the prescription drug. Such a survey can rapidly provide a much more reliable database than spontaneous reporting. With a survey, you get both a frequency of the various side effects and a reasonable estimate of the number of patients treated, which permits the calculation of accurate rates for the adverse effects observed. This is in marked contrast to the data obtained from an entirely spontaneous adverse reaction database, where it is impossible to determine what the efficiency of reporting is. Therefore, it is extremely difficult to estimate correct rates of occurrence of individual adverse effects. The spontaneous databases are more useful for the qualitative evaluation of what can happen with a drug than for the quantitative evaluation of its true frequency. This type of adverse reaction survey study can pave the way for a switch effort in much less time than needed if reliance is placed solely on spontaneous reports for collection of data.
If the principal barrier to switch has been a lack of clinical experience with a drug, this can be remedied by the collection of a large adverse reaction database. Once this is done, it is usually straightforward to establish that the drug is safe in prescription use. This is a major advance on the road to OTC approval, but it certainly does not yet prove that the drug will be safe and effective in the hands of consumers without the benefit of a learned intermediary. In order to establish this additional point, it is almost always necessary to supplement the analysis of adverse reaction databases with clinical studies in realistic conditions, using the labeling composed for the OTC product.
We will discuss the peculiar aspects of the design of clinical studies suitable for such purposes later, but for now it is sufficient to note that they may usually proceed with the objectives of establishing efficacy and common side effects only, and that very rare side effects have already been evaluated in the prescription use setting.
Regardless of the reasons underlying a drug's prescription-only status, once a decision is taken that a drug should be moved OTC, it is extremely important to get early interaction with the regulatory agencies. This can establish at an early stage whether or not they have concerns that the company has not yet considered. The obvious concerns of safety and efficacy are not always the principal issues obstructing a switch. It is possible in some cases that FDA has no concerns in these two areas, but that self-medication use is prevented by some other peripheral but still highly important consideration. Examples of such problems are indications which the FDA does not regard as self-diagnosable, and such problems as spread of antibiotic resistance by OTC use of an antibiotic that might adversely affect the overall public health picture.
It should be remembered that FDA's principal concern in considering an Rx-to-OTC switch is from a public health perspective. This is in contrast to the usual viewpoint of the pharmaceutical companies, which tends to be focused on the treatment of the individual patient. The FDA's positions may be better understood by remembering that they tend to take the big picture, whereas the pharmaceutical company tends to concentrate on narrower issues. There is nothing that will facilitate the Rx-to-OTC switch of a drug more powerfully than convincing the Agency that its OTC availability will benefit public health.
Other issues that may concern the FDA far more than the industry, are precedent-setting issues. The FDA functions in an environment in which they have ongoing responsibility for the approval and switch of many different types of drugs. They may feel that the precedent set by a particular switch could be damaging in terms of their overall policy posture, even though they have relatively little concern about the switch itself. If this is the situation, careful negotiation with the FDA and care in how the switch is presented to minimize setting an awkward precedent can often resolve the issue.
Another broad-scale public health concern which may worry the FDA is the implied message given to the consumer by the OTC availability of a particular compound. This concern is illustrated by the situation with soluble fiber cholesterol-lowering agents of the psyllium type. These agents have been shown to lower cholesterol, but only to a very small degree. It was felt by the FDA that, if they become established with claims of cholesterol reduction, the population may be misled into feeling that they have made major inroads into their cholesterol problems when, in fact, they have not. The message communicated to the consumer by making these compounds available constituted a barrier to this use.
Early negotiation with the FDA will assist in identifying their concerns and will help in obtaining their insight into the types of studies required to resolve the difficulties presented by any given case. The skill of the regulatory department in structuring and presenting a switch proposal is vital to its success.
The timing of an Rx-to-OTC switch project is always a major contributor to its success. The timing is influenced by both regulatory and commercial considerations. The completeness of the available database is critical and can set the timing of a switch. Often, however, the key factor in deciding when a switch effort should begin will be commercial. This involves the major benefits to a company in moving a drug to OTC status at approximately the same time as its patent expires. By doing this, the company may greatly mitigate the loss of patent protection. A switch can offset the precipitous decline in the innovator's share of the Rx market. At this difficult time for a company, nothing is welcomed more than the rapid growth of an OTC market that, in some cases, can be even larger than the original prescription sales. Typically, once a drug has gone OTC, it is sold at a lower price with smaller profit margins, but the total volume tends to increase several-fold. The result can be a highly favorable economic situation for the company.
Unfortunately, in many cases, a switch at the time of patent expiration does not occur and a long delay intervenes before OTC status is reached. This is generally due to the tendency within companies to seriously examine the need for an OTC switch only a year or two before patent expiration looms. This will be too late to complete the necessary studies and regulatory applications in time for a smooth transition. In order to make a seamless transition at the time of greatest opportunity for a company, it is necessary to plan for the OTC switch many years in advance. Nothing can substitute for an awareness of the OTC potential of the company's portfolio of drugs so that suitable programs can be designed and put into action on a timely basis.
There are two fundamentally different types of Rx-to-OTC switches from the standpoint of the scope of the research program required. Switch programs can vary from large NDA programs as extensive and expensive as anything found in the new chemical entity development, to programs consisting of little more than a single study. What influences the basic size and expense for an Rx-to-OTC switch is whether or not you propose to change either the indication or the dose of the drug when you bring it into the OTC market. If the indication or the dose is to be changed, you will be involved with an entirely new NDA, which is needed to show the fundamental efficacy and safety of the drug, either at its new dose or in its new indication. Such a program obviously will require several years and involve extensive expenditure. In startling contrast to this are the programs of modest size often required for the switch of drugs that will be taken into the OTC market at their existing prescription dosage and for their existing prescription indications. Here, the regulatory agencies will generally accept the concept that there is no need to prove again the basic safety and efficacy of the drug, because this has already been done in the primary new chemical entity NDA. Such a repetition would not provide useful new data. What will be required is an actual use study, to show that the proposed labeling for OTC use is effective in enabling patients to use the drug properly. Also, it may be necessary to address whatever specific factor it is that has been previously obstructing the drug from OTC use. For example, if there is a question as to whether the prescription indication that will now be taken OTC is self-diagnosable, then a study of self-diagnosis will be required. This occurred with the vaginal anti-fungal compounds, which were long kept on prescription status because of questions as to whether women could effectively diagnose vaginal candidia-sis themselves. Only a single study was required to resolve this issue. It was extremely unusual for the pharmaceutical industry, in that it involved no drugs of any kind. It was simply a study of women's ability to self-diagnose but it resolved the one outstanding issue that had blocked OTC approval.
The time required to carry out studies on such special questions can vary, considerably depending on the complexity of the question. However, it is typically a brief program and its budget is commonly small by the standards of the pharmaceutical industry. It is obvious that in the planning and preparation of a switch program, it is essential not to assume that a full safety and efficacy program will be required. Rather, early communication with the regulatory agencies is needed in order to establish what barriers actually exist.
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