This report presents the results of the investigations and researches on thinking for the development and evaluation of“new nonprescription drugs”, which were supported by the 1998 and 1999 grants from the Ministry of Health and Welfare Scientific Research Fund. The views expressed are solely those of the authors and do not reflect the policy of the MHW.



　Introduction


　Nonprescription drugs have played a significant role in the improvement of the health and life of people. Recently, some prescription drugs have been switched to nonprescription status, as sufficient clinical experiences have been accumulated and the ingredients are confirmed to be effective and safe by reexamination, or nonprescription drugs have been newly formulated with combination of ingredients not clinically used so far. These so-called“new nonprescription drugs”(switch over-the-counter drugs：SOTCs, or direct over-the-counter drugs：DOTCs) (See the end of this text) have been felt, particularly after switching of H2 blockers to OTC status, to need reviewing in respect to the methods of development and assessment as well as the postmarketing surveillance.

　In answer to this need, the Central Pharmaceutical Affairs Council held sessions on attitude toward the approval and examination of“new nonprescription drugs”, and published basic thinking summarized under 5 headings. Based on this thinking, the present research team studied the trial protocol and the method of postmarketing surveillance for collection of data needed to develop and evaluate“new nonprescription drugs”. The results of this research are presented in the following.

　Although there is room for further investigations in the method of the development of nonprescription drugs, the team expects the present results to serve as references in the future development of new nonprescription drugs.


　Chapter 1. Clinical Trials of New Nonprescription Drugs


　The clinical assessment of new nonprescription drugs has so far been performed on the basis of data from clinical trials for verification of the efficacy and safety of new nonprescription drugs (ordinary clinical trials), or on the basis of data from the development and postmarketing surveillance of these drugs used as prescription drugs. We investigated the clinical trial (method of assessment) of the nonprescription drugs as used in the actual situations.

　Although our investigation has been mainly concerned with SOTCs, it would be appropriate to perform premarketing assessment, based on the assumption for postmarketing actual use, on DOTCs too, depending on the method of development (trial).

　It is considered beneficial to examine and evaluate before marketing the new nonprescription drugs in situations similar to those in the postmarketing actual use. Prior to such a trial, investigation of the understanding of the label claims for a candidate new nonprescription drug is sometimes performed in some foreign countries. It may be advisable to perform such an investigation as necessary in Japan too.

　Since there can be some features that could not be detected before marketing on account of limited population size, etc., it may be necessary to re-confirm the appropriateness of the candidate product as a nonprescription drug by postmarketing surveillance.


　General Statement


　1. Basic Thinking

　Actual Use Trial (AUT) (Note：Further refinement is needed for the terms used, etc.).

　The actual use trial is conducted to evaluate the efficacy and safety of a candidate“new nonprescription drug”on those subjects who can represent the consumer population under those conditions which are similar to the conditions of actual use. Because of this nature, this trial is conducted mainly by pharmacists, but it is assumed that cooperation by doctors and/or dentists at some point in the course of trial has been ensured. In evaluation of the potential efficacy of the candidate drug in the consumer population, this AUT is the most important verification test, and should be scientific, ethical and reliable.

　The candidate drug is required to comply with the basic policy agreed on at the meeting of the Central Pharmaceutical Affairs Council Special Commission on Nonprescription Drugs in December, 1998. Ideas leading to the clinical trial and the appropriateness of its conduct should be carefully evaluated by utilizing the clinical trial consultation of the pharmaceutical organization, etc.

　2. Range of Application

　The conduct of“AUT”should be considered for any drug intended to be submitted for approval as a“new nonprescription drug”. Terminology in Good Clinical Practice (GCP) is followed in this.

　1) SOTC

　In principle, if the prescribed dosage and administration has been already evaluated and determined from the results of trials of the prescription drug, or if the candidate drug has a reliable record of satisfactory results as an OTC drug outside Japan, dosage-response test is not performed but a verification trial based on phase 3 trial in the“clinical trial”of prescription drugs is conducted. It is possible to conduct“AUT”as a verification trial by contriving an appropriate trial design. (Note：Though“AUT”is a type of study that is performed as an addition to the usual clinical study, it is advisable to avoid overlapping of trials by modifying the method and design of the study.)

　In case the candidate drug differs from its prescription form in dosage and administration or in that it is combined with other drugs, e.g.

　a) Change in dosage and administration such as reduction in dosage, as compared with the prescription form, and
　b) Prepared as a combined drug, with reduction in dosage as compared with the prescription form.

　It is necessary to conduct a trial for determination of dosage and administration prior to“AUT”, with past clinical trials, good-quality clinical data from specialists and reports based on postmarketing experience with the prescription form as references, and to elucidate the actual state of use such as a low incidence of adverse reactions in treatments performed in accordance with warnings and indications as well as a low risk of abuse in wide-spread use. If two or more active ingredients are combined, it is required to demonstrate that all ingredients are effective and the safety and efficacy of the ingredients are not reduced when the ingredients are combined.

　It should be always kept in mind, however, that the contents of the trial could vary depending on the candidate drug. All available data, that had been accumulated in the past, should be utilized in determining which trials should be conducted.

　For instance, the efficacy and safety of a drug can be verified by“AUT”, provided that the drug is a single-agent drug or combined oral drug or drug for external application without change in dosage and administration, and that the indications for it can be appropriately rephrased and safety measures such as use of earlier expiration date and smaller package are ensured.

　2) DOTC

　Although trials equivalent to“AUT”should be required, it is necessary to determine individually whether a clinical trial corresponding to the clinical trial of a new prescription drug should be conducted separately from“AUT”, or there should be a clinical trial designed to generate the information properly obtained by“AUT”.

　3. Things to remember

　Clinical trials should be conducted according to GCP. This means, 1) consents from the subjects of the clinical trials are indispensable, 2) the records kept by the subjects are used as the original data in“AUT”, and 3) the sponsor should keep up monitoring of the pharmacies and medical centers that cooperated in the clinical trial.


　Particulars (AUT Design)


　1. Objective

　Obviously, it is essential that the objective of a clinical trial is clear.

　2. Institutions (Pharmacies and Clinics) and Investigators

　Although“AUT”is conducted on condition that doctors cooperate, it is unavoidable from the objective of“AUT”that pharmacies should be the main institution responsible for the trial.

　For instance, it would be appropriate to select subjects (screening for qualified subjects) at medical centers in many cases, but the subsequent trial should preferably be conducted at pharmacies even in such a case.

　Ensuring doctors' cooperation is prerequisite for the conduct of the trial. It is imperative to establish a cooperative relation with the medical center, so that necessary measures can be taken for the trial subjects in emergency.

　At the pharmacy where“AUT”is conducted, a pharmacist responsible for the trial is needed. The selected pharmacy should be highly reliable with a good record as a dispenser of nonprescription and prescription drugs, capable of controlling medication histories of the subjects, and able to provide the environment suitable for obtaining informed consent. The qualifications of the pharmacist responsible for the trial will be specified separately as necessary.

　In case medical specialists are needed for evaluation of the efficacy and safety depending on the contents of the trial and the nature of the drug, doctors (hospitals, clinics) play a central role. Since the objects are nonprescription drugs, however, it is necessary to design the trial serving as“AUT”in such a way that the pharmacists, and not doctors who diagnose and explain, play a central role in explanation.

　3. Establishment of the Clinical Trial Review Board and Its Function

　The clinical trial review board examines the ethical and scientific appropriateness of the clinical trial from the standpoint of the subjects.

　In“AUT”, regional medical association, dental association, pharmacists' association, and non-specialist individuals respected for learning and experience should be asked to participate and/or cooperate in the organization of the clinical trial review board.

　4. Procedure to Obtain Informed Consents from Subjects

　In accordance with GCP, the consent should be obtained directly from the subject as a rule. The subject or an approved individual representing the subject is informed of all the aspects of the trial by use of a document, and if the subject (or, if unavoidable, representative) voluntarily consents, the document is saved.

　The contents of the written information are the same as specified by the procedure to obtain informed consent for prescription drugs.

　5. Trial Design

　In verification trials, the trial design should be a randomized, double-blind, comparative study that yields the results which can be scientifically proved. (Note：If a clinical trial designed as specified here is not conducted, the reason for not using the design should be explicitly stated.)

　Because nonprescription drugs are indicated in subjective symptoms or for symptomatic treatment in light therapies, the inactive placebo is used as the control as a rule.

　If a standard drug is used as the control, the reason for such an exceptional use must be clearly stated. In such a case, the clinical trial verifies non-inferiority according to the new statistic guideline. The grounds for specifying the target number of cases should also be described. If laboratory tests are needed, the kinds of tests should be clearly stated in the protocol.

　6. Duration of use

　Since nonprescription drugs are used for symptomatic treatment, it is not advisable to continue using the drug after disappearance of the symptoms. For this reason, the duration of the clinical trial should in principle agree with the duration of use specified in the precautions for the drug use.

　The actual duration of use is recorded as a part of information for assessment.

　Follow-up is conducted after the termination of use, as necessary.

　7. Selection of Subjects

　Symptoms indicating the investigational drug are decided on beforehand, and the individuals confirmed to have such symptoms are allowed to participate in the trial.

　“AUT”is conducted, as a rule, on those patients who present, as core symptoms, those symptoms which will be written as the indications in the approval application.

　The individuals are permitted to participate in the trial only if they meet the conditions approved by the Clinical Trial Review Board and gave the informed consent. In“AUT”, it may be allowed to confirm the eligibility of patients for the trial of the investigational drug by reviewing the complaints, past history, physical findings, data from simple laboratory tests and/or provocation tests at a medical center, and then select the confirmed patients. It may also be permitted, depending upon the investigational drug, to select those individuals whom the pharmacists judged to indicate that drug on the basis of product information at pharmacies where the drug is purchased.

　8. Assessment of Efficacy and Safety

　The efficacy of a nonprescription drug is evaluated by the subjects themselves with the disappearance of symptoms and improvement of the severity of symptoms as primary outcome measures, by use of a reproducible and objective rating scale.

　For verification of the evaluation of efficacy and the compliance with medication rule, the diary kept by the subjects (daily as a rule) are utilized. This diary contains the criteria for evaluation easily understood by the subjects. When the subjects evaluate subjective symptoms by themselves, the pharmacist helps them by explaining the criteria for evaluation, as necessary.

　The subjects evaluate the state of compliance with the indications and efficacy, dosage and administration, and precautions for use (particularly such important cautions as warning, etc.) in the use of the investigational drug. In assessment of the response rate, the response rate obtained with the drug taken according to the instruction on dosage and administration is used as the primary variable. Interval between the initiation of treatment and its termination (either due to the disappearance or improvement of symptoms or due to failure to respond or aggravation) is also used as an outcome measure.

　The event described as adverse event is used as the safety measure. Depending on the seriousness of the adverse event, the pharmacist or doctor clarifies causality between that event and the drug, and reports the results to the sponsor.

　Compliance in respect to the taking of drug is verified by checking the recovered unused portion of the drug against the case report or the diary kept by the subject. Since the drug is frequently taken only when it is needed in“AUT”, it is necessary to verify the state of drug taking. Distribution, storage and recovery of the investigational drug are performed by the pharmacists who participate in the clinical trial.

　Data on non-compliance with the indications, dosage and administration, and precautions for use (particularly such important cautions as warning, etc.) are analyzed, sometimes with stratification by age.

　It is required to provide clear information, obtained through the aforesaid evaluations, on such matters as appropriateness of information provided to the target population for that drug (whether or not labels and attached document are easy to read, easy to understand, easy to interpret, and clear about the use for which the product is intended), usage not described on the label (non-recommended dosage or duration of treatment, indications not specified by the claims, use in inappropriate population, etc.), risk of overdosage(particularly in children and adolescents), and risk of abuse (if the product has a characteristic specified under the risk of abuse). Besides the above information, it is also required to provide information about the reported interactions between the indications/efficacy, dosage/administration, as well as precautions for use, entered in the approval application, and the safety as well as diet/craving in the target population for the that drug, interaction between that drug and other drugs, compliance with the directed usage and warnings, drug taking pattern and self treatment pattern. The safety and efficacy for a certain fixed period after treatment are also evaluated, as necessary.


　Chapter 2. Surveillance on Understanding of New Nonprescription Drugs


　It is an important feature of nonprescription drugs that the consumers take the drug on their own judgment based on appropriate information. Accordingly, if the consumer cannot understand relevant information (indications, dosage and administration, contraindications listed in the precautions, need for consulting, etc.) from label claims on a new nonprescription drug, appropriate use of that new nonprescription drug is out of the question.

　In Western countries, a premarketing test (surveillance) is sometimes performed on the general public without using the actual drug, to see if the provisional label claims are correctly understood.

　Because it seemed to represent a sound thinking to investigate the consumers' understanding of label claims on new nonprescription drugs prior to marketing, then conduct clinical trials reflecting the results of such premarketing studies, and market the product with proper label claims, the feasibility of this approach was examined for cold remedies, indigestion remedies and drugs for external application. It was concluded that the majority of answers would be correct if people filled the blanks as they read the label claims, while it did not reflect the actual state of use if people filled the blanks without reading the label claims, so that the usual questionnaire would not yield particularly meaningful information.

　Meanwhile,“the Committee on the Improvement of Product Information for Nonprescription Drugs”repeatedly examined the label claims that could be easily understood by the consumers, and produced a revised version of“the Guideline for the Preparation of Product Information on Nonprescription Drugs”, which was already sent to the regulatory organizations (Iyaku-hatsu No. 983, No. 984：12.8.1999). The product information composed according to this new guideline would be easier to understand as compared with the previous labeling statement, and allow the clinical trials to be conducted in accordance with this information in most cases.

　From the above, there seems to be little justification for imposing such a premarketing test (surveillance) on all new nonprescription drugs uniformly.

　However, there may arise a need for such a premarketing test (surveillance), e.g., for new nonprescription drugs with the mechanism of action or indications that had been so far unknown in the nonprescription drug, or those with a peculiar dosage and administration. Needless to say, label claims should be easy to understand. Further investigation is necessary for the range of new nonprescription drugs needing such a premarketing test (surveillance) and for the method of test (surveillance).


　Chapter 3 Postmarketing Surveillance (PMS) for New OTC Drugs


　For new OTC drugs, it is required to collect and examine information about the state of occurrence of adverse events and the actual state of proper drug use after marketing by some appropriate investigation. Based on the results of such an investigation, appropriate measures are taken as necessary to prevent the occurrence or spread of any danger to public health associated with the drug or to ensure the proper use of the drug.

　Direct over-the-counter drugs (DOTCs) undergo reexamination at a prescribed time after approval, while switch over-the-counter drugs (SOTCs) are required to receive postmarketing surveillance on adverse reactions, etc. for a certain fixed period (3 years as a rule) after approval according to the postmarketing surveillance protocol. To confirm that no unexpected adverse events occur or no improper use is made, it is advisable to carry out an efficient, concentrated investigation in early postmarketing days.

　In planning a postmarketing surveillance for a drug, it is necessary to verify the information obtained before marketing including the results of actual use trials (AUT), and to consider carefully what information about the drug should be collected after marketing. Particularly, for those drugs that have been shown by premarketing information to need postmarketing data supplementation on certain matters, it is crucial to plan the postmarketing surveillance in such a way that the information needed is certain to be obtained.

　In case a postmarketing surveillance revealed any fact that had not been expected before marketing, it goes without saying that an appropriate measure should be taken swiftly, and the collected information be quickly evaluated and examined. Depending on the results of such an examination, the postmarketing surveillance plan may have to be revised to include certain additional items.


　General Statement


　1. The collection, evaluation and examination of information concerning safety, largely consisting of the reports of adverse events from doctors and pharmacists, by manufacturers (or importers) should be performed continuously as long as the product concerned is marketed.

　2. During the postmarketing surveillance period which has been specified at the time of approval, an efficient, concentrated investigation must be carried out to collect information about adverse events as well as that supplementing the premarketing information (results of AUT, etc.).

　3. It is also necessary to investigate quantitatively, with participation or cooperation by pharmacies, etc. whether or not the users properly used the drug. If this investigation is accompanied by the study of efficacy and safety, the information obtained would supplement the results of premarketing AUT.

　4. It is advisable to keep the following points in mind in the investigation of the actual state of use：
　−In selecting the pharmacies participating in the investigation, efforts must be made to increase the accuracy of the investigation by asking those highly reliable pharmacies which practice proper control of the medication histories.
　−The requirements for the pharmacists participating in the investigation may have to be studied separately, as necessary.

　5. The results of investigation must be evaluated objectively. If the printed information is found to be inadequate in some respects, corrective measures should be taken quickly such as revision of the document, etc.


　Particulars


　1. Concentrated Early Postmarketing Surveillance on Adverse Events

　1) It is necessary to generate an environment that helps collection of a wide range of postmarketing reports including information on proper use and the appropriateness of the product as a nonprescription drug, regardless of the presence or absence of adverse events, by providing the pharmacies, etc. with questionnaire forms, which will be attached to all the packages of the product as a rule and handed out when the product is sold.
　　 If the“adverse event”is present, further follow-up should naturally be performed by use of the adverse reaction questionnaire form.

　2) In planning the follow-up, it would be a good idea to ask indiscriminately all the pharmacies which newly handle the product to participate in the surveillance.

　3) It is advisable to standardize the questionnaire form and questions separately for the oral drugs, drugs for external application, and drugs classified by the indication.

　4) To ensure the reliability of surveillance, measures to ensure objectivity should be considered such as participation of outside personnel in the in-house assessment committee and assessment by the third party organization.

　2. Surveillance on the Actual State of Use

　1) The state of actual use is investigated by use of consumer questionnaire, such as whether or not the product is properly used in compliance with the precautions including contraindications as well as the dosage and administration.
　　 Questions about the efficacy and safety can be added to the questionnaire.

　2) During the period of surveillance on the actual state of use of new nonprescription drugs, it is necessary to collect that number of cases which makes it possible to grasp the actual state of use. To ensure the reliability of the surveillance, it is advisable to keep the questionnaire recovery rate above a certain level.

　Note) New nonprescription drugs are classified into Class (1) to (3) in application for approval. The products that fall under Class (3) are not included as a rule.

　Application Class (1)：Drugs containing new active ingredients (DOTC)

　Application Class (2)：Drugs containing those active ingredients which are not new active ingredients and not contained in the approved nonprescription drugs as the active ingredient (SOTC)

　Application Class (3)：Drugs composed of those ingredients which are contained as active ingredients in the approved nonprescription drugs but not contained as active ingredients in the approved nonprescription drugs belonging to the same indication group as the investigational drug, combination of approved nonprescription drugs and active ingredients in the said indication group, and drugs differing in the indications and the dosage/administration (exclusive of drugs belonging to Class (4) or (5) or drugs meeting the criteria for approval. Descriptions of the Approval Classes (4) and (5) are omitted.

　(Reference)

　(a) Thinking on examination for approval of the submitted nonprescription drug that contains for the first time one or more active ingredients so far used only in the prescription drugs (so-called switch OTC).

　1. The prescription drug containing the said active ingredient (so-called switch ingredient) should have passed re-examination or re-assessment.

　2. Whether or not the submitted drug is appropriate as a nonprescription drug is determined, with the opinion of the Pharmaceutical Affairs Council as reference, in consideration of the incidence of the adverse reactions to the switch ingredient, the dosage and administration entered in the application, the state of use as a nonprescription drug outside Japan, and the results of reexamination or reassessment.

　3. To ensure the proper use and safety, conditions for approval are attached which include, besides postmarketing surveillance, the method of providing information, sales method, advertisement and promotion.

　4. Because postmarketing surveillance is required, the submitted drug is classified on approval as the drug designated by the Minister of Health and Welfare under the Pharmaceutical Affairs Law Article 29.

　5. For a certain fixed period (3 years as a rule), it is required to conduct a postmarketing surveillance (PMS) in accordance with the postmarketing surveillance protocol. The results of surveillance are put in order at one year after marketing, and, if required, the approved items and approval conditions are reassessed with the opinion of the Pharmaceutical Affairs Council as reference.

　(b) Thinking on examination for approval of the submitted nonprescription drug that contains active ingredient (so-called direct OTC)

　1. Whether or not the submitted drug is appropriate as a nonprescription drug is determined, with the opinion of the Central Pharmaceutical Affairs Council as reference, in consideration of the dosage and administration, the state of use as a nonprescription drug outside Japan, and the incidence of the adverse reactions.

　2. To ensure the proper use and safety, conditions for approval are attached which include, besides the specified period of postmarketing surveillance, the method of providing information, sales method, advertisement and promotion.

　3. Because postmarketing surveillance is required, the submitted drug is classified on approval as the drug designated by the Minister of Health and Welfare under the Pharmaceutical Affairs Law Article 29.

　4. The results of surveillance are put in order at one year after marketing, and, if required, the approved items and approval conditions are reassessed with the opinion of the Central Pharmaceutical Affairs Council as reference.