In Medicine, What Are Indications?

Indications: Medical terms, also called indications, refer to the applicable scope and standards of methods such as drugs and surgery. As the "indications" generally refer to the symptoms of certain diseases, they also include certain non-disease conditions, so the exact wording should be "indications".

Indications I. Overview

Indications refer to the applicable scope and standards of drugs and surgery. From a medical point of view, an indication is for a certain treatment method or examination method. The indication for a certain treatment method or examination means a disease suitable for the treatment method or examination method. For example: recurrent chronic tonsillitis is an indication for tonsil surgery. Repeated chronic tonsillitis is an indication for tonsillectomy, and the reverse can be said. Repeated chronic tonsillitis is suitable for tonsillectomy.

Indications 2. "Indications" and "Indications"

"Indication" is a term commonly used in medical books and drug instructions. However, when used, many people often misuse it as an "indication."

The most authoritative written reference book in China, "Ci Hai" (1989 edition), is annotated in this way: "Indications" refer to diseases or conditions that are suitable for a certain treatment. For example, if maggots develop into abscesses, an incision should be performed, and abscess formation is an indication for incisions; for example, quinine is effective in the treatment of acute episodes of malaria, and acute episodes of malaria are used as indications for the use of quinine ^[1] .

[] Indications III. Requirements for writing drug instructions [Indications]

China's State Food and Drug Administration (CFDA), the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regulations and guidelines have stipulated the principles and main contents of writing prescription drug instructions [indications]. China's drug instructions [indications] must comply with the relevant regulations of our country. The FDA and EMA regulations and guidelines provide some details, and the recommendations can be used as a reference for writing a description of [indications] in our country ^[2] .

Indications (I) Requirements of China

1. The "Procedures for the Specification of Chemical Drugs and Therapeutic Biological Products" issued in 2006 stipulated in principle that "[indications] shall be accurately used for prevention, treatment, diagnosis, and remission according to the use of the drug. Or to help treat a disease (state) or symptom. "

2. "Guiding Principles for the Instructions for Chemical Drugs and Biological Products (Second Draft)" The guidelines, drafted by the Drug Evaluation Center of the China Drug Administration in 2004, have not been formally announced for implementation, but can be used as a reference for writing instructions. The contents of the [Indications] item are as follows:

(1) Except for drugs that are exempt from clinical research, the drug indications to be written should be supported by data from adequate, strictly controlled clinical trials conducted in China.

(2) This item should also include the following additional information:

a. When the evidence of drug safety and effectiveness comes from a certain degree of disease, a certain syndrome, or a specific population under certain symptoms (such as mild patients or patients in special age groups), this item should be carried out in the above situation. Describe and explain the scope of drug applications.

b. If based on the protection of the efficacy of this drug, this drug is not used as a first-line drug and is only available for certain states (for example, cases resistant to other drugs), which should be explained in this item.

c. For drugs intended for long-term use, if there is only evidence of the effectiveness of short-term use, this item should be explained; if the indication for long-term use is different from short-term use, this item should be explained separately for each indication.

3. This item must state:

(1) This medicine is suitable for the treatment, prevention or diagnosis of a known disease or condition. For example, penicillin is used to treat lung infections caused by sensitive pneumococci.

(2) This medicine is suitable for the treatment, prevention or diagnosis of important symptoms of a known disease or condition. Such as hydrochlorothiazide for the treatment of congestive heart failure edema.

(3) This medicine is suitable for the relief of symptoms related to a known disease or condition. For example, chlorpheniramine maleate (pirmin) is used to relieve the symptoms of rhinitis and nasal congestion.

(4) This medicine is used for the treatment of certain diseases or conditions. "

FDA Indications (II) FDA requirements

The United States Federal Regulations [21CFR201.57 (c) (2)] is the main regulatory basis for FDA prescription drug specifications [indications and applications]. The main contents are summarized below.

1. The item should state the clinical value of the drug. "This item should state that a drug is suitable for the treatment, prevention, alleviation, cure, or diagnosis of a recognized disease or condition or its manifestations, or for a disease related to a recognized disease or condition. Relief of symptoms. "The item should include the following information, if the conditions listed are appropriate:

(1) If a drug is used only in combination with the main treatment (such as diet, surgery, behavior change, or other drugs), that drug should be used as an adjunct to the main treatment.

(2) If evidence is obtained, only in a selected subpopulation of a larger population (such as patients with mild disease or patients of a particular age group), to support the safety and effectiveness of the drug or biological product, or if the indication is Approvals based on alternative end points under 21CFR314.510 or 601.41 should briefly describe the restrictions on the use of the drug and the uncertainty of any expected clinical benefit, and explain the discussion of the evidence obtained with reference to the [clinical research] item.

(3) If special tests are necessary for the selection or monitoring of patients in need of a drug (such as microbial sensitivity tests), the characteristics of such tests should be described.

(4) If application limitations or uncertainties in expected clinical benefit are related to recommended dosing intervals, appropriate duration of treatment (if such treatment should be restricted), or any dose adjustment, this information should be briefly described and referenced [Usage usage] item for more detailed information.

(5) If safety is considered so that the drug should be reserved for special conditions (such as cases refractory to other drugs), a description of this information should be listed.

(6) If there are special conditions that must be met before long-term use (such as the demonstration of drug reactivity in a short-term trial by a specific patient), such conditions should be stated; if the indications for long-term use are different from short-term use, the respective uses Special conditions. "

2. Description of lack of evidence of effectiveness or safety "if a drug is generally considered to be effective for a use or if the drug is generally used in a certain state, but most of the evidence related to this use and state shows that the drug Ineffective or therapeutic benefits of the product generally do not outweigh its risks. The FDA may require this item to state that there is no evidence of the effectiveness or safety of the drug for that use or state. "

3. Compared with other drugs, there should be a lot of evidence to support "any description of the safety or effectiveness of a drug compared with other drugs (except biological products) should be sufficient from the definition of 21CFR314.126 (b) Substantial evidence from well-controlled studies supports this requirement unless this requirement is waived under 21 CFR 201.58 or 314.126 (c). Such descriptions of biological products must be supported by substantial evidence. "

4. Indications should have substantial evidence of effectiveness in support of "All indications for drugs (excluding biological products) listed in this item must obtain substantial effectiveness from adequately well-controlled studies as defined in 21CFR314.126 (b) Evidence supports, unless such a requirement is waived under 21CFR 201.58 or 314.126 (c). Indications or uses not included in this item should not be implied or suggested in other items of the specification. All indications for biological products included in this item Must be supported by substantial evidence of validity. Indications or uses not included in this project must not be implied or suggested in other items in the description. "

EMA Indications (3) EMA requirements

The EMA Product Feature Summary Guiding Principles (SmPC) stipulates the prescription drug instructions [indications] as follows:

1. The indication should be clearly and concisely described and the target disease or state should be clearly identified, distinguishing between treatment (treatment of symptoms, treatment of the disease or slowing of the progress or progression of the disease), prevention (primary or secondary) and Indications for diagnosis. If appropriate, target groups should be identified, especially when the patient population is restricted.

2. Study endpoints should generally not be included unless such a formulation is specified, which is appropriate for the indication in accordance with the Guidelines of the Committee on Human Medicines (CHMP). The goal of prevention indication can only be described in general terms. The same should be done for the target population.

3. When the results of subsequent studies provide further explanations or information on approved indications, if the data does not constitute a new indication itself, such information may be considered for inclusion in Section 5.1 (ie, pharmacodynamic characteristics section).

4. If relevant, it may also include mandatory conditions that are not well-suited for the application of products included in other parts of SmPC, such as accompanying dietary measures, lifestyle changes, or other treatments.

5. Describe which age group the product is suitable for, and specify age restrictions.

[] Indications IV. Existing problems in China's drug instructions [Indications]

1. At present, the descriptions of the manuals for domestic drug registration [indications] are mostly too simple, and even just list the names of the diseases or symptoms used, such as: "used for bronchial asthma", "used for the treatment of depression" and "used for" In moderate to severe pain. "

2. In addition to diseases or symptoms of clinical application, many requirements of the FDA include application limitations and uncertainty of clinical benefit, special trial characteristics for patient selection or monitoring, and uncertainty of application limitations or expected clinical benefit. There are many omissions in domestic manuals, such as adjustments to the drug regimen, retention for special profiles from safety considerations, special conditions that must be met before long-term use, indications for long-term use, and special body conditions that differ from short-term use.

3. The omission of application restrictions is common. This practice substantially expands the indications for medicines, and expands the indications to diseases or symptoms that have not been confirmed, even ineffective or unsafe.

[] Indications V. Approval Suggestions for Drug Instructions [Indications]

1. Indications approved under the accelerated approval process

( 1 ) Application limitation and uncertainty of clinical benefit

The instructions for approving a drug based on alternative or clinical endpoints that may determine the occurrence of a reversible condition or death should include a brief description of drug application restrictions and uncertainties in expected clinical benefit and a description of the [Clinical Study] section that provides evidence for discussion .

Descriptions of any uncertainties in drug application restrictions and anticipated clinical benefits are first expressed through identified alternative or clinical endpoints that support accelerated approval, and then by specific clinical benefits that have yet to be established. This description should appear immediately after the approved indication, not in a separate section or paragraph, because this information provides specific details of the indication.

For medical personnel who frequently prescribe accelerated approval of approved drugs, it is helpful to include a description of the indications and applications for accelerated approval, as this provides a unique framework and basis for drugs approved in this way that are different from other indications ^[3] .

( 2 ) Continue approval

Applicants usually need to perform additional post-marketing clinical trials to confirm and describe the clinical benefit of a drug based on alternative or clinical endpoints that can be determined to occur earlier than irreversible conditions or death, and for indications that have accelerated approval. Although the required post-marketing research requirements are usually not included in the prospectus, a simple summary of confirmatory research can further emphasize the application limitations that support accelerated approval information. Therefore, the [Indications and Applications] section should include a description that states that continued approval for the indication depends on the clinical benefit requirements of the drug as confirmed by the confirmatory trial.

When outlining post-marketing research requirements, reference should be made to evidence of clinical benefit and its interpretation. It is good to do so when it is possible to identify specific expected clinical benefits that will be the purpose of the post-marketing study. Give examples as follows: "Continued approval of this indication depends on evidence and description of clinical benefit in confirmatory trials, or continued approval of this indication depends on confirmation of improved trials to improve survival."

2. When clinical benefits are confirmed

After successfully obtaining evidence and descriptions of clinical benefits in post-marketing studies, the information in the [Indications and Applications] section should be revised. Indication descriptions should generally reflect the population and status where safety and effectiveness are actually demonstrated, including any new or remaining application restrictions. Previous descriptions of application and continued approval should be deleted or modified. In addition, other parts of the instructions (eg, [Adverse Reactions] and [Clinical Studies]) should also be revised to reflect new information.

3. Indications for withdrawal of accelerated approval

Drugs or indications approved in accordance with the accelerated approval process may be revoked at the request of the applicant or by the FDA for the following reasons: the applicant did not make due efforts to conduct any required post-marketing studies; the required verification and description Studies that anticipate the effects of irreversible conditions, death, or other clinical benefits, have not confirmed and explained this effect or benefit; Other evidence indicates that the drug is unsafe or ineffective under the conditions of use.

If the accelerated approval indication is withdrawn while other approved indications remain, the instructions must be revised. For example, information related to withdrawal indications must be removed from several sections of the label (eg, [Indications and Applications], [Usage and Dosage], and [Clinical Studies]) so that the label does not imply or suggest that the drug is approved for withdrawal Indications. In addition to the deletion of information, sometimes manuals may be given to add appropriate new information related to withdrawal indications.