website development rockville md


(website development rockville md)American Food and Drug Administration(Food and Drug Administration,FDA)At2022year1The month was released“Reference(referencelisted drug,RLD)After the instructions are revised, simplify the application for new drugs(abbreviated new drugapplication,ANDA)Revision of the manual”Draft guidance principle for enterprises[1]。2020year11The month was released“Anti -tumor drugs in the combination scheme”Draft guidance principle for enterprises[2]。And China has no similar guidance principles at present,Detailed introduction in this articleFDAthis2Principles of guidance,Hope to ChinaRLDThe revision of the instructions after the instructions and the anti -tumor drug in the combined medication plan“Cross -description”Implementation is helpful;The supervision of the drug manuals of these two situations is also inspired。

1RLDAfter the manual is revisedANDARevision of the manual”Draft introduction of guidance principles for enterprises

After the draft of the guidance principle is finalized,RepresentativeFDAThe current view of this theme。It does not give anyone any right,rightFDAOr the public has no binding power。If it meets the requirements of applicable regulations,Can use alternative method。To discuss alternatives,Please be responsible for the guidance principleFDAStaff contact。

1.1 Foreword of the guidance principle

The guidance principleFDAPharmaceutical Evaluation and Research Center's imitation drug office preparation。The principle of the guidance is to helpANDAApplicants and holdersRLDAfter the approved instructions are revised,Update its instructions[3]。The guidance principle provides identificationRLDUpdate and submitting update generic drugs of the manual(generic drug)InstructionsANDASuggestions to revise or supplement。The guidance principle has been revised2000year4Monthly“RLDAfter the manual is revisedANDARevision of the manual”Guidance principles for enterprises[4],After the fixed manuscript will be replaced2000year4The guidance principle of the month。and2000The annual version of the major changes compared to,Including updates about how to getRLDManual change information and how to goFDAAfter submitting modificationANDADetails of the instructions。

(website development rockville md)In this guidance principle,FDAUse“Approved manual”or“manual”,Refers to the application of new drugs(newdrug application,NDA)andANDAThe instructions approved in China。This term includes but not limited to:Prescription information(prescribing information,PI)、FDAApplying patients for instructions[Medication(medication guides)、Instructions for use(instructions for use)Information with patients(patient information),Also known as patient packaging instructions(patient package inserts)]And carton and container label。The approved instructions include prescription drugs and some over -the -counter drugs(over-the-counter,OTC)。

The content of this file does not have legal effect,Do not restrain the public in any way,Unless it is clearly included in the contract。This document is only aimed at clearing the existing requirements stipulated by the public。FDAGuidance Principles(Including the guidance principle)It should only be regarded as a suggestion,Unless quoting specific supervision or statutory requirements。FDAIn the principle of guidance“should”Use,Suggestion or recommendation,Instead of。

1.2 The background of the guidance principle introduced

(website development rockville md)ANDARefers to the basis“Federal food、Medicine and Cosmetics Act”(FD&C Act)First505(j)Drug application submitted and approved,This drug is a copy of the previously approved drug。“replica”The word usually refers to“Have the same active ingredients as listed drugs、Dosage、Specification、Drugs and drugs with conditions and conditions”。However,Terms used in the guidance principle“replica”It does not mean that all aspects are the same as listed medicines。These drugs are usually called“Imitation”。ANDADepend onFDADetermine the previously approved drug products(which isRLD)It is safe and effective。ANDAUsually it must include the following information on the displayed generic drugs:(1)Active ingredient、Conditions of Use、Route of administration、Dosage、Specifications and manuals and instructionsRLDsame(There are some allowable differences);(2)andRLDBiological equivalent。

In addition to the difference in approved approved or due to generic drugs andRLD“Produced or distributed by different manufacturers”,Except for changes required,Microcontroller must beRLDHave the same instructions。FDARegulations provides imitation drugs andRLD“Produced or distributed by different manufacturers”Time,Examples that may be allowed to allow differences,Including deletion of instructions or other aspects of patent or exclusive protection,as well as“Based on the currentFDAThe instructions made by the instructions or other guidance principles of the manual。”

(website development rockville md)Generally,All drug listing applications(NDAandANDA)The holders have continuous obligations to ensure that their product manuals are accurate、Non -false or misleading。As a new information obtained,Make the manual inaccurate、When false or misleading,Application holders must take measures to update their instructions。If the medicine is false or misleading,Or do not provide enough instructions and sufficient warnings,Then the medicine is a violation of the bidding medicine(misbrand)。

(website development rockville md)ApprovedRLDmanual,For various reasons,Revised by its application holder,And according to the appropriate report category,Submit the application information to complete the revision[5-6]。FDAApproveRLDAfter the manual changes are changed,RequireANDAThe holder updates its instructions。Revise、TowardsFDASubmit and implement the revisionANDAmanual,To ensure that the generic drugs continue to be corresponding toRLDIt's as safe and effective, very important。ifFDAFindANDAPharmaceutical manual andRLDThe manual is no longer the same,FDACoverANDAApproval。forANDAapplicant,FDAIt is recommended that the applicant submit the modification as soon as possibleANDAmanual,Because the instructions of generic drugs are usually requiredRLDThe instructions are the same(There are some allowable differences)。ANDAThe applicant has the responsibility to trackRLDChange of the manual,TimeFDAAfter submitting modificationANDAmanual。

In some cases,ANDAApplicants may want to update their instructions,Even ifRLDThe manual is not updated。E.g,Delete due to patents or exclusive protectionNDA RLDThe manual contains indications productsANDAapplicant,The product manual should,To contain this indication。SeeFD&C ActFirst505(j)(2)(A)(v)strip。ifANDAThe applicant made some changes to its products,The product manual should be updated accordingly(Such as the change of the container closed system)。Want to understand more information,Please checkFDA“ANDAsubmit—according toGDUFASupplement before approval”Guidance principles for enterprises(2017year10moon,First1Version)[6]and“Change after the approval of the raw medicine”Draft guidance principle for enterprises(2018year9moon)[7]。

If it is abolished due to safety or effectivenessRLDApplication,You may need to update or go publicANDAProduct manual。“Comprehensive appropriation method 2021”[Pu.L.No.116-133(2020year12moon)]Including an increaseFD&CActFirst503DRegulations。First503DIt provides some reference for updating some referencesRLDProcedure of generic drug instructions,TheseRLDApproved by reasons for safety or effectiveness。FDAThere are also draft guidance principles about this topic,But the draft guidance principle does not involve the basisFD&CActFirst503DProgram for update instructions,Because it is in the first503DThe previous release was promulgated[See“RLDUpdate after the listing application is canceledANDAmanual”Draft guidance principle(2016year7moon)[8]]。Counted due to safety or effectivenessNDA RLDTime,renewANDAThe manual is not within the scope of the guidance principle,Applicant should refer toFD&C ActFirst503Dstrip,or“RLDUpdate after the listing application is canceledANDAmanual”Draft guidance principle(If it is appropriate)。

1.3 How to get relatedRLDInformation about the manual

ANDAApplicants and holders should be tracked routinelyDrugs@FDARecently approved updateRLDmanual,And make any necessary revisions to its instructions。Drugs@FDAThe webpage ishttps:

also,FDAAlso maintain the list service(LISTSERVs),Provide new approval and announcement information related to the instructions update。Relevant email update,Please subscribe toCDERChange of drug safety instructions(CDER Drug Safety LabelingChanges)andCDERnews(CDER New),Websitehttps:

(website development rockville md)All approvedRLDThe manual can be fromFDAInformation disclosure。The applicant who hopes to use this mechanism to obtain the manual should pass the mail、Fax or the Internet sends a written application to the following address:

American Food and Drug Administration(Food and Drug Administration)

Information disclosure(Division of Freedom of Information)

Executive Secretariat Office(Office of the Executive Secretariat,OC)

Fisher Lane5630No1035room(5630 Fishers Lane, Room 1035)

Maryland,Lockeville 20857(Rockville, MD 20857)


1.4 How to submit the modified manual

1.4.1 program In accordance with the decree,ANDAThe change must be submitted through the electronics gateway in electronic format,Such asFDA“Provide supervision submission in electronic format——Some people apply and use medicine with medicineeCTDCode related submission”Guidance principles for enterprises(2020year2moon,First7Version)[9]Described。caution,Submit files of certain types(Such as some positive electron emission fault scanning drugs)Electronic technology files can be exempted(eCTD)Requirement[9]。

ANDAApplicants and holders should be based onFDAofeCTDWebpage“Content title and hierarchical structure table(ComprehensiveTable of Contents Headings and Hierarchy)”,Submit their instruction documents in appropriate modules and chapters[10]。

Such submitted information should include:FDA 356hsheet;Letter of application;Patent and exclusive description of the application letter(If needed);Revised manual;according to21 CFR 314.94(A)(8)(iv)Described,The drawingANDAManual andRLDThe approved manual comparison,And comment and explain all the differences。

1.4.2 Types of submitted information ANDAApplicants and holders should pay attention,Generally,Submitting self -recommended instructions during the review cycle can affect the target date[11]。In some limited circumstances,Applicants can beANDASubmit after approval andRLDRevised instructions corresponding to the instructions。

(1)Not approvedANDAs:For those who have not yet approvedANDA,Applicants should follow21 CFR 314.96The procedures andFDA“ANDAsubmit——according toGDUFASimplify the revision of the application of new drugs”Guidance principles for enterprises[11]Advice,Change of the instructions for submission instructions,With a revisedRLDThe update of the manual is the same。

(2)TemporaryANDAs:For temporary approvalANDAs,Applicants should submit the content of the instructions,The revision of the application with the temporary approvalRLDThe update of the manual is the same。In order to submit,According to patent and patent(or)Elementary protection can be legally approvedANDAsGet the final approval of the earliest date,For temporary approvalANDASuggestions of the revision time and content,SeeFDA“ANDAsubmit——Temporary approvalANDARevision and final approval request”Guidance principles for enterprises(2020year9moon)[12]。

(3)ApprovedANDAs:For approvedANDAs,ANDAsThe holder must submit itANDAsUpdate content of the manual,In order toRLDThe update of the manual is the same[Patent(or)Except for exclusive protection claims],Use21CFR 314.70The appropriate report category overview。Other suggestions can beFDA“ApprovedNDAorANDAChange”(2004year4moon,First1Version)[5]and“ANDAsubmit—according toGDUFASupplement before approval”Guidance principles for enterprises(2017year10moon,First1Version)[6]Investigate。

1.4.3 Other considerations When submitting the update content,ANDApplicants and holders should consider all aspects of the manual,To ensure its submitted information andRLDThe update of the manual is the same。E.g,When the update instructions are specific projects(Such as warning and precautions)Time,ANDApplicants and holders should consider whether they are with other projects with the instructions(If usual)Update consistency,BecauseRLDThe manual was updated。

2 The cross -description of anti -tumor drugs in the combination scheme for the guidance principle used by enterprises[2

After the draft of the guidance principle is finalized,RepresentativeFDAThe current view of the theme。It does not give anyone any right,rightFDAOr the public has no binding power。If it meets the requirements of applicable regulations,Can be replaced。To discuss alternatives,Please be responsible for the guidance principleFDAStaff contact。

2.1 Foreword of the guidance principle

The guidance principleFDAIncreased Cancer Excellence Center and Drug Evaluation and Research Center and Biological Products Evaluation and Research Center。Anti -tumor drugs are added to the current scheme through drugs or research drug products(investigational drug product)New solution that can produce better effects with the joint scheme can produce better effects。The approval of anti -tumor drugs is usually based on this new plan。As far as the guidance principle is concerned,“Combined scheme(combinationregimen)”It refers to two or more drugs that are listed separately,At least1Pymal medicine basis1Items or multiple clinical trials of sufficient and good control,Approved jointly used indications;The joint development of two or more new research drugs used in joint use,Be“Two or more new research drugs jointly used in combination”Guidance principles for enterprises(2013year6moon)[13]The meaning described in。

(website development rockville md)in tradition,Applicants do not need to change the previously approved drug instructions,To describe how to use the drug in the new scheme。However,More and more recentlyNDAApplication with biological product license(biologicslicense application,BLA)A cross -manual of the tumor drug combination plan。The purpose of the guidance principle is to explainFDASuggestions on the relevant information of anti -tumor drugs approved for combined schemes into the instructions,Including important considerations of these drug cross。This guidance principle does not involve all possible problems related to the instructions of antitumor drugs used in the combined scheme。Applicants who propose a cross -description of the antitumor drug combination plan shall contact the review department,In order to obtain information about the cross instructions of their respective products。

Generally speaking,FDAThe guidance principle document does not establish a legal responsibility for enforcement。on the contrary,Guidance principle describes the current view of the bureau's current theme,And it should only be regarded as a suggestion,Unless quoting specific supervision or statutory requirements。existFDAUse in the principle of guidance“should”The word means suggestion or recommendation,But not to regulate。

2.2 The background and application of the guidance principle introduced

In this guidance principle,“Cross -description(crosslabeling)”The definition is,In the joint scheme of the approved specific indication certificate,The information contained in two or more anti -tumor drug products that have been approved in the product manual。Two or two drugs used in the joint schemes of the cross instructions of more than two drugs,Can provide clear、Agrowth and easy -to -understand information,In order。The purpose of the cross instructions is to provide complementary and consistent information in the product instructions for the drugs used in the combined drug plan,Instead。

20century70Age,FDAFrequent use of total relief rate as the basis for approval of anti -tumor drugs,Then turn to other efficacy indicators。The clinical trial of most anti -tumor drugs follows the total alleviation rate as a key efficacy indicator for evaluation and affecting clinical decision -making。Because malignant tumors usually do not subscribe naturally naturally,Therefore, the relief rate can be attributed to the treatment intervention,Not the natural history of disease。whenFDAWhen the evaluation of cross -instructions application application,The consistency of the total relief rate of history and current clinical trials,Can estimate the efficacy of each drug in the antitumor drug combination scheme。

The scope of application of the guidance principle is limited to the following anti -tumor drugs:(1)The applicant has the security effective data of the new joint scheme of the tumor disease or has the right to reference for it;(2)ApplicantFDAsubmitted1Application,These include a manual in this new joint plan.;(3)This application provides evidence to support the applicant's drugs in the total effect of the joint plan。

The suggestions in the guidance principle are not applicable to drugs outside the scope。Applicants in the field of non -tumor therapy if they want to discuss whether the cross -description is suitable for their application,You should contact the appropriate review department。

2.3 Submit a procedure for the application for cross -instructions

2.3.1 Submitting time specified in the specified cross instructions (1)Applicants should discuss the proposal content of the planned application,Including application in new drugs/Pre -meeting or supplementation of biological product license applicationsNDA/BLAAt the previous meeting,Proposal of cross -marking new anti -tumor drug combination scheme。(2)Ideal,The cross instructions of each drug determined in the joint scheme will appear at the same time。However,The individual application of the cross instructions may be approved in order in order,Because the time for the applicant to submit the application may be different。

2.3.2 Submitted information (1)Seeking a cross -instruction manual with one or more other drugs to use the drugs to use drugs,Both must submit the original application or validity supplementary application of the cross -description。(2)If the applicant is the application holder of each drug in the joint plan,Or if the applicant gets a letter of authorization from the appropriate application holder,The applicant seeking a cross -description,You can refer to the efficacy of the proof joint scheme contained in another application。

(website development rockville md)2.4 The content of the manual

Overview of this section of the guidance principle,The consideration of the instructions for the selection of the selection。This section is not detailed。If the applicant wants to submit1Application for cross -instructions for anti -tumor drugs approved for joint schemes,The specific questions should be made for the application,Consult the corresponding anti -tumor prescription drug review department。Specific items and small items about the instructions,Applicants should checkFDASuggestions of the instructions and guidance principles[14]。

For every new medicine submitted as a separate packaging product in the original application,It is intended to be combined with one or more new drugs or one or more approved drugs,The instruction manual of the new drug should include information on the safety and effectiveness of the combination of medication(As described below)And limited to the information of their respective drugs[13]。

For approved drugs,The proposal to change the approved manual,It should include the security effective information of the drug combined with other drugs in the combined scheme。

The following is a suggestion that the applicant should consider when submitting a cross -description of the cross instructions。

(1) Indications and applications、Usage and dosage and clinical research project

①Indications and applications(First1item):The indication of the joint scheme should be the same as that of all drugs approved for the joint scheme.,But except the following situation:The applicant's drug should be listed in the joint scheme;Other drugs in the joint scheme should use the determined name or proprietary name。This order is applied to all instructions related to the joint medication solution of the naming format。

②Dosage(First2item):Although this item should show other drugs in the joint scheme[15],But generally only the recommended dose of the applicant's drug in the joint plan。Dose adjustment instructions should usually be limited to the applicant's drug,Unless there is an adverse reaction that needs to be adjusted to the dose of drugs in other drugs or combined schemes。Preparation and usage information should usually only include the applicant's drug。

(website development rockville md)③Clinical study(First14item):The description of the clinical research of the joint plan shall be the same as the instruction manual of all drugs applied for cross -instructions.。

(2)Compared with the applicant's drug alone,When the combined medication plan causes major new security issues,In the manual of the applicant's drug and other drugs in the plan,It should include information about other drugs in the combined medication scheme。Examples include, not limited to the following content。

(website development rockville md)①Warning and precautions(First5item):It should include interaction or new clinical significant adverse reactions and(or)The unique information of the joint scheme of risk。Applicants' drug instructions should usually be omitted,Only attribute to the warnings and precautions of other drugs in the combined medication scheme。

②Adverse reactions(First6item):The clinical trial experience of the combined medication plan of the cross instructions should include the adverse reactions observed in the test that supports the approved indication。

③Patient's notice(First17item):Medical care providers should convey the information about the joint plan conveyed to the patient or nursing staff,It should be limited to the unique toxicity and unique preparations related to the joint scheme and the administration instructions。

(3) The following projects should usually only include information related to the applicant's drug(Instead of other drugs used in the combination scheme);However,There may be exceptions(E.g,In the joint plan1When the pharmaceutical dynamics of planting drugs is changed by another drug in the plan)。Dosage and specifications(First3item);Taboo(First4item);medicine interactions(First7item);Special crowd medicine(First8item);Excessive medicine(First10item);Traits(First11item);Clinical pharmacology(First12item);Non -clinical toxicology(First13item);references(First15item);Packing and storage(First16item)。

3 Conclusion

In this articleFDAGuidance principles for the management of drug manuals,The management of Chinese drug instructions is as follows2Point enlightenment。

3.1 China should accelerateRLDAfter the instructions are revised

FDA“RLDAfter the manual is revisedANDARevision of the manual”The draft guidance principle for enterprises pointed out“The instructions for generic drugs are usually requiredRLDThe instructions are the same(There are some allowable differences)”“ANDAThe applicant has the responsibility to trackRLDChange of the manual,TimeFDAAfter submitting modificationANDAmanual。”The guidance principle provides a variety of acquisitionsRLDHow to change information in the manual。The guidance principle also informed the program for submitted modified generic drug manuals and specific information submitted。

It is recommended that the holder of the listing license in China actively tracksRLDChange of the manual,Revised the generics in time in time,To ensure that generic drugs continue to be corresponding toRLDJust as safe and effective。It is recommended that the Chinese pharmaceutical regulatory authorities are based on the actual situation of our country,Formulation andFDA“RLDAfter the manual is revisedANDARevision of the manual”Similar guidance principles for the draft guidance principles for enterprises and take relevant regulatory measures,IncludRLDThe way to change the manual,To promote and accelerateRLDAfter the instructions are revised。

3.2 Anti -tumor drugs in China's joint plan should be adopted“Cross -description”

FDA“Anti -tumor drugs in the combination scheme”In the draft guidance principles for enterprises,So -called“Cross -description”It refers to the relevant information incorporated by the instructions of anti -tumor drugs approved for combined schemes。Suggestions for the guidance,Among them“Including information on the safety and effectiveness of the combined medication and the information limited to their respective drugs”;And the cross -instructions of the approved drugs,“It should include the security effective information of the drug combined with other drugs in the combined scheme。”The guidance principle also made suggestions on the content of some specific projects of the cross -description。This“Cross -description”Can provide clear、Agrowth and easy -to -understand information,It is conducive to this type of antitumor drugs safely and effectively。

It is recommended that the list of anti -tumor drugs in the joint plan of China,refer toFDAThe guidance principle,Similar“Cross -description”,Ensure that this type of anti -tumor drug is used in clinical safety and effectively。It is recommended that my country's pharmaceutical regulatory authorities are based on my country's experience and clinical needs,Develop similar guidance principles and regulatory measures,To promote this“Cross -description”Implementation。

Conflict All authors declare that there is no conflict of interest

(website development rockville md)references(slightly)

Come source:Xiao Huilai.FDARegarding the instructions of generic drugs and antitumor drugs2Introduction to guidance principles [J]. Drug Evaluation Study, 2022, 45(4): 605-610.