the new drug approval process

8/7/2019 The New Drug Approval Process

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THE NEW DRUGTHE NEW DRUGAPPROVAL PROCESSAPPROVAL PROCESS

ANDANDCLINICAL TRIALSCLINICAL TRIALS

By By Kasturi PandaKasturi Panda

M.Pharm(PharmaM.Pharm(Pharma- -Tech)Tech)


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F OOD AND DRUG ADMINISTRATIONF OOD AND DRUG ADMINISTRATION(F DA)(F DA)

The FDA oversees the NDA process.It mainly focuses on theThe FDA oversees the NDA process.It mainly focuses on thedisclosure of the ingredients and formulation,assay disclosure of the ingredients and formulation,assay methods,manufacuring processesand all animal and humanmethods,manufacuring processesand all animal and humantestingtesting

Amendments were made in 1962 which focused on bothAmendments were made in 1962 which focused on bothsaftey and efficacy of new drug products prior to approval saftey and efficacy of new drug products prior to approval and requires investigstor to file Investigational New Drugand requires investigstor to file Investigational New DrugApplication(INDs) prior to testing new drugs in humans.Application(INDs) prior to testing new drugs in humans.

Center of Drug Evaluation And Researh(CDER) under FDA isCenter of Drug Evaluation And Researh(CDER) under FDA is

responsible for drugs and drug efficacy of all prescriptionresponsible for drugs and drug efficacy of all prescriptionand over the counter drug products prior to marketing.and over the counter drug products prior to marketing.

CDER is responsible for monitoring drug saftey after initial CDER is responsible for monitoring drug saftey after initial market approval and has the authority to withdraw frommarket approval and has the authority to withdraw fromthe market posing significant health risk.the market posing significant health risk.


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OVER VIEW O F THE DRUG APPROVALOVER VIEW O F THE DRUG APPROVALPROCESSPROCESS

The development process is divided into twoThe development process is divided into twosection:section:

1. Preclinical testing:

Lead compound selection and animal testing of Lead compound selection and animal testing of new chemicals.new chemicals.

2 Clinical testing:Administration of new chemicals to humanAdministration of new chemicals to human

beingsbeings


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RUR DISCOVERYAND

EAD COMPOUNDSELECTION

BIOLO-GICAL

ACTIVITYTESTING

FORMULATIONDEVELOPMENT

SAFTEY TESTINGIN ANIMALS

INDAPPLICATION

CLINICALHOLD

IND FILING

INDAPPROVAL

PHASE 1 TRIAL PHASE 2 TRIAL PRASE 3 TRIAL

NDAFILING

FDA DISAPPROVAL FDA CONDITIONAL APPROVALFDA APPROVAL

MARKET

POST APPROVAL SAFTEY REPORTS TO FDA

CHEMICAL SYNTHESIS


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DRUG DISCOVERY AND LEADDRUG DISCOVERY AND LEADCOMPOUND SLECTIONCOMPOUND SLECTION

A chemical with potential therapeutic benefits is known asA chemical with potential therapeutic benefits is known asa lead compound,must first be identified & researchersa lead compound,must first be identified & researchersusevarious high throughput assay techniques to rapidly usevarious high throughput assay techniques to rapidly screen large numbr of chemicals for biological activity.screen large numbr of chemicals for biological activity.Random screening as the name implies,requires biological Random screening as the name implies,requires biological testing of a large variety of diverse compounds fromtesting of a large variety of diverse compounds fromexisting chemical libraries.existing chemical libraries.A more mechanismA more mechanism- -based drug design is targated synthesisbased drug design is targated synthesis,on researchers focus on one step in a targeted for drug,on researchers focus on one step in a targeted for drugintervention.While an extensive knowledge of the diseaseintervention.While an extensive knowledge of the disease

state is requried this more directed approach increases thestate is requried this more directed approach increases thelikelihood of successfully identifying the lead compound.likelihood of successfully identifying the lead compound.Combination of these discovery techniques is used toCombination of these discovery techniques is used toidentify the lead compounds.identify the lead compounds.


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PRECLINICAL TESTINGPRECLINICAL TESTING

PRECLINICAL TESTING INCLUDE:PRECLINICAL TESTING INCLUDE:Discovery testing to ensure biological activity inDiscovery testing to ensure biological activity in- -vivovivoChemical synthesis & scale up to ensureChemical synthesis & scale up to ensureadequate quantities of high purity can be made.adequate quantities of high purity can be made.Formulation development and stability testing toFormulation development and stability testing tocharacterize various chemical properties,developcharacterize various chemical properties,develop

the initial drug delivery system & determine thethe initial drug delivery system & determine thestability of the compound.stability of the compound.Animal saftey testing to ensure limited toxicitiesAnimal saftey testing to ensure limited toxicitiesof the lead agent.of the lead agent.


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During discovery testing testing the specific`s of During discovery testing testing the specific`s of the compounds properties such as, mechanisimthe compounds properties such as, mechanisimof action in animal models,compound of action in animal models,compound specificity,duration of action and SAR arespecificity,duration of action and SAR aredetermined.determined.The phisiochemical property of the activeThe phisiochemical property of the activecompound are determined and the drug delivery compound are determined and the drug delivery system to be used in human testing begins to besystem to be used in human testing begins to bedeveloped during this phase.developed during this phase.Often times the most appropriate animal model Often times the most appropriate animal model to predict human response is not known.to predict human response is not known.


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Thus toxicity studies are conducted in at least Thus toxicity studies are conducted in at least two animal species, one rodents and another nontwo animal species, one rodents and another nonrodent to obtain a comprehensive view of therodent to obtain a comprehensive view of thepotential toxicity.potential toxicity.

Animal should be given the new drug product by Animal should be given the new drug product by the same route as intended for human.the same route as intended for human.Generally once discovery testing showsGenerally once discovery testing showstherapeutic promise the chemical synthesis, fd,therapeutic promise the chemical synthesis, fd,and animal safety testing occurs concurrently and animal safety testing occurs concurrently


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INVESTIGATION AND NEW DRUGINVESTIGATION AND NEW DRUGAPPLICATIONSAPPLICATIONS

An investigation new drug application must beAn investigation new drug application must befiled whanges ith the FDA and approved prior tofiled whanges ith the FDA and approved prior toadministering new drug products to humans.administering new drug products to humans.IND includes all pre clinical animal data and theIND includes all pre clinical animal data and thename and locations of the investigators who will name and locations of the investigators who will be performing the planned clinical trials.be performing the planned clinical trials.The clinical trials where IND is not required areThe clinical trials where IND is not required arelebel changes or a new indication.lebel changes or a new indication.

Major changes in advertisingMajor changes in advertising


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Change in route of administration, dose,Change in route of administration, dose,or patient population that significantly or patient population that significantly increases the risk of the drug.increases the risk of the drug.It is not required if the trial is exempt It is not required if the trial is exempt according to the above criteria regardlessaccording to the above criteria regardlessto whether a placebo is employed as ato whether a placebo is employed as acontrol group.control group.


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PHASE 1 CLINICAL TRIALSPHASE 1 CLINICAL TRIALS

The first series of experiments performed inThe first series of experiments performed inhuman beings occur during phase 1 clinical human beings occur during phase 1 clinical testing.generally 20testing.generally 20- -30 healthy volunteers are30 healthy volunteers arechoose.choose.In phase 1 trial the starting dose is generally In phase 1 trial the starting dose is generally low,often 1/10 of the highest no effect dose inlow,often 1/10 of the highest no effect dose inanimal models.after initial treatment is completed animal models.after initial treatment is completed additional subjects may be recruited and additional subjects may be recruited and administersd higher doses to determine theadministersd higher doses to determine themaximum tolerated dose without significant sidemaximum tolerated dose without significant sideeffect.effect.During this phase the prelimnary ADME data of During this phase the prelimnary ADME data of

the parent drug and all metabolites are evaluated the parent drug and all metabolites are evaluated


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PH ASE 2 CLINICAL TRIALSPH ASE 2 CLINICAL TRIALS

Phase 2 clinical trial shifts its focus from saftey toPhase 2 clinical trial shifts its focus from saftey toefficacy.A large number of people participateefficacy.A large number of people participate(100(100- -300) where majority of the people suffer300) where majority of the people sufferfrom targeted illness.from targeted illness.Side effect from the new drug is also investigetedSide effect from the new drug is also investigetedClinical protocols for phase 2 trial must be sent toClinical protocols for phase 2 trial must be sent tothe FDA as amendments to the IND prior tothe FDA as amendments to the IND prior tobeginning of the trial.beginning of the trial.


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PH ASE 3 CLINNICAL TRIALSPH ASE 3 CLINNICAL TRIALS

Scientists carefully review of the preclinical andScientists carefully review of the preclinical andclinical data in evaluating the propossed phase 3clinical data in evaluating the propossed phase 3protocol.protocol.

Specific area of the proposed phase 3 trialsSpecific area of the proposed phase 3 trialsare;inclusion/exclusion criteria,dosingare;inclusion/exclusion criteria,dosingregimen,method and timing of dataregimen,method and timing of datacollecyion,duration of treatment & follow upcollecyion,duration of treatment & follow upassesment,binding of the drug product and plansassesment,binding of the drug product and plansto access compliance with theto access compliance with theprotocol,identification of primary outcomeprotocol,identification of primary outcomevariables,methods to account for dropouts.variables,methods to account for dropouts.


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It is the longest and most comprehensive trialsIt is the longest and most comprehensive trialsregarding efficacy and saftey of new regarding efficacy and saftey of new compounds.significantly larger number of peoplecompounds.significantly larger number of peopleare choosen (1000are choosen (1000- -3000patients)who are3000patients)who areafflicted with targeted illness are tested.afflicted with targeted illness are tested.The new drug may be compared to the existingThe new drug may be compared to the existingtherapeutic regimen or to placebo.therapeutic regimen or to placebo.

The final marketedformulation of the drugThe final marketedformulation of the drugproduct should be optimised prior to the start of product should be optimised prior to the start of these phase 3 clinical trials.these phase 3 clinical trials.


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PH ASE 4 CLINICAL TRIALSPH ASE 4 CLINICAL TRIALS

Phase 4 trials are post Phase 4 trials are post- -approval clinical trialsapproval clinical trialsdesigned for 1 of the several reasons.the NDAdesigned for 1 of the several reasons.the NDAmay mandate phase 4 testing in a specific patient may mandate phase 4 testing in a specific patient population to further assess efficacy and sidepopulation to further assess efficacy and sideeffects.effects.Companies may also choose to conduct additional Companies may also choose to conduct additional clinical trials to more fully understand how their clinical trials to more fully understand how their product compares to other commercially availableproduct compares to other commercially availabletherapeutic regimentherapeutic regimen


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If the document is sufficiently complete the NdaIf the document is sufficiently complete the Ndais accepted for review and assigned a priority is accepted for review and assigned a priority statusstatusThe NDAs for new chemical entities are classified The NDAs for new chemical entities are classified as either P priority review or S standard as either P priority review or S standard review.review.A P rating is given to new drug products withA P rating is given to new drug products withimproved therapeutic effects and improved therapeutic effects and

saftey,and/orside effects in comparision to thesaftey,and/orside effects in comparision to thecurrenty marketed drug. The NDAs assigned P currenty marketed drug. The NDAs assigned P are expected to be reviewed in a more timely are expected to be reviewed in a more timely manner than those assigned S.manner than those assigned S.The decision to accept the NDA is made within 60The decision to accept the NDA is made within 60

days of the date of submission.days of the date of submission.Once the NDA is approved the FDA has 180 daysOnce the NDA is approved the FDA has 180 daysfrom the date of submission to complete thefrom the date of submission to complete thereview and give the decision of approval or not.review and give the decision of approval or not.


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POST APPROVAL ACTIVITIESPOST APPROVAL ACTIVITIES

1.1. SAFTEY MONITSAFTEY MONITORINGORINGAfter the NDA has been granted and merketingAfter the NDA has been granted and merketingof the drug product is initiated,the drug saftey of the drug product is initiated,the drug saftey

is still monitored.sponsers of NDA must submit is still monitored.sponsers of NDA must submit reports of adverse events periodically reports of adverse events periodically For the new drugs these are submitted quaterly For the new drugs these are submitted quaterly for 3 yrs and then annually.for 3 yrs and then annually.

Serious adverse events may require minor Serious adverse events may require minor labeling changes or addition of warning or labeling changes or addition of warning or precaution statement.if serious saftey cocernsprecaution statement.if serious saftey cocernsarise FDA may withdraw approval.arise FDA may withdraw approval.


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CHANGES TO AN APPROVED PRODUCTCHANGES TO AN APPROVED PRODUCTAny changes made to an FDA approved dr Any changes made to an FDA approved drug ug

product inproduct including component or cluding component or composition,chemical synthesis,manufacturingcomposition,chemical synthesis,manufacturingprocess,site,analytical methods,batch size,or process,site,analytical methods,batch size,or labelling must be submitted to the FDA.labelling must be submitted to the FDA.Depending on the type of change & the impact of Depending on the type of change & the impact of change on the quality of drug product notificationchange on the quality of drug product notificationto the FDA should be made through annual to the FDA should be made through annual reports or supplemental new drugreports or supplemental new drugapplications(SNDA).applications(SNDA).


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